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  1. Expression changes of hippocampal energy metabolism enzymes contribute to behavioural abnormalities during chronic morphine treatment

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    Xiao-Lan Chen; Jing-Gen Liu; Gang Lu; Ying-Xia Gong; Liang-Cai Zhao; Jie Chen; Zhi-Qiang Chi; Yi-Ming Yang; Zhong Chen; Qing-lin Li

    2007-01-01

    Dependence and impairment of learning and memory are two well-established features caused by abused drugs such as opioids. The hippocampus is an important region associated with both drug dependence and learning and memory. However, the molecular events in hippocampus following exposure to abused drugs such as opioids are not well understood. Here we examined the effect of chronic morphine treatment on hippocampal protein expression by proteomic analyses. We found that chronic exposure of mice to morphine for 10 days produced robust morphine withdrawal jumping and memory impairment, and also resulted in a significant downregulation of hippocampal protein levels of three metabolic enzymes, including Fe-S protein 1 of NADH dehydrogenase, dihydrolipoamide acetyltransferase or E2 component of the pyruvate dehydrogenase complex and lactate dehydrogenase 2. Further real-time quantitative PCR analyses confirmed that the levels of the corresponding mRNAs were also remarkably reduced. Consistent with these findings, lower ATP levels and an impaired ability to convert glucose into ATP were also observed in the hippocampus of chronically treated mice. Opioid antagonist naltrexone administrated concomitantly with morphine significantly suppressed morphine withdrawal jumping and reversed the downregulation of these proteins. Acute exposure to morphine also produced robust morphine withdrawal jumping and significant memory impairment, but failed to decrease the expression of these three proteins. Intrahippocampal injection of D-glucose before morphine administration significantly enhanced ATP levels and suppressed morphine withdrawal jumping and memory impairment in acute morphine-treated but not in chronic morphine-treated mice. Intraperitoneal injection of high dose of D-glucose shows a similar effect on morphine-induced withdrawal jumping as the central treatment. Taken together, our results suggest that reduced expression of the three metabolic enzymes in the hippocampus as

  2. Morphine treatment enhances glutamatergic input onto neurons of the nucleus accumbens via both disinhibitory and stimulating effect.

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    Yuan, Kejing; Sheng, Huan; Song, Jiaojiao; Yang, Li; Cui, Dongyang; Ma, Qianqian; Zhang, Wen; Lai, Bin; Chen, Ming; Zheng, Ping

    2017-11-01

    Drug addiction is a chronic brain disorder characterized by the compulsive repeated use of drugs. The reinforcing effect of repeated use of drugs on reward plays an important role in morphine-induced addictive behaviors. The nucleus accumbens (NAc) is an important site where morphine treatment produces its reinforcing effect on reward. However, how morphine treatment produces its reinforcing effect on reward in the NAc remains to be clarified. In the present study, we studied the influence of morphine treatment on the effects of DA and observed whether morphine treatment could directly change glutamatergic synaptic transmission in the NAc. We also explored the functional significance of morphine-induced potentiation of glutamatergic synaptic transmission in the NAc at behavioral level. Our results show that (1) morphine treatment removes the inhibitory effect of DA on glutamatergic input onto NAc neurons; (2) morphine treatment potentiates glutamatergic input onto NAc neurons, especially the one from the basolateral amygdala (BLA) to the NAc; (3) blockade of glutamatergic synaptic transmission in the NAc or ablation of projection neurons from BLA to NAc significantly decreases morphine treatment-induced increase in locomotor activity. These results suggest that morphine treatment enhances glutamatergic input onto neurons of the NAc via both disinhibitory and stimulating effect and therefore increases locomotor activity. © 2016 Society for the Study of Addiction.

  3. Acute morphine alters GABAergic transmission in the central amygdala during naloxone-precipitated morphine withdrawal: role of cyclic AMP

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    Michal eBajo

    2014-06-01

    Full Text Available The central amygdala (CeA plays an important role in opioid addiction. Therefore, we examined the effects of naloxone-precipitated morphine withdrawal (WD on GABAergic transmission in rat CeA neurons using whole-cell recordings with naloxone in the bath. The basal frequency of miniature inhibitory postsynaptic currents (mIPSCs increased in CeA neurons from WD compared to placebo rats. Acute morphine (10 M had mixed effects (> 20% change from baseline on mIPSCs in placebo and WD rats. In most CeA neurons (64% from placebo rats, morphine significantly decreased mIPSC frequency and amplitude. In 32% of placebo neurons, morphine significantly increased mIPSC amplitudes but had no effect on mIPSC frequency. In WD rats, acute morphine significantly increased mIPSC frequency but had no effect on mIPSC amplitude in 41% of CeA neurons. In 45% of cells, acute morphine significantly decreased mIPSC frequency and amplitude. Pre-treatment with the cyclic AMP inhibitor (R-adenosine, cyclic 3’,5’-(hydrogenphosphorothioate triethylammonium (RP, prevented acute morphine-induced potentiation of mIPSCs. Pre-treatment of slices with the Gi/o G-protein subunit inhibitor pertussis toxin (PTX did not prevent the acute morphine-induced enhancement or inhibition of mIPSCs. PTX and RP decreased basal mIPSC frequencies and amplitudes only in WD rats. The results suggest that inhibition of GABAergic transmission in the CeA by acute morphine is mediated by PTX-insensitive mechanisms, although PTX-sensitive mechanisms cannot be ruled out for non-morphine responsive cells; by contrast, potentiation of GABAergic transmission is mediated by activated cAMP signaling that also mediates the increased basal GABAergic transmission in WD rats. Our data indicate that during the acute phase of WD, the CeA opioid and GABAergic systems undergo neuroadaptative changes conditioned by a previous chronic morphine exposure and dependence.

  4. Amnesia induced by morphine in spatial memory retrieval inhibited in morphine-sensitized rats.

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    Farahmandfar, Maryam; Naghdi, Nasser; Karimian, Seyed Morteza; Kadivar, Mehdi; Zarrindast, Mohammad-Reza

    2012-05-15

    The present study investigated the effect of morphine sensitization on the impairment of spatial memory retrieval induced by acute morphine in adult male rats. Spatial memory was assessed by 2-day Morris water maze task which included training and test day. On the training day, rats were trained by a single training session of 8 trials. On the test day, a probe trial consisting of 60s free swim period without a platform and the visible test were administered. Morphine sensitization was induced by subcutaneous (s.c.) injection of morphine, once daily for 3 days followed by 5 days without drug treatment before training. The results indicated that acute administration of morphine (7.5mg/kg, s.c.) before testing impaired spatial memory on the test day. Pre-test morphine-induced amnesia decreased in morphine-sensitized (15 and 20mg/kg, s.c.) rats. Improvement in spatial memory retrieval in morphine-sensitized rats was inhibited by once daily administration of naloxone (1 and 2mg/kg, s.c.) 30 min prior to the injection of morphine for three days. The results suggest that morphine sensitization reverses the impairment of spatial memory retrieval induced by acute morphine and it is implied that mu-opioid receptors may play an important role in this effect. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Repeated morphine treatment influences operant and spatial learning differentially

    Institute of Scientific and Technical Information of China (English)

    Mei-Na WANG; Zhi-Fang DONG; Jun CAO; Lin XU

    2006-01-01

    Objective To investigate whether repeated morphine exposure or prolonged withdrawal could influence operant and spatial learning differentially. Methods Animals were chronically treated with morphine or subjected to morphine withdrawal. Then, they were subjected to two kinds of learning: operant conditioning and spatial learning.Results The acquisition of both simple appetitive and cued operant learning was impaired after repeated morphine treatment. Withdrawal for 5 weeks alleviated the impairments. Single morphine exposure disrupted the retrieval of operant memory but had no effect on rats after 5-week withdrawal. Contrarily, neither chronic morphine exposure nor 5-week withdrawal influenced spatial learning task of the Morris water maze. Nevertheless, the retrieval of spatial memory was impaired by repeated morphine exposure but not by 5-week withdrawal. Conclusion These observations suggest that repeated morphine exposure can influence different types of learning at different aspects, implicating that the formation of opiate addiction may usurp memory mechanisms differentially.

  6. Altered levels of β-endorphin fragments after chronic morphine treatment of guinea-pig ileum in vivo and in vivo

    NARCIS (Netherlands)

    Opmeer, F.A.; Loeber, J.G.; Ree, J.M. van

    1980-01-01

    The isolated myenteric plexus-longitudinal muscle of the guinea-pig ilem (GPI) was used as testsystem to study the influence of chronic morphine treatment on the levels of enkephalins, β-endorphin and some of its fragments. The peptides were assayed by means of a combination of high pressure liquid

  7. Dose-dependent opposite effects of gabapentin on the depressive action of morphine on a C-fibre reflex in the rat.

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    Pollin, Bernard; Roy-Ledoux, Randy; le Bars, Daniel; Adam, Frédéric

    2011-09-01

    Gabapentin is a structural analogue of gamma-amino-butyric acid with anticonvulsant activity. Recently, indications for its use were extended to the management of acute pain in the postoperative period. The effects of pre-administration of gabapentin on the depressive action of intravenous morphine were studied on the C-fibre reflex elicited by a wide range of stimulus intensities. The reflex was elicited by electrical stimulation of the sural nerve and recorded from the ipsilateral biceps femoris muscle in halothane anaesthetized rats with either an intact neuraxis or a brainstem previously transected at the level of the obex. As previously reported, 6 mg/kg intravenous morphine both increased the threshold and decreased the slope of the stimulus-response recruitment curve. The C-fibre reflex was not modified following intravenous gabapentin. Gabapentin pre-treatment at lower doses (0.01-7.5 mg/kg) not only antagonized the depressive effect of morphine, but caused facilitation of the reflex. At higher doses (10-50 mg/kg), gabapentin pre-treatment potentiated the depressive effect of morphine. In obex-transected rats, the facilitation of the C-fibre reflex, seen following 1 mg/kg gabapentin and 6 mg/kg morphine, disappeared and was replaced by a strong reinforcement of the depressive effect of morphine. It is concluded that a strong synergy between the effects of gabapentin and morphine can be seen at the spinal level. However, radically opposite effects with supraspinal origins thwart this mechanism. From the clinical standpoint, these results incite cautiousness in the use of combinations of gabapentin and opioids. Copyright © 2011. Published by Elsevier Ltd.

  8. The role of GABAB receptors in morphine self-administration

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    Effat Ramshini

    2013-01-01

    Full Text Available Background: There is only little information about the effects of GABA receptors agonist and antagonist on morphine self-administration. Present study was designed to assess role of GABAB receptors in the regulation of morphine-reinforced self-administration. Methods: This study was performed in four groups of rats: (1 Saline group, which received saline in the self-administration session. (2 Morphine group, which received morphine in saline solution in the self-administration session. (3 Baclofen + Morphine group, which received both baclofen 20 min before self- administration test and morphine in the self-administration session. (4 Phaclofen + Morphine group, which received both phaclofen 20 min before self- administration test and morphine in the self-administration session. The number of lever pressing and self-infusion were recorded. Results: Morphine significantly increased the number of active lever pressing dose dependently in self-administration session in comparative with saline group. Administration of baclofen, 20 min before morphine self-administration produced significant decrease in the initiation of morphine self-administration during all session. Conversely, pre-treatment of phaclofen increased the number of active lever pressing and self-infusion in this test. Conclusion: Our results indicated a short-term treatment by baclofen, reduced morphine-maintenance response in a dose-dependent manner, suggesting that GABAB receptor agonists could be useful for reversing the neuroadaptations related to opiates.

  9. Morphine as first medication for treatment of cancer pain

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    Beatriz C. Nunes

    2014-07-01

    Full Text Available BACKGROUND AND OBJECTIVES: the medications used according to the recommendation of the World Health Organization do not promote pain relief in a number of patients with cancer pain. The aim of this study was to evaluate the use of morphine as first medication for the treatment of moderate cancer pain in patients with advanced and/or metastatic disease, as an option to the recommendations of the World Health Organization analgesic ladder. METHOD: sixty patients without opioid therapy, with >18 years of age, were randomized into two groups. G1 patients received medication according to the analgesic ladder and started treatment with non-opioids in the first, weak opioids in the second, and strong opioids in the third step; G2 patients received morphine as first analgesic medication. The efficacy and tolerability of initial use of morphine were evaluated every two weeks for three months. RESULTS: the groups were similar with respect to demographic data. There was no significant difference between the groups regarding pain intensity, quality of life, physical capacity, satisfaction with treatment, need for complementation and dose of morphine. In G1 there was a higher incidence of nausea (p = 0.0088, drowsiness (p = 0.0005, constipation (p = 0.0071 and dizziness (p = 0.0376 in the second visit and drowsiness (p = 0.05 in the third. CONCLUSIONS: the use of morphine as first medication for pain treatment did not promote better analgesic effect than the ladder recommended by World Health Organization, with higher incidence of adverse effects.

  10. The Combination of Mitragynine and Morphine Prevents the Development of Morphine Tolerance in Mice

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    Sharida Fakurazi

    2013-01-01

    Full Text Available Mitragynine (MG is the major active alkaloid found in Mitragyna speciosa Korth. In the present study, we investigated the enhancement of analgesic action of MG when combined with morphine and the effect of the combination on the development of tolerance towards morphine. Mice were administered intraperitoneally with a dose of MG (15 and 25 mg/kg b.wt combined with morphine (5 mg/kg b.wt respectively for 9 days. The antinociceptive effect was evaluated by a hot plate test. The protein expression of cyclic adenosine monophosphate (cAMP and cAMP response element binding (CREB was analyzed by immunoblot. Toxicological parameters especially liver and kidney function tests were assessed after the combination treatment with MG and morphine. The concurrent administration of MG and morphine showed significant (p < 0.05 increase in latency time when compared to morphine alone group and the outstanding analgesic effects in the combination regimens were maintained until day 9. For the protein expression, there was a significant increment of cAMP and CREB levels (p < 0.05 in group treated with 5 mg/kg morphine but there was no significant change of these protein expressions when MG was combined with morphine. There was a significant changes in toxicological parameters of various treated groups. The combination treatment of MG and morphine effectively reduce the tolerance due to the chronic administration of morphine.

  11. Stereospecific effects of morphine on plasma opioid peptide levels and nociception in dogs

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    Adams, M.L.; Morris, D.L.; Dewey, W.L.

    1986-03-05

    ..beta..-endorphin, (met)enkephalin, and (leu)enkephalin were quantitated in canine plasma by radioimmunoassay (RIA) after extraction of the peptides on Sep Pak C18 cartridges. Plasma samples were taken one hour after a 10 mg/kg s.c. injection of (-)-morphine SO/sub 4/ or (+)-morphine HBr. Antinociception, measured by a dog tail-flick test, and morphine-induced emesis, salivation, diarrhea, and ataxia were quantitated before sampling. Control levels for each dog were taken one week earlier at the same time of day after saline injections. Antinociception, morphine signs, and opioid peptide levels in plasma were significantly increased by (-)-morphine. Antinociception increased from zero to 83.54 +/- 11.0%. The number of morphine signs increased from zero to 2.9 +/- 0.28 per dog. ..beta..-endorphin levels increased from 44.52 +/- 4.25 to 90.6 +/- 7.38 pg/ml; (met)enkephalin levels increased from 253.56 +/- 22.04 to 497.1 +/- 58.12 pg/ml; (leu)-enkephalin increased from 141.65 +/- 12.9 to 313.24 +/- 35.95 pg/ml. None of these effects were observed in the dogs that received (+)-morphine. The conclude that morphine stereospecifically inhibits nociception, induces observable signs, and increases plasma opioid peptide levels in dogs.

  12. Stereospecific effects of morphine on plasma opioid peptide levels and nociception in dogs

    International Nuclear Information System (INIS)

    Adams, M.L.; Morris, D.L.; Dewey, W.L.

    1986-01-01

    β-endorphin, [met]enkephalin, and [leu]enkephalin were quantitated in canine plasma by radioimmunoassay (RIA) after extraction of the peptides on Sep Pak C18 cartridges. Plasma samples were taken one hour after a 10 mg/kg s.c. injection of (-)-morphine SO 4 or (+)-morphine HBr. Antinociception, measured by a dog tail-flick test, and morphine-induced emesis, salivation, diarrhea, and ataxia were quantitated before sampling. Control levels for each dog were taken one week earlier at the same time of day after saline injections. Antinociception, morphine signs, and opioid peptide levels in plasma were significantly increased by (-)-morphine. Antinociception increased from zero to 83.54 +/- 11.0%. The number of morphine signs increased from zero to 2.9 +/- 0.28 per dog. β-endorphin levels increased from 44.52 +/- 4.25 to 90.6 +/- 7.38 pg/ml; [met]enkephalin levels increased from 253.56 +/- 22.04 to 497.1 +/- 58.12 pg/ml; [leu]-enkephalin increased from 141.65 +/- 12.9 to 313.24 +/- 35.95 pg/ml. None of these effects were observed in the dogs that received (+)-morphine. The conclude that morphine stereospecifically inhibits nociception, induces observable signs, and increases plasma opioid peptide levels in dogs

  13. Treadmill exercise attenuates the severity of physical dependence, anxiety, depressive-like behavior and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment.

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    Alizadeh, Maryam; Zahedi-Khorasani, Mahdi; Miladi-Gorji, Hossein

    2018-05-30

    This study was designed to examine whether treadmill exercise would attenuate the severity of physical dependence, methadone-induced anxiety, depression and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment (MMT). The rats were chronically treated with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 14 days. The exercising rats receiving MMT were forced to run on a motorized treadmill for 30 days during morphine withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that naloxone- precipitated opioid withdrawal signs were decreased in exercising morphine-dependent rats receiving MMT than sedentary rats. Also, the exercising morphine-dependent rats receiving MMT exhibited an increased time on open arms, preference for sucrose and a lower morphine preference ratio than sedentary rats. We conclude that treadmill exercise decreased the severity of physical dependence, anxiety/depressive-like behaviors and also the voluntary morphine consumption in morphine withdrawn rats receiving MMT. Thus, exercise may benefit in the treatment of addicts during MMT. Copyright © 2018. Published by Elsevier B.V.

  14. Cardiac adverse effects of naloxone-precipitated morphine withdrawal on right ventricle: Role of corticotropin-releasing factor (CRF) 1 receptor

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    Navarro-Zaragoza, J.; Martínez-Laorden, E.; Mora, L.; Hidalgo, J.; Milanés, M.V.; Laorden, M.L., E-mail: laorden@um.es

    2014-02-15

    Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic–pituitary–adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts. - Highlights: • Morphine withdrawal caused an increase in myocardial sympathetic activity. • ERK regulates TH phosphorylation after naloxone-induced morphine withdrawal. • CRF1R is involved in cardiac adaptive changes during morphine dependence.

  15. Cardiac adverse effects of naloxone-precipitated morphine withdrawal on right ventricle: Role of corticotropin-releasing factor (CRF) 1 receptor

    International Nuclear Information System (INIS)

    Navarro-Zaragoza, J.; Martínez-Laorden, E.; Mora, L.; Hidalgo, J.; Milanés, M.V.; Laorden, M.L.

    2014-01-01

    Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic–pituitary–adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts. - Highlights: • Morphine withdrawal caused an increase in myocardial sympathetic activity. • ERK regulates TH phosphorylation after naloxone-induced morphine withdrawal. • CRF1R is involved in cardiac adaptive changes during morphine dependence

  16. Effects of different doses of glucose and insulin on morphine state-dependent memory of passive avoidance in mice.

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    Jafari, M R; Zarrindast, M R; Djahanguiri, B

    2004-10-01

    Behavioral effects of morphine, including its effect on memory, have been demonstrated to be influenced by glucose pretreatment. The measurement of step-down latency in passive avoidance has been used to study memory in laboratory animals. The pre-training injection of 5 mg/kg morphine impaired memory, which was restored when 24 h later the same dose of the drug was administered. To investigate the effects of glucose and insulin alone or in combination with morphine, on pre-test day, on memory recall in mice. The effects of different doses of glucose (50, 100, and 200 mg/kg, IP) and insulin (5, 10, and 20 IU/kg, IP) alone or in combination with morphine, have been studied in mice. The blood glucose level and locomotor activity of the animals were also measured. Although the administration of glucose alone showed no effect on morphine-induced memory impairment, its co-administration with morphine resulted in a significant and dose-dependent memory enhancement compared with the effects of morphine administration alone. Like glucose, the administration of different doses of insulin alone produced no change in the memory, but when the drug was co-administered with morphine, it significantly reduced morphine-induced memory retrieval. The effect of insulin was the opposite of glucose. None of the animals subjected to insulin treatment showed convulsions. Glucose is suggested to increase, on the test day, the morphine-induced memory enhancement by three different mechanisms: cholinergic or opioidergic modulations, or regulation of the ATP-dependent potassium channels.

  17. Acupuncture suppresses reinstatement of morphine-seeking behavior induced by a complex cue in rats.

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    Lee, Bong Hyo; Lim, Sung Chul; Jeon, Hyeon Jeong; Kim, Jae Su; Lee, Yun Kyu; Lee, Hyun Jong; In, Sunghyun; Kim, Hee Young; Yoon, Seong Shoon; Yang, Chae Ha

    2013-08-26

    Morphine causes physical and psychological dependence for individuals after repeated-use. Above all, our previous study showed that acupuncture attenuated reinstatement of morphine-seeking behavior induced by pharmacological cue. In this study, we investigated whether acupuncture could suppress the reinstatement of morphine-seeking behavior induced by the combination of environmental and pharmacological cues and the possible neuronal involvement. Male Sprague-Dawley rats were trained to self-administer morphine (1.0 mg/kg) for 3 weeks. Following the withdrawal phase (7 days), the effects of acupuncture on reinstatement of morphine-seeking behavior were investigated. For the investigation of neuronal involvement, the GABAA receptor antagonist bicuculline and the GABAB receptor antagonist SCH 50911 were pre-treated. Morphine-seeking behavior induced by combination of re-exposure to the operant chamber and morphine injection was suppressed perfectly by acupuncture at SI5, but not at the control acupoint LI5 and this effect was blocked by pre-treatment with the GABA receptor antagonists. This study suggests that acupuncture at SI5 can be considered as a predominant therapy for the reinstatement of morphine-seeking behavior in humans. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  18. OPRM1 c.118A>G Polymorphism and Duration of Morphine Treatment Associated with Morphine Doses and Quality-of-Life in Palliative Cancer Pain Settings

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    Aline Hajj

    2017-03-01

    Full Text Available Despite increased attention on assessment and management, pain remains the most persistent symptom in patients with cancer, in particular in end-of-life settings, with detrimental impact on their quality-of-life (QOL. We conducted this study to evaluate the added value of determining some genetic and non-genetic factors to optimize cancer pain treatment. Eighty-nine patients were included in the study for the evaluation of palliative cancer pain management. The regression analysis showed that age, OPRM1 single nucleotide polymorphism (SNP, as well as the duration of morphine treatment were significantly associated with morphine doses at 24 h (given by infusion pump; p = 0.043, 0.029, and <0.001, respectively. The mean doses of morphine decreased with age but increased with the duration of morphine treatment. In addition, patients with AG genotype c.118A>G OPRM1 needed a higher dose of morphine than AA patients. Moreover, metastases, OPRM1 SNP, age, and gender were significantly associated with the QOL in our population. In particular, AA patients for OPRM1 SNP had significantly lower cognitive function than AG patients, a result not previously reported in the literature. These findings could help increase the effectiveness of morphine treatment and enhance the QOL of patients in regards to personalized medicine.

  19. Ajoene restored behavioral patterns and liver glutathione level in morphine treated C57BL6 mice.

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    Yun, Jaesuk; Oliynyk, Sergiy; Lee, Yeonju; Kim, Jieun; Yun, Kyunghwa; Jeon, Raok; Ryu, Jae-Ha; Oh, Seikwan

    2017-01-01

    Oxidative stress exacerbates drug dependence induced by administration of opiate analgesics such as morphine-induced tolerance and physical dependence associated with the reduction in hepatic glutathione (GSH) level. Ajoene obtained from garlic (Allium sativum L.) has been reported for anti-tumorigenic, anti-oxidative and neuroprotective properties, however, little is known about its effect on morphine-induced dependence. Therefore, this study aimed at the effect of ajoene on physical and/or psychological dependence and liver GSH content in morphine-treated mice. Conditioned place preference (CPP) test and measurement of morphine withdrawal syndrome were performed in C57BL6 mice for behavioral experiments. Thereafter, mice were sacrificed for measurement of serum and liver GSH levels. Ajoene restored CPP and naloxone-precipitated jumping behavior in mice exposed to morphine. Moreover, the reduced level of liver GSH content in morphine treated mice was back to normal after ajoene administration. Taken together, ajoene improved behavioral patterns in mice exposed to morphine suggesting its potential therapeutic benefit against morphine-induced dependence.

  20. Attenuation of morphine withdrawal signs, blood cortisol and glucose level with forced exercise in comparison with clonidine

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    Majid Motaghinejad

    2014-01-01

    Full Text Available Background: Morphine withdrawal usually results in undesired outcomes , despite partial benefits of alternative medication such as methadone, because of the lack of mental sedation during the withdrawal period, may not lead to the desired result. In this study, forced exercise by treadmill is used to manage morphine dependence in animal model. Materials and Methods: Forty adult male mice were divided into 5 groups, from which 4 groups became dependent by increasing daily doses of morphine for 6 days (20-45 mg/kg, SC. Afterwards, the animals were treated for 21 days by either of the following protocol: Positive control (dependent received once daily 45 mg/kg of morphine sulfate (SC for 21 day, group under treatment by clonidine (0.4 mg/kg, SC for 21 day group under treatment by forced exercise by treadmill for 21 day, group under treatment by combination of clonidine (0.4 mg/kg, SC and forced exercise by treadmill for 21day and the negative control group(independent received saline injection like other groups. Each of this administration was injected at 8 AM. Finally, in the test day (day 28, all animals received a single dose of naloxone (3 mg/kg, SC at 8 AM and then were observed for withdrawal signs, and Total Withdrawal Score (TWS was determined as described previously. After withdrawal sign evaluation for evaluation of stress level of dependent mice, blood cortisol and glucose level were measured in non-fasting situations well. Results: This study showed that TWS significantly decreased in all treatment groups in comparison with positive control group (P < 0.001. Moreover, blood cortisol and glucose level significantly decreased in group under treatment by clonidine (0.4 mg/kg and group under treatment by combination of clonidine (0.4 mg/kg and forced exercise by treadmill groups in comparison with control positive (dependent (P < 0.05. Conclusion: This study suggested that forced exercise can be useful as adjunct therapy in dependent people

  1. Pharmacological consequences of long-term morphine treatment in patients with cancer and chronic non-malignant pain

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    Andersen, Gertrud; Sjøgren, Per; Hansen, Steen Honoré

    2004-01-01

    In patients with pain of malignant origin morphine may be administered in high and often increasing doses during extended periods of time. In patients with chronic pain of non-malignant origin morphine may be an important remedy, and in these cases the goal is to keep the morphine dose stable. Th....... The pharmacokinetic as well as the pharmacodynamic consequences of long-term morphine treatment with special reference to the two most important metabolites of morphine morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) remain to be settled....

  2. Effects of BDNF receptor antagonist on the severity of physical and psychological dependence, morphine-induced locomotor sensitization and the ventral tegmental area-nucleus accumbens BDNF levels in morphine- dependent and withdrawn rats.

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    Khalil-Khalili, Masoumeh; Rashidy-Pour, Ali; Bandegi, Ahmad Reza; Yousefi, Behpoor; Jorjani, Hassan; Miladi-Gorji, Hossein

    2018-03-06

    This study examined the effects of systemic administration of the TrkB receptor antagonist (ANA-12) on the severity of physical and psychological dependence and morphine-induced locomotor sensitization, the ventral tegmental area (VTA)-nucleus accumbens (NAc) BDNF levels in morphine-dependent and withdrawn rats. Rats were injected with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 10 days. Then, rats were tested for naloxone-precipitated morphine withdrawal signs, the anxiety (the elevated plus maze-EPM) after the last morphine injection and injection of ANA12 (ip). Also, morphine-induced locomotor sensitization was evaluated after morphine challenge followed by an injection of ANA-12 in morphine-withdrawn rats. The VTA-NAc BDNF levels were assessed in morphine-dependent and withdrawn rats. The overall Gellert-Holtzman score was significantly higher in morphine-dependent rats receiving ANA-12 than in those receiving saline. Also, the percentage of time spent in the open arms in control and morphine-dependent rats receiving ANA-12 were higher compared to the Cont/Sal and D/Sal rats, respectively. There was no significant difference in the locomotor activity and the VTA-NAc BDNF levels between D/Sal/morphine and D/ANA-12/morphine groups after morphine withdrawal. We conclude that the systemic administration of ANA-12 exacerbates the severity of physical dependence on morphine and partially attenuates the anxiety-like behavior in morphine-dependent rats. However, ANA-12 did not affect morphine-induced locomotor sensitization and the VTA-NAc BDNF levels in morphine-dependent and withdrawn rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Attenuation of Morphine Physical Dependence and Blood Levels of Cortisol by Central and Systemic Administration of Ramelteon in Rat

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    Majid Motaghinejad

    2015-05-01

    Full Text Available Background: Chronic administration of morphine cause physical dependence but the exact mechanism of this phenomenon remains unclear. The aim of this study is the assessment of systemic and intracerebroventricular (icv administration of ramelteon (a melatonin receptor agonist on morphine physical dependence. Methods: 88 adult male rats were divided into 2 major groups, namely “systematic” and “central” administration of ramelteon. In the first category, systemic administration of ramelteon at various dosages (10, 20, and 40 mg/kg was assessed on dependent animals and withdrawal signs were compared with positive (received morphine and saline as systemic administration, negative control (saline and group under treatment by ramelteon (40 mg/kg groups. In the second category, central administration of ramelteon at various dosages (25, 50, or 100 μg, was assessed on dependent animals and withdrawal signs were compared with the positive control (received morphine and saline as icv and negative control (saline groups, and the group under treatment by ramelteon (50 μg/5 μl/rat. On the test day, all animals received naloxone (3 mg/kg and were observed for withdrawal signs. Total withdrawal score (TWS was also determined. Finally, to evaluate the stress level of dependent rats, blood cortisols were measured. Results: Central administration of ramelteon in all doses and systemic administration in high doses attenuate withdrawal syndrome in comparison with the dependent positive control group (P<0.05. Both central and systemic administrations of ramelteon can attenuate the blood cortisol level in comparison with the dependent positive control group (P<0.05. Conclusion: In conclusion, we found that central administration of ramelteon attenuated morphine withdrawal symptoms and cortisol level as a stress marker.

  4. Resveratrol reverses morphine-induced neuroinflammation in morphine-tolerant rats by reversal HDAC1 expression

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    Ru-Yin Tsai

    2016-06-01

    Conclusion: Resveratrol restores the antinociceptive effect of morphine by reversing morphine infusion-induced spinal cord neuroinflammation and increase in TNFR1 expression. The reversal of the morphine-induced increase in TNFR1 expression by resveratrol is partially due to reversal of the morphine infusion-induced increase in HDAC1 expression. Resveratrol pretreatment can be used as an adjuvant in clinical pain management for patients who need long-term morphine treatment or with neuropathic pain.

  5. Effect of Pentylenetetrazol on Morphine State-Dependent Memory in Rat

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    Marziyeh Tavassoli

    2017-09-01

    Full Text Available Abstract Background: Learning and memory are among the higher functions of the brain. State-dependent memory (STM is a type of memory in which the recall of a learned behavior is happend only in the same sensory and physiologic condition in which the behavior is encoded. The STM is seen with some drugs, e.g. the morphine. The pentylenetetrazol (PTZ is a durg which is used for the induction of seizure in experimental models. Some studies have been revealed different effects of the PTZ on brain higher function (learning, memory …. The aim of present study was to explore the effect of PTZ on morphine-induced STM. Materials and Methods: In this study, male adult Wistar rats (190-220 g were used. Animals in 3 groups (n=8 during 3 sessions (learning/memory, STM and interaction were studied. During 48 hour (training and test the learning and memory of animals were studied in inhibitory avoidance apparatus. The step-through latency in the test day was used as a criterion for memory. Post-training injection of saline or morphine (2.5, 5 and 7.5 mg/kg-ip in different groups was carried out. In addition, the pre-test injection of morphine at the same doses was made to study the STM. Moreover, the interaction of pre-test single-dose PTZ (60 mg/kg-ip on STM was studied. The locomotion of the animals was measured using the open field. Results: The post-training injection of morphine (2.5, 5 and 7.5 mg/kg-ip impaired the inhibitory memory of rats compared to control group (p<0.001. The post-training and pre-test injections of the same dose of morphine (7.5 mg/kg-ip reversed the impaired memory compared to morphine (2.5 and 5 mg/kg-ip, (p<0.001. The pre-test PTZ (60 mg/kg-ip maintained the morphine (7.5 mg/kg-ip STM (p<0.001. Conclusion: The present study revealed that the post-training ip injection of different doses of morphine results in the impairment of inhibitory avoidance memory in rat. In addition, the pre-test injection of the same doses of morphine

  6. Upregulation of miR-375 level ameliorates morphine analgesic tolerance in mouse dorsal root ganglia by inhibiting the JAK2/STAT3 pathway

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    Li HQ

    2017-05-01

    Full Text Available Haiqin Li, Rong Tao, Jing Wang, Lingjie Xia Department of Clinical Pain, The People’s Hospital of Henan Province, Zhengzhou, People’s Republic of China Abstract: Several lines of evidence indicate that microRNAs (miRNAs modulate tolerance to the analgesic effects of morphine via regulation of pain-related genes, making dysregulation of miRNA levels a clinical target for controlling opioid tolerance. However, the precise mechanisms by which miRNAs regulate opioid tolerance are unclear. In the present study, we noted that the miR-375 level was downregulated but the expression of Janus kinase 2 (JAK2 was upregulated in mouse dorsal root ganglia (DRG following chronic morphine treatment. The miR-375 levels and JAK2 expression were correlated with the progression of morphine tolerance, and upregulation of miR-375 level could significantly hinder morphine tolerance. This was ameliorated by JAK2 knockdown. Prolonged morphine exposure induced the expression of brain-derived neurotrophic factor (BDNF in a time-dependent manner in the DRG. This was regulated by the miR-375 and JAK2–signal transducer and activator of transcription 3 (STAT3 pathway, and inhibition of this pathway decreased BDNF production, and thus, attenuated morphine tolerance. More importantly, we found that miR-375 could target JAK2 and increase BDNF expression in a JAK2/STAT3 pathway-dependent manner. Keywords: morphine tolerance, miR-375, JAK2, BDNF

  7. A review of morphine and morphine-6-glucuronide's pharmacokinetic-pharmacodynamic relationships in experimental and clinical pain

    DEFF Research Database (Denmark)

    Sverrisdóttir, Eva; Lund, Trine Meldgaard; Olesen, Anne Estrup

    2015-01-01

    Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can...... a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates....... Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course...

  8. Effects of Electroacupuncture Treatment on Bone Cancer Pain Model with Morphine Tolerance

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    Lei Sima

    2016-01-01

    Full Text Available Objective. To explore the efficacy of electroacupuncture treatment in cancer induced bone pain (CIBP rat model with morphine tolerance and explore changes of calcitonin-gene related peptide (CGRP expression in dorsal root ganglion (DRG. Methods. Forty SD rats were divided into five groups: sham, CIBP (B, CIBP + morphine (BM, CIBP + electroacupuncture (BE, and CIBP + morphine + electroacupuncture (BME. B, BM, BE, and BME groups were prepared CIBP model. The latter three groups then accepted morphine, electroacupuncture, and morphine combined electroacupuncture, separately, nine days consecutively (M1 to M9. Mechanical withdraw threshold (MWT was evaluated. Results. BE group only had differences in M1, M2, and M3 compared to B group (P<0.01. From M5, BM group showed significantly decreased MWT. Electroacupuncture could obtain analgesic effects only at early stage (M1 to M5. From M5 to M9, BME had the differences with BM group (P<0.01. IOD value of CGRP in BM and BME was substantially less than in B group. CGRP in BME was significantly lower than that in BM group (P<0.01. Conclusion. When used in combination with electroacupuncture, morphine could result in improving analgesic effects and reducing tolerance. CGRP may be associated with pain behaviors.

  9. Effect of environmental enrichment on physical and psychological dependence signs and voluntary morphine consumption in morphine-dependent and morphine-withdrawn rats.

    Science.gov (United States)

    Hammami-Abrand Abadi, Arezoo; Miladi-Gorji, Hossein; Bigdeli, Imanollah

    2016-04-01

    This study was designed to examine the effect of environmental enrichment during morphine dependency and withdrawal on the severity of naloxone-precipitated withdrawal signs, anxiety, and depressive-like behaviors and voluntary morphine consumption in morphine-dependent rats. The rats were injected with bi-daily doses (10 mg/kg, 12 h intervals) of morphine for 14 days following rearing in a standard environment (SE) or enriched environment (EE) during the development of morphine dependence and withdrawal. Then, rats were tested for withdrawal signs after naloxone injection, anxiety (the elevated plus maze) and depression-related behavior (sucrose preference test), and voluntary consumption of morphine using a two-bottle choice paradigm, in morphine-dependent and morphine-withdrawn rats. The results showed that EE decreased naloxone-precipitated withdrawal signs, but not anxiety or sucrose preference during dependence on morphine. The EE-withdrawn rats showed an increase in the elevated plus maze open arm time and entries and higher levels of sucrose preference than SE rats. Voluntary consumption of morphine was lower in the EE-withdrawn rats than in the SE groups in the second period of drug intake. Thus, exposure to EE reduced the severity of morphine dependence and voluntary consumption of morphine, alongside reductions in anxiety and depression-related behavior in morphine-withdrawn rats.

  10. Involvement of the K+-Cl- co-transporter KCC2 in the sensitization to morphine-induced hyperlocomotion under chronic treatment with zolpidem in the mesolimbic system.

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    Shibasaki, Masahiro; Masukawa, Daiki; Ishii, Kazunori; Yamagishi, Yui; Mori, Tomohisa; Suzuki, Tsutomu

    2013-06-01

    Benzodiazepines are commonly used as sedatives, sleeping aids, and anti-anxiety drugs. However, chronic treatment with benzodiazepines is known to induce dependence, which is considered related to neuroplastic changes in the mesolimbic system. This study investigated the involvement of K(+) -Cl(-) co-transporter 2 (KCC2) in the sensitization to morphine-induced hyperlocomotion after chronic treatment with zolpidem [a selective agonist of γ-aminobutyric acid A-type receptor (GABAA R) α1 subunit]. In this study, chronic treatment with zolpidem enhanced morphine-induced hyperlocomotion, which is accompanied by the up-regulation of KCC2 in the limbic forebrain. We also found that chronic treatment with zolpidem induced the down-regulation of protein phosphatase-1 (PP-1) as well as the up-regulation of phosphorylated protein kinase C γ (pPKCγ). Furthermore, PP-1 directly associated with KCC2 and pPKCγ, whereas pPKCγ did not associate with KCC2. On the other hand, pre-treatment with furosemide (a KCC2 inhibitor) suppressed the enhancing effects of zolpidem on morphine-induced hyperlocomotion. These results suggest that the mesolimbic dopaminergic system could be amenable to neuroplastic change through a pPKCγ-PP-1-KCC2 pathway by chronic treatment with zolpidem. © 2013 International Society for Neurochemistry.

  11. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone

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    Atefeh Aminian

    2016-07-01

    Full Text Available Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg, animals received intraperitoneal injections of morphine (5 mg/kg/day and/or naltrexone (20 mg/kg/day, an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy.

  12. Inability of naloxone to change brain morphine levels in tolerant mice

    International Nuclear Information System (INIS)

    Dum, J.; Meyer, G.; Hoellt, V.; Herz, A.; Catlin, D.H.

    1977-01-01

    The effect of naloxone on brain morphine concentrations was measured in naive and morphine-dependent mice using radioimmunoassay and gas-liquid chromatography. No displacement of morphine from the brain by naloxone could be observed in naive mice acutely injected with morphine or in pellet-implanted mice at increasing intervals after removal of the morphine pellets. The suggestion of a change in affinity of opiate receptors during the development of tolerance/dependence, which had been made on the basis of the displacement of morphine by naloxone found by other workers, is thus not supported by the present results

  13. Effect of chronic morphine treatment on β-endorphin biosynthesis by the rat neurointermediate lobe

    International Nuclear Information System (INIS)

    Gianoulakis, C.; Drouin, J.-N.; Seidah, N.G.; Kalant, H.; Chretien, M.

    1981-01-01

    The effect of chronic morphine treatment on the in vitro biosynthesis of β-endorphin by rat pars intermedia was investigated. Tolerance and physical dependence were induced in 200 g rats by the subcutaneous implantation of 75 mg morphine pellets for either 3 days or 15 days. Immediately following sacrifice of the animals the neurointermediate lobes were removed and incubated with [ 3 H]phenylalanine. The protein extracts of the lobes were analyzed for the incorporation of the labelled amino acid into total protein, pro-opiomelanocortin, β-lipotropin (β-LPH) and β-endorphin. The biosynthesized products were purified by immunoprecipitation with an antiserum to β-endorphin. The identity and purity of β-endorphin were verified by polyacrylamide disc gel electrophoresis with sodium dodecyl sulfate, and mircrosequencing. The identity of pro-opiomelanocortin (POMC) was verified by peptide mapping of its tryptic digestion products. The results showed that morphine treatment induced a decrease in the incorporation of the radioactive amino acid into total protein, pro-opiomelanocortin, β-LPH and β-endorphin. The decrease was more pronounced for the incorporation into β-LPH and β-endorphin than into pro-opiomelanocortin and total proteins, suggesting an effect of morphine treatment on the processing of the pro-opiomelanocortin to its final maturation products. (Auth.)

  14. Implication of mGlu5 receptor in the enhancement of morphine-induced hyperlocomotion under chronic treatment with zolpidem.

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    Shibasaki, Masahiro; Ishii, Kazunori; Masukawa, Daiki; Ando, Koji; Ikekubo, Yuiko; Ishikawa, Yutori; Shibasaki, Yumiko; Mori, Tomohisa; Suzuki, Tsutomu

    2014-09-05

    Long-term exposure to zolpidem induces drug dependence, and it is well known that the balance between the GABAergic and glutamatergic systems plays a critical role in maintaining the neuronal network. In the present study, we investigated the interaction between GABAA receptor α1 subunit and mGlu5 receptor in the limbic forebrain including the N.Acc. after treatment with zolpidem for 7 days. mGlu5 receptor protein levels were significantly increased after treatment with zolpidem for 7 days, and this change was accompanied by the up-regulation of phospholipase Cβ1 and calcium/calmodulin-dependent protein kinase IIα, which are downstream of mGlu5 receptor in the limbic forebrain. To confirm that mGlu5 receptor is directly involved in dopamine-related behavior in mice following chronic treatment with zolpidem, we measured morphine-induced hyperlocomotion after chronic treatment with zolpidem in the presence or absence of an mGlu5 receptor antagonist. Although chronic treatment with zolpidem significantly enhanced morphine-induced hyperlocomotion, this enhancement of morphine-induced hyperlocomotion was suppressed by treating it with the mGlu5 receptor antagonist MPEP. These results suggest that chronic treatment with zolpidem caused neural plasticity in response to activation of the mesolimbic dopaminergic system accompanied by an increase in mGlu5 receptor. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Endogenous cholinergic neurotransmission contributes to behavioral sensitization to morphine.

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    Dusica Bajic

    Full Text Available Neuroplasticity in the mesolimbic dopaminergic system is critical for behavioral adaptations associated with opioid reward and addiction. These processes may be influenced by cholinergic transmission arising from the laterodorsal tegmental nucleus (LDTg, a main source of acetylcholine to mesolimbic dopaminergic neurons. To examine this possibility we asked if chronic systemic morphine administration affects expression of genes in ventral and ventrolateral periaqueductal gray at the level of the LDTg using rtPCR. Specifically, we examined gene expression changes in the area of interest using Neurotransmitters and Receptors PCR array between chronic morphine and saline control groups. Analysis suggested that chronic morphine administration led to changes in expression of genes associated, in part, with cholinergic neurotransmission. Furthermore, using a quantitative immunofluorescent technique, we found that chronic morphine treatment produced a significant increase in immunolabeling of the cholinergic marker (vesicular acetylcholine transporter in neurons of the LDTg. Finally, systemic administration of the nonselective and noncompetitive neuronal nicotinic antagonist mecamylamine (0.5 or 2 mg/kg dose-dependently blocked the expression, and to a lesser extent the development, of locomotor sensitization. The same treatment had no effect on acute morphine antinociception, antinociceptive tolerance or dependence to chronic morphine. Taken together, the results suggest that endogenous nicotinic cholinergic neurotransmission selectively contributes to behavioral sensitization to morphine and this process may, in part, involve cholinergic neurons within the LDTg.

  16. Comparison of Morphine, Morphine-Lidocaine, and Morphine-Lidocaine-Ketamine Infusions in Dogs Using an Incision-Induced Pain Model.

    Science.gov (United States)

    Chiavaccini, Ludovica; Claude, Andrew K; Meyer, Robert E

    We aimed to compare antinociceptive effects of IV infusions of morphine (M), morphine-lidocaine (ML), or morphine-lidocaine-ketamine (MLK) combined, in a mild-to-moderate pain model in dogs. Eighteen adult hounds were heavily sedated with IV morphine (0.2 mg/kg) and dexmedetomidine to undergo thoracic skin incisions. After reversal, dogs were randomly assigned to receive loading doses of lidocaine and ketamine (MLK), lidocaine and saline (ML), or equivalent volume of saline (M), followed by 18 hr constant infusions of morphine (0.12 mg/kg/hr), lidocaine (3 mg/kg/hr) and ketamine (0.6 mg/kg/hr); morphine (0.12 mg/kg/hr) and lidocaine (3 mg/kg/hr); or morphine (0.12 mg/kg/hr), respectively. Pain was assessed with Short Form Glasgow Composite Measure Pain Scale and mechanical nociception with von Frey filaments (VFFS). Data were analyzed with linear mixed model on ranks. Independently of treatment, Short Form Glasgow Composite Measure Pain Scale was significantly higher than baseline for 24 hr (p < .0001), while VFFS was significantly lower than baseline for 48 hr post-recovery (p < .0001), with no difference between MLK and M groups. The ML group recorded significantly lower VFFS (p = .02) than the M group for the entire study. In conclusion, there was no significant analgesic difference between MLK and M alone.

  17. The γ-aminobutyric acid type B (GABAB) receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens.

    Science.gov (United States)

    Fu, Zhenyu; Yang, Hongfa; Xiao, Yuqiang; Zhao, Gang; Huang, Haiyan

    2012-07-10

    Repeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA) system is involved in morphine dependence. However, the effect of a GABAB receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear. We used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo. The present study demonstrated that morphine challenge (3 mg/kg, s.c.) obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5 mg/kg) significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3 days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge. Our results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse.

  18. Preincisional and postoperative epidural morphine, ropivacaine, ketamine, and naloxone treatment for postoperative pain management in upper abdominal surgery.

    Science.gov (United States)

    Lai, Hou-Chuan; Hsieh, Chung-Bao; Wong, Chih-Shung; Yeh, Chun-Chang; Wu, Zhi-Fu

    2016-09-01

    Previous studies have shown that preincisional epidural morphine, bupivacaine, and ketamine combined with epidural anesthesia (EA) and general anesthesia (GA) provided pre-emptive analgesia for upper abdominal surgery. Recent studies reported that ultralow-dose naloxone enhanced the antinociceptive effect of morphine in rats. This study investigated the benefits of preincisional and postoperative epidural morphine + ropivacaine + ketamine + naloxone (M + R + K + N) treatment for achieving postoperative pain relief in upper abdominal surgery. Eighty American Society of Anesthesiology I-II patients scheduled for major upper abdominal surgery were allocated to four groups in a randomized, single-blinded study. All patients received combined GA and EA with a continuous epidural infusion of 2% lidocaine (6-8 mL/h) 30 minutes after pain regimen. After GA induction, in Group I, an epidural pain control regimen (total 10 mL) was administered using 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg; M + R); in Group II, 1% lidocaine 8 (mL) + morphine (2 mg) + ropivacaine (20 mg) + ketamine (20 mg; M + R + K); in Group III, 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg) + naloxone (2 μg; M + R + N); and in Group IV, 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg) + ketamine (20 mg) + naloxone (2 μg; M + R + K + N), respectively. All patients received patient-controlled epidural analgesia (PCEA) with different pain regimens to control subsequent postoperative pain for 3 days following surgery. During the 3-day period following surgery, PCEA consumption (mL), numerical rating scale (NRS) score while cough/moving, and analgesic-related adverse effects were recorded. Total PCEA consumption for the 3-day observation period was 161.5±17.8 mL, 103.2±21.7 mL, 152.4±25.6 mL, and 74.1±16.9 mL for Groups I, II, III, and IV, respectively. (p pain management than preincisional

  19. Pain Levels Within 24 Hours After UFE: A Comparison of Morphine and Fentanyl Patient-Controlled Analgesia

    International Nuclear Information System (INIS)

    Kim, Hyun S.; Czuczman, Gregory J.; Nicholson, Wanda K.; Pham, Luu D.; Richman, Jeffrey M.

    2008-01-01

    The purpose of this study was to assess the presence and severity of pain levels during 24 h after uterine fibroid embolization (UFE) for symptomatic leiomyomata and compare the effectiveness and adverse effects of morphine patient-controlled analgesia (PCA) versus fentanyl PCA. We carried out a prospective, nonrandomized study of 200 consecutive women who received UFE and morphine or fentanyl PCA after UFE. Pain perception levels were obtained on a 0-10 scale for the 24-h period after UFE. Linear regression methods were used to determine pain trends and differences in pain trends between two groups and the association between pain scores and patient covariates. One hundred eighty-five patients (92.5%) reported greater-than-baseline pain after UFE, and 198 patients (99%) required IV opioid PCA. One hundred thirty-six patients (68.0%) developed nausea during the 24-h period. Seventy-two patients (36%) received morphine PCA and 128 (64%) received fentanyl PCA, without demographic differences. The mean dose of morphine used was 33.8 ± 26.7 mg, while the mean dose of fentanyl was 698.7 ± 537.4 μg. Using this regimen, patients who received morphine PCA had significantly lower pain levels than those who received fentanyl PCA (p < 0.0001). We conclude that patients develop pain requiring IV opioid PCA within 24 h after UFE. Morphine PCA is more effective in reducing post-uterine artery embolization pain than fentanyl PCA. Nausea is a significant adverse effect from opioid PCA.

  20. Effect of Genistein on reproductive parameter and serum nitric oxide levels in morphine-treated mice

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    Cyrus Jalili

    2016-02-01

    Full Text Available Background: The predominant phytoestrogen in soy and derived products is the isoflavone Genistein. Genistein has antioxidant properties. Morphine is a main psychoactive chemical in opium that can increase the generation of free radicals and therefore it could adversely affects the spermatogenesis. Objective: The main goal was to investigate whether the Genistein could protect morphine adverse effects on sperm cells viability, count, motility, and testis histology and testosterone hormone and nitric oxide in blood serum. Materials and Methods: In this study, various doses of Genistein (0, 1, 2, and 3 mg/kg and Genistein plus morphine (0, 1, 2, and 3 mg/kg were administered interaperitoneally to 48 male mice for 30 consequent days. These mice were randomly assigned to 8 groups (n=6 and sperm parameters (sperm cells viability, count, motility and morphology, testis weight and histology, testosterone hormone (ELISA method, FSH and LH hormones (immunoradiometry and serum nitric oxide (griess assay were analyzed and compared. Results: The results indicated that morphine administration significantly decreased testosterone (0.03 ng/mg LH and FSH level, histological parameters, count, viability (55.3%, morphology and motility of sperm cells (1%, testis weight (0.08 gr and increase nitric oxide compared to saline group (p=0.00. However, administration of Genistein and Genistein plus morphine significantly boosted motility, morphology, count, viability of sperm cells, seminiferous tubules diameter, germinal thickness, testosterone, LH and FSH while decrease nitric oxide level in all groups compared to morphine group (p<0.025. Conclusion: It seems that Genistein administration could increase the quality of spermatozoa and prevent morphine- induced adverse effects on sperm parameters.

  1. Abnormal nociception and opiate sensitivity of STOP null mice exhibiting elevated levels of the endogenous alkaloid morphine

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    Aunis Dominique

    2010-12-01

    Full Text Available Abstract Background- Mice deficient for the stable tubule only peptide (STOP display altered dopaminergic neurotransmission associated with severe behavioural defects including disorganized locomotor activity. Endogenous morphine, which is present in nervous tissues and synthesized from dopamine, may contribute to these behavioral alterations since it is thought to play a role in normal and pathological neurotransmission. Results- In this study, we showed that STOP null brain structures, including cortex, hippocampus, cerebellum and spinal cord, contain high endogenous morphine amounts. The presence of elevated levels of morphine was associated with the presence of a higher density of mu opioid receptor with a higher affinity for morphine in STOP null brains. Interestingly, STOP null mice exhibited significantly lower nociceptive thresholds to thermal and mechanical stimulations. They also had abnormal behavioural responses to the administration of exogenous morphine and naloxone. Low dose of morphine (1 mg/kg, i.p. produced a significant mechanical antinociception in STOP null mice whereas it has no effect on wild-type mice. High concentration of naloxone (1 mg/kg was pronociceptive for both mice strain, a lower concentration (0.1 mg/kg was found to increase the mean mechanical nociceptive threshold only in the case of STOP null mice. Conclusions- Together, our data show that STOP null mice displayed elevated levels of endogenous morphine, as well as an increase of morphine receptor affinity and density in brain. This was correlated with hypernociception and impaired pharmacological sensitivity to mu opioid receptor ligands.

  2. Role of hippocampal and prefrontal cortical signaling pathways in dextromethorphan effect on morphine-induced memory impairment in rats.

    Science.gov (United States)

    Ghasemzadeh, Zahra; Rezayof, Ameneh

    2016-02-01

    Evidence suggests that dextromethorphan (DM), an NMDA receptor antagonist, induces memory impairment. Considering that DM is widely used in cough-treating medications, and the co-abuse of DM with morphine has recently been reported, the aims of the present study was (1) to investigate whether there is a functional interaction between morphine and DM in passive avoidance learning and (2) to assess the possible role of the hippocampal and prefrontal cortical (PFC) signaling pathways in the effects of the drugs on memory formation. Our findings indicated that post-training or pre-test administration of morphine (2 and 6 mg/kg) or DM (10-30 mg/kg) impaired memory consolidation and retrieval which was associated with the attenuation of the levels of phosphorylated Ca(2+)/calmodulin-dependent protein kinase II (p-CAMKII) and cAMP responsive element-binding protein (p-CREB) in the targeted sites. Moreover, the memory impairment induced by post-training administration of morphine was reversed by pre-test administration of the same dose of morphine or DM (30 mg/kg), indicating state-dependent learning (SDL) and a cross-SDL between the drugs. It is important to note that the levels of p-CAMKII/CAMKII and p-CREB/CREB in the hippocampus and the PFC increased in drugs-induced SDL. In addition, DM administration potentiated morphine-induced SDL which was related to the enhanced levels of hippocampal and PFC CAMKII-CREB signaling pathways. It can be concluded that there is a relationship between the hippocampus and the PFC in the effect of DM and/or morphine on memory retrieval. Moreover, a cross SDL can be induced between the co-administration of DM and morphine. Interestingly, CAMKII-CREB signaling pathways also mediate the drugs-induced SDL. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Effect of agmatine on the development of morphine dependence in rats: potential role of cAMP system

    Science.gov (United States)

    Aricioglu, Feyza; Means, Andrea; Regunathan, Soundar

    2010-01-01

    Agmatine is an endogenous amine derived from arginine that potentiates morphine analgesia and blocks symptoms of naloxone-precipitated morphine withdrawal in rats. In this study, we sought to determine whether treatment with agmatine during the development of morphine dependence inhibits the withdrawal symptoms and that the effect is mediated by cAMP system. Exposure of rats to morphine for 7 days resulted in marked naloxone-induced withdrawal symptoms and agmatine treatment along with morphine significantly decreasing the withdrawal symptoms. The levels of cAMP were markedly increased in morphine-treated rat brain slices when incubated with naloxone and this increase was significantly reduced in rats treated with morphine and agmatine. The induction of tyrosine hydroxylase after morphine exposure was also reduced in locus coeruleus when agmatine was administered along with morphine. We conclude that agmatine reduces the development of dependence to morphine and that this effect is probably mediated by the inhibition of cAMP signaling pathway during chronic morphine exposure. PMID:15541421

  4. Is pre-emptive administration of ketamine a significant adjunction to intravenous morphine analgesia for controlling postoperative pain? A randomized, double-blind, placebo-controlled clinical trial.

    Science.gov (United States)

    Fiorelli, Alfonso; Mazzella, Antonio; Passavanti, Beatrice; Sansone, Pasquale; Chiodini, Paolo; Iannotti, Mario; Aurilio, Caterina; Santini, Mario; Pace, Maria Caterina

    2015-09-01

    To evaluate if the pre-emptive administration of ketamine would potentiate the effect of intravenous morphine analgesia in the management of post-thoracotomy pain. This was a unicentre, double-blind, placebo-controlled, parallel-group, prospective study. Patients were randomly assigned to receive 1 mg/kg ketamine (ketamine group) or an equivalent dose of normal saline (placebo group) before thoracotomy in 1:1 ratio. All patients received postoperatively intravenous morphine administration as additional analgesic regimen. Primary end-point was the pain relief measured with Visual Analogue Scale at rest. The secondary end-points were the reduction of inflammatory response expressed by plasma C-reactive protein levels, the morphine consumption and the rate of side effects. The measurements were carried out 6, 12, 24, 36 and 48 hours postoperatively. A total of 75 patients were randomized of whom 38 were allocated to ketamine group and 37 to placebo group. Baseline characteristics were comparable. Ketamine compared with placebo group showed a significant reduction of pain scores (P = 0.01), C-reactive protein (P morphine consumption (P psychological side effects related to the use of ketamine were registered. The administration of ketamine before surgery may be an effective adjunct to intravenous morphine analgesia in acute post-thoracotomy pain management. In ketamine group, satisfaction of pain relief was significantly higher with a significant reduction of inflammatory response and morphine consumption compared with placebo group. Our results, if confirmed by larger studies, may be of clinical relevance in situations where epidural analgesia or other analgesic procedures different from systemic opioid analgesia are unavailable or contraindicated. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  5. Characterisation of tramadol, morphine and tapentadol in an acute pain model in Beagle dogs.

    Science.gov (United States)

    Kögel, Babette; Terlinden, Rolf; Schneider, Johannes

    2014-05-01

    To evaluate the analgesic potential of the centrally acting analgesics tramadol, morphine and the novel analgesic tapentadol in a pre-clinical research model of acute nociceptive pain, the tail-flick model in dogs. Prospective part-randomized pre-clinical research trial. Fifteen male Beagle dogs (HsdCpb:DOBE), aged 12-15 months. On different occasions separated by at least 1 week, dogs received intravenous (IV) administrations of tramadol (6.81, 10.0 mg kg(-1) ), tapentadol (2.15, 4.64, 6.81 mg kg(-1) ) or morphine (0.464, 0.681, 1.0 mg kg(-1) ) with subsequent measurement of tail withdrawal latencies from a thermal stimulus (for each treatment n = 5). Blood samples were collected immediately after the pharmacodynamic measurements of tramadol to determine pharmacokinetics and the active metabolite O-demethyltramadol (M1). Tapentadol and morphine induced dose-dependent antinociception with ED50-values of 4.3 mg kg(-1) and 0.71 mg kg(-1) , respectively. In contrast, tramadol did not induce antinociception at any dose tested. Measurements of the serum levels of tramadol and the M1 metabolite revealed only marginal amounts of the M1 metabolite, which explains the absence of the antinociceptive effect of tramadol in this experimental pain model in dogs. Different breeds of dogs might not or only poorly respond to treatment with tramadol due to low metabolism of the drug. Tapentadol and morphine which act directly on μ-opioid receptors without the need for metabolic activation are demonstrated to induce potent antinociception in the experimental model used and should also provide a reliable pain management in the clinical situation. The non-opioid mechanisms of tramadol do not provide antinociception in this experimental setting. This contrasts to many clinical situations described in the literature, where tramadol appears to provide useful analgesia in dogs for post-operative pain relief and in more chronically pain states. © 2014 Association of Veterinary

  6. Effects of chronic morphine and morphine withdrawal on gene expression in rat peripheral blood mononuclear cells.

    OpenAIRE

    Desjardins , Stephane; Belkai , Emilie; Crete , Dominique; Cordonnier , Laurie; Scherrmann , Jean-Michel; Noble , Florence; Marie-Claire , Cynthia

    2008-01-01

    International audience; Chronic morphine treatment alters gene expression in brain structures. There are increasing evidences showing a correlation, in gene expression modulation, between blood cells and brain in psychological troubles. To test whether gene expression regulation in blood cells could be found in drug addiction, we investigated gene expression profiles in peripheral blood mononuclear (PBMC) cells of saline and morphine-treated rats. In rats chronically treated with morphine, th...

  7. Evaluation of the Effectiveness of Two Morphine Protocols to Treat Neonatal Abstinence Syndrome in a Level II Nursery in a Community Hospital.

    Science.gov (United States)

    DeAtley, Heather N; Burton, Amanda; Fraley, Michelle DeLuca; Haltom, Joan

    2017-07-01

    The authors sought to evaluate the impact on length of hospital stay and treatment duration of morphine after implementation of a change in the institutional protocol for managing neonatal abstinence syndrome (NAS) in an effort to improve patient outcomes. A single-center, retrospective chart review was conducted at a Level II nursery in a community hospital in Kentucky. Fifty-nine neonates born between January 1, 2014, and December 31, 2015, who were diagnosed with NAS and received morphine for treatment were included. The protocol 1 group consisted of 33 neonates who received an initial dose of morphine 0.04 mg/kg/dose administered orally every 4 hours (January 1-December 31, 2014), and the protocol 2 group consisted of 26 neonates who received an initial dose of morphine 0.06 mg/kg/dose administered orally every 3 hours (January 1-November 30, 2015), after a change in the protocol for managing NAS was implemented on January 1, 2015. Data were reviewed and compared between the two protocol groups to determine the impact that the dosage change had on length of hospital stay and morphine treatment duration. The average length of stay decreased by 7 days in the protocol 2 group compared with the protocol 1 group (21 vs 28.65 days). The average duration of treatment decreased by 7 days in the protocol 2 group compared with the protocol 1 group (18.3 vs 25.4 days). These differences between groups were not statistically significant, however, because the population size was not large enough to achieve adequate power. These results indicate that protocol 2 displayed the potential to decrease length of stay and duration of treatment compared with protocol 1 at this facility; however, balancing higher starting doses with the risk of oversedation will continue to challenge the health care team. Concern for oversedation when using the higher starting dose in protocol 2 has prompted further research (e.g., protocol 3, initial morphine 0.05 mg/kg/dose every 3 hrs). Continued

  8. Relationships among morphine metabolism, pain and side effects during long-term treatment

    DEFF Research Database (Denmark)

    Andersen, Gertrud; Christrup, Lona Louring; Sjøgren, Per

    2003-01-01

    The two metabolites of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), have been studied intensively in animals and humans during the past 30 years in order to elucidate their precise action and possible contribution to the desired effects and side effects seen after...... morphine administration. M3G and M6G are formed by morphine glucuronidation, mainly in the liver, and are excreted by the kidneys. The metabolites are found in the cerebrospinal fluid after single as well as multiple doses of morphine. M6G binds to opioid receptors, and animal studies have demonstrated...... of the studies have used lower doses of M6G than of morphine. M3G displays very low affinity for opioid receptors and has no analgesic activity. Animal studies have shown that M3G may antagonize the analgesic effect of morphine and M6G, but no human studies have demonstrated this. M3G has also been connected...

  9. Investigation and analysis of oncologists' knowledge of morphine usage in cancer pain treatment

    Directory of Open Access Journals (Sweden)

    Liu W

    2014-05-01

    also identified major impediment factors on clinical use of morphine.Results: Among the 127 respondents, morphine controlled-release tablets were the most popular drug chosen to treat severe cancer pain (76 respondents, 35.8%. Participants who reported having received training in cancer pain management and drug use demonstrated a significantly higher mean score of basic knowledge compared with their untrained peers (11.51±2.60 versus 9.28±3.68, t=2.48, P=0.022. The top four barriers to widespread clinical use of morphine for cancer pain were 1 insufficient analgesia administration training for medical personnel, 2 poor patient compliance, 3 drug side effects, and 4 concerns surrounding drug addiction.Conclusion: The oncologists in the People's Republic of China simultaneously lack comprehensive knowledge and harbor misconceptions with regard to cancer pain treatment and morphine's clinical application. Creating professional training initiatives for oncologists is necessary to enhance their awareness and expertise in morphine use for cancer pain treatment.Keywords: pain management, training, clinical application

  10. Morphine Produces Immunosuppressive Effects in Non-human Primates at the Proteomic and Cellular Levels

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Joseph N.; Ortiz, Gabriel M.; Angel, Thomas E.; Jacobs, Jon M.; Gritsenko, Marina A.; Chan, Eric Y.; Purdy, David E.; Murnane, Robert D.; Larsen, Kay; Palermo, Robert E.; Shukla, Anil K.; Clauss, Therese RW; Katze, Michael G.; McCune, Joseph M.; Smith, Richard D.

    2012-05-11

    Morphine has long been known to have immunosuppressive properties in vivo, but the molecular and immunologic changes induced by it are incompletely understood. As a prelude to understanding how these changes might interact with lentiviral infection in vivo, animals from two non-human primate (NHP) species [African green monkey (AGMs) and pigtailed macaque (PTs)] were provided morphine and studied using a systems biology approach. Biological specimens were obtained from multiple sources (e.g., lymph node, colon, cerebrospinal fluid (CSF), and peripheral blood) before and after the administration of morphine (titrated up to a maximum dose of 5 mg/kg over a period of 20 days). Cellular immune, plasma cytokine, and proteome changes were measured and morphine-induced changes in these parameters were assessed on an inter-organ, inter-individual, and inter-species basis. In both species, morphine was associated with decreased levels of (Ki-67+) T cell activation but with only minimal changes in overall T cell counts, neutrophil counts, and NK cells counts. While changes in T cell maturation were observed, these varied across the various tissue/fluid compartments studied. Proteomic analysis revealed a morphine-induced suppressive effect in the lymph node, with decreased abundance of protein mediators involved in the functional categories of energy metabolism, signaling, and maintenance of cell structure. These findings have relevance for understanding the impact of heroin addiction and the opioids used to treat addiction as well as on the interplay between opioid abuse and the response to infection with agents such as the human immunodeficiency virus, type 1 (HIV).

  11. The Role of Endogenous D2 Receptor Levels in Morphine Addiction: A Correlative Study of Morphine Place Conditioning and In Vivo [3H]-Raclopride Binding

    Energy Technology Data Exchange (ETDEWEB)

    Khan, N.; Gatley, S.

    2004-01-01

    Dopamine is a neurotransmitter that has a wide array of effects on an individual’s mental state. It is vital in the regulation of motor skills and in generating the effects of substance abuse. This study examined the dopamine D2 receptors found in the striatum of the brain. The impetus for investigating this receptor lies in the perception that it plays an influential role in drug addiction. It has been conjectured on the basis of human PET studies that possession of low levels of D2 receptors will heighten an individual’s susceptibility to drug addiction. However, an alternative explanation of low D2 receptor levels in drug dependent individuals is that these levels are a consequence of drug abuse. To understand this phenomenon, the present study employed the paradigm of conditioned place preference (CPP). In CPP, individuals of an out-bred mouse strain are observed to spend time in environments where they had previously been exposed to a drug that is abused by humans. The drug chosen for our studies was morphine because it has been previously shown to generate a robust place preference in mice and is a prototypic abused drug in humans. D2 receptor levels were quantified using an in vivo binding study involving [3H]raclopride, a radioactive compound that binds to D2 receptors. The results showed a significant place preference for morphine following the conditioning procedure. Additionally, data from the binding analysis agreed with previous studies that the striatum contains high levels of D2 receptors. However, there was no consistent relationship between the extent of morphine CPP and D2 receptor levels as revealed by [3H]-RAC binding. This finding does not support the hypothesis that low levels of D2 receptors predispose a mouse to easy morphine conditioning. Further experiments are required to determine the ability to generalize our findings to other species and other drugs of abuse.

  12. Morphine Preconditioning Downregulates MicroRNA-134 Expression Against Oxygen-Glucose Deprivation Injuries in Cultured Neurons of Mice.

    Science.gov (United States)

    Meng, Fanjun; Li, Yan; Chi, Wenying; Li, Junfa

    2016-07-01

    Brain protection by narcotics such as morphine is clinically relevant due to the extensive use of narcotics in the perioperative period. Morphine preconditioning induces neuroprotection in neurons, but it remains uncertain whether microRNA-134 (miR-134) is involved in morphine preconditioning against oxygen-glucose deprivation-induced injuries in primary cortical neurons of mice. The present study examined this issue. After cortical neurons of mice were cultured in vitro for 6 days, the neurons were transfected by respective virus vector, such as lentiviral vector (LV)-miR-control-GFP, LV-pre-miR-134-GFP, LV-pre-miR-134-inhibitor-GFP for 24 hours; after being normally cultured for 3 days again, morphine preconditioning was performed by incubating the transfected primary neurons with morphine (3 μM) for 1 hour, and then neuronal cells were exposed to oxygen-glucose deprivation (OGD) for 1 hour and oxygen-glucose recovery for 12 hours. The neuronal cells survival rate and the amount of apoptotic neurons were determined by MTT assay or TUNEL staining at designated time; and the expression levels of miR-134 were detected using real-time reverse transcription polymerase chain reaction at the same time. The neuronal cell survival rate was significantly higher, and the amount of apoptotic neurons was significantly decreased in neurons preconditioned with morphine before OGD than that of OGD alone. The neuroprotection induced by morphine preconditioning was partially blocked by upregulating miR-134 expression, and was enhanced by downregulating miR-134 expression. The expression of miR-134 was significantly decreased in morphine-preconditioned neurons alone without transfection. By downregulating miR-134 expression, morphine preconditioning protects primary cortical neurons of mice against injuries induced by OGD.

  13. Eldecalcitol normalizes bone turnover markers regardless of their pre-treatment levels.

    Science.gov (United States)

    Shiraki, Masataka; Saito, Hitoshi; Matsumoto, Toshio

    2012-09-01

    Three-year treatment with eldecalcitol has been shown to improve lumbar and total hip bone mineral density (BMD), decrease bone turnover markers, and lower the incidences of vertebral and wrist fractures in patients with osteoporosis more than with treatment with alfacalcidol under vitamin D repletion. The purpose of this study was to determine whether there was a risk of eldecalcitol causing severely suppressed bone turnover in osteoporosis patients with low pre-treatment levels of bone turnover markers. Post-hoc analysis was conducted on the data from a 3-year, randomized, double-blind, active-comparator, clinical trial of eldecalcitol versus alfacalcidol under vitamin D repletion conducted in Japan. Enrolled patients with baseline measurements of bone turnover markers were stratified into tertiles according to their pre-treatment levels of serum bone-specific alkaline phosphatase, serum procollagen type I N-terminal propeptide, or urinary collagen-N-telopeptide. Eldecalcitol treatment rapidly reduced bone turnover markers, and kept them within the normal range. However, in the patients whose baseline values for bone turnover were low, eldecalcitol treatment did not further reduce bone turnover markers during the 3-year treatment period. Further long-term observation may be required to reach the conclusion. CLINICALTRIALS.GOV NUMBER: NCT00144456. Eldecalcitol normalizes, but does not overly suppress, bone turnover regardless of baseline levels of bone turnover markers. Thus, it is unlikely that eldecalcitol treatment will increase the risk of severely suppressed bone turnover and therefore deterioration of bone quality, at least for a treatment duration of 3 years.

  14. Morphine metabolites

    DEFF Research Database (Denmark)

    Christrup, Lona Louring

    1997-01-01

    , morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are the major metabolites of morphine. The metabolism of morphine occurs not only in the liver, but may also take place in the brain and the kidneys. The glucuronides are mainly eliminated via bile and urine. Glucuronides as a rule...... are considered as highly polar metabolites unable to cross the blood-brain barrier. Although morphine glucuronidation has been demonstrated in human brain tissue, the capacity is very low compared to that of the liver, indicating that the M3G and M6G concentrations observed in the cerebrospinal fluid (CSF) after...... systemic administration reflect hepatic metabolism of morphine and that the morphine glucuronides, despite their high polarity, can penetrate into the brain. Like morphine, M6G has been shown to be relatively more selective for mu-receptors than for delta- and kappa-receptors while M3G does not appear...

  15. The Comparison of Intrathecal Morphine and IV Morphine PCA on Pain Control, Patient Satisfaction, Morphine Consumption, and Adverse Effects in Patients Undergoing Reduction Mammoplasty.

    Science.gov (United States)

    Karamese, Mehtap; Akdağ, Osman; Kara, İnci; Yıldıran, Gokce Unal; Tosun, Zekeriya

    2015-01-01

    Following breast reduction procedures, the level of postoperative pain can be severe, and sufficient pain control influences a patient's physiological, immunological, and psychological status. The aim of this study was to examine the use of intrathecal morphine (ITM) in breast reduction surgery with patient-controlled analgesia (PCA). Sixty-two female patients who underwent breast reductions with the same technique participated in this study. The study group (ITM + PCA) included 32 patients; a single shot (0.2 mg) of ITM and intravenous morphine with PCA were administered. In the control group, morphine PCA alone was intravenously administered to 30 patients. Comparisons between the groups of cumulative morphine consumption, visual analog scale scores, and patient satisfaction scores, which were the primary outcome measures, and adverse effects, which were the secondary outcome measures, were conducted. The patients in the 2 groups had similar degrees of pain and satisfaction scores. The study group had lower cumulative morphine consumption (P = .001) than the PCA-only control group; there was no statistically significant difference in adverse effects between the 2 groups. Intrathecal morphine may effectively control pain with lower total morphine consumption following breast reduction surgery.

  16. Premedication with gabapentin, alprazolam or a placebo for abdominal hysterectomy: Effect on pre-operative anxiety, post-operative pain and morphine consumption

    Directory of Open Access Journals (Sweden)

    Tim Thomas Joseph

    2014-01-01

    Full Text Available Background and Aims : Utility of gabapentin for pre-operative anxiolysis as compared to commonly administered alprazolam is not evident. The aim of the present study was to compare the effects of pre-operative oral gabapentin 600 mg, alprazolam 0.5 mg or a placebo on pre-operative anxiety along with post-operative pain and morphine consumption. Methods: Seventy five patients scheduled for abdominal hysterectomy under general anaesthesia were included. Groups gabapentin, alprazolam and placebo, received oral gabapentin 600 mg, alprazolam 0.5 mg and one capsule of oral B-complex forte with Vitamin C respectively, on the night prior to surgery and 2 h prior to surgery. Visual analogue scale (VAS was used to measure the anxiety and post-operative pain. All patients received patient-controlled analgesia. Statistical tests used were Kruskal-Wallis test, Wilcoxon signed rank test and one-way ANOVA. Results: Alprazolam provided significant anxiolysis (median [interquartile range] baseline VAS score 35 [15.5, 52] to 20 [6.5, 34.5] after drug administration; P = 0.007. Gabapentin did not provide significant decrease in anxiety (median [interquartile range] VAS score 21 [7.5, 41] to 20 [6.5, 34.5]; P = 0.782. First analgesic request time (median [interquartile range in minutes] was longer in group gabapentin (17.5 [10, 41.25] compared to group placebo (10 [5, 15] (P = 0.019 but comparable to that in group alprazolam (15 [10, 30]. Cumulative morphine consumption at different time periods and total morphine consumption (mean [standard deviation] at the end of study period (38.65 [18.04], 39.91 [15.73], 44.29 [16.02] mg in group gabapentin, alprazolam and placebo respectively were comparable. Conclusion: Gabapentin 600 mg does not have significant anxiolytic effect compared to alprazolam 0.5 mg. Alprazolam 0.5 mg was found to be an effective anxiolytic in the pre-operative period. Neither alprazolam nor gabapentin, when compared to placebo showed any opioid

  17. Effects of environmental enrichment during abstinence in morphine dependent parents on anxiety, depressive-like behaviors and voluntary morphine consumption in rat offspring.

    Science.gov (United States)

    Pooriamehr, Alireza; Sabahi, Parviz; Miladi-Gorji, Hossein

    2017-08-24

    Chronic morphine exposure during puberty increased morphine-induced rewarding effects and sensitization in the next generation. Given the well-known beneficial effects of environmental enrichment on the severity of physical and psychological dependence on morphine, we examined effects of enriched environment during morphine abstinence in morphine dependent parental rats before mating on the anxiety and depressive-like behaviors, and voluntary morphine consumption in their offspring. Paternal and/or maternal rats were injected with bi-daily doses (10mg/kg, 12h intervals) of morphine for 14days followed by rearing in a standard environment (SE) or enriched environment (EE) during 30days of morphine abstinence before mating. The pubertal male and female rat offspring were tested for anxiety (the elevated plus maze- EPM) and depression (sucrose preference test-SPT), and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that EE experience in morphine-dependent both parents result in an increase in the percentage of time spent into open arms/time spent on both arms using EPM in male offspring, higher levels of sucrose preference in female offspring and lower levels of voluntary morphine consumption in male and female offspring. Thus, EE experience in morphine-dependent both parents reduced anxiety, depressive-like behavior and also the voluntary morphine consumption in their offspring during puberty which may prevent the vulnerability of the next generation to drug abuse. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Withdrawal of repeated morphine enhances histamine-induced scratching responses in mice.

    Science.gov (United States)

    Abe, Kenji; Kobayashi, Kanayo; Yoshino, Saori; Taguchi, Kyoji; Nojima, Hiroshi

    2015-04-01

    An itch is experientially well known that the scratching response of conditions such as atopic dermatitis is enhanced under psychological stress. Morphine is typical narcotic drug that induces a scratching response upon local application as an adverse drug reaction. Although long-term treatment with morphine will cause tolerance and dependence, morphine withdrawal can cause psychologically and physiologically stressful changes in humans. In this study, we evaluated the effects of morphine withdrawal on histamine-induced scratching behavior in mice. Administration of morphine with progressively increasing doses (10-50 mg/kg, i.p.) was performed for 5 consecutive days. At 3, 24, 48, and 72 hr after spontaneous withdrawal from the final morphine dose, histamine was intradermally injected into the rostral part of the back and then the number of bouts of scratching in 60 min was recorded and summed. We found that at 24 hr after morphine withdrawal there was a significant increase in histamine-induced scratching behavior. The spinal c-Fos positive cells were also significantly increased. The relative adrenal weight increased and the relative thymus weight decreased, both significantly. Moreover, the plasma corticosterone levels changed in parallel with the number of scratching bouts. These results suggest that morphine withdrawal induces a stressed state and enhances in histamine-induced scratching behavior. Increased reaction against histamine in the cervical vertebrae will participate in this stress-induced itch enhancement.

  19. Comparison of Pre and Post-Treatment Orexin A Levels in Patients with Subclinical Hypothyroidism

    Directory of Open Access Journals (Sweden)

    Muhammed Erdal

    2010-01-01

    Full Text Available Aim: Subclinical hypothyroidism is a clinical condition mostly observed in women, the prevalence of which increases by age. Sleepiness and appetite problems are observed in subclinical hypothyroidism. Orexins play a role in the physiological regulations like the stabilization of cardiovascular functions and the sleep-alert cycle. Similarities in the physiological regulation areas of orexins and the clinical findings of hypothyroidism were influential in the planning of this research. Additionally, homosisteine, which is influential on the cardiovascular system and the plasma level of which changes by eating (as is the case with orexins, was also analyzed. Besides, the change in the lipid profiles of the patients was also observed. Material and Methods: Nineteen pre-menopausal female patients (mean age=39.58±12.58, mean BMI= 26.7±4.9 included in this study. Following 12 hours fasting blood samples were taken from brachial vein. All patients were given 50µg/day L-T4 TSH levels were examined in every 4-6 weeks to adjust the L-T4 doses. When euthyroidism was ensured, a re-evaluation was made 4 months later. Results:  Pre-treatment plasma orexin A levels of 19 patients with pre-menopausal subclinical hypothyroidism increased significantly following a treatment of l-tiroxin for 4 months (pre-treatment orexin level median=1.20 mg/dl (mean: 1.33±0.28 post-treatment median=1.82 mg/dl (mean: 1.70±0.42 p=0.007. A significant change in the level of plasma total homosisteine and lipid profile was not detected. Conclusions: Advanced studies are needed to study the physiological effects of orexin levels in cases with subclinical hypothyroidism and the possible benefits in treatment.

  20. Dopamine D4 Receptor Counteracts Morphine-Induced Changes in µ Opioid Receptor Signaling in the Striosomes of the Rat Caudate Putamen

    Directory of Open Access Journals (Sweden)

    Diana Suárez-Boomgaard

    2014-01-01

    Full Text Available The mu opioid receptor (MOR is critical in mediating morphine analgesia. However, prolonged exposure to morphine induces adaptive changes in this receptor leading to the development of tolerance and addiction. In the present work we have studied whether the continuous administration of morphine induces changes in MOR protein levels, its pharmacological profile, and MOR-mediated G-protein activation in the striosomal compartment of the rat CPu, by using immunohistochemistry and receptor and DAMGO-stimulated [35S]GTPγS autoradiography. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment in the absence of changes in enkephalin and dynorphin mRNA levels. In addition, co-treatment of morphine with the dopamine D4 receptor (D4R agonist PD168,077 fully counteracts these adaptive changes in MOR, in spite of the fact that continuous PD168,077 treatment increases the [3H]DAMGO Bmax values to the same degree as seen after continuous morphine treatment. Thus, in spite of the fact that both receptors can be coupled to Gi/0 protein, the present results give support for the existence of antagonistic functional D4R-MOR receptor-receptor interactions in the adaptive changes occurring in MOR of striosomes on continuous administration of morphine.

  1. Morphine hyposensitivity in streptozotocin-diabetic rats: Reversal by dietary l-arginine treatment.

    Science.gov (United States)

    Lotfipour, Shahrdad; Smith, Maree T

    2018-01-01

    Painful diabetic neuropathy (PDN) is a long-term complication of diabetes. Defining symptoms include mechanical allodynia (pain due to light pressure or touch) and morphine hyposensitivity. In our previous work using the streptozotocin (STZ)-diabetic rat model of PDN, morphine hyposensitivity developed in a temporal manner with efficacy abolished at 3 months post-STZ and maintained for 6 months post-STZ. As this time course mimicked that for the temporal development of hyposensitivity to the pain-relieving effects of the furoxan nitric oxide (NO) donor, PRG150 (3-methylfuroxan-4-carbaldehyde) in STZ-diabetic rats, we hypothesized that progressive depletion of endogenous NO bioactivity may underpin the temporal loss of morphine sensitivity in STZ-diabetic rats. Furthermore, we hypothesized that replenishment of NO bioactivity may restore morphine sensitivity in these animals. Diabetes was induced in male Dark Agouti rats by intravenous injection of STZ (85 mg/kg). Diabetes was confirmed on day 7 if blood glucose concentrations were ≥15 mmol/L. Mechanical allodynia was fully developed in the bilateral hindpaws by 3 weeks of STZ-diabetes in rats and this was maintained for the study duration. Morphine hyposensitivity developed in a temporal manner with efficacy abolished by 3 months post-STZ. Administration of dietary l-arginine (NO precursor) at 1 g/d to STZ-diabetic rats according to a 15-week prevention protocol initiated at 9 weeks post-STZ prevented abolition of morphine efficacy. When given as an 8-week intervention protocol in rats where morphine efficacy was abolished, dietary l-arginine at 1 g/d progressively rescued morphine efficacy and potency. Our findings implicate NO depletion in the development of morphine hyposensitivity in STZ-diabetic rats. © 2017 John Wiley & Sons Australia, Ltd.

  2. No morphine sparing effect of ketamine added to morphine for patient-controlled intravenous analgesia after uterine artery embolization

    DEFF Research Database (Denmark)

    Jensen, Luana Leonora; Handberg, Gitte; Helbo-Hansen, H S

    2008-01-01

    BACKGROUND: Pain following embolization of the uterine arteries (UAEs) is variable and may be very severe requiring large doses of parenteral opioids for relief. The present study tested the hypothesis that the addition of ketamine to i.v. patient-controlled morphine reduces the amount of morphine...... required for pain-control during the first 24 h after UAE embolization. METHODS: Fifty-six patients undergoing UAE embolization for treatment of symptomatic uterine leiomyomata were randomized to receive either 2 mg/ml of morphine (Control group, n=30) or 2 mg/ml of both morphine and ketamine (Ketamine......, visual disturbances, anxiety, dreaming and hallucinations, if any, were recorded for 24 h after embolization. RESULTS: The mean +/- SD 24-h consumption of patient-controlled morphine was 38.3 +/- 21.0 mg in the Ketamine group vs. 33.3 +/- 18.3 mg in the Control group (NS). The difference between...

  3. Changing M3G/M6G ratios and pharmacodynamics in a cancer patient during long-term morphine treatment

    DEFF Research Database (Denmark)

    Andersen, Gertrud; Christrup, Lona Louring; Sjøgren, Per

    2002-01-01

    A cancer patient receiving long-term oral sustained-release morphine treatment and periodically presenting with unusually high plasma M3G/M6G ratios is described. We found the patient's formation of M6G more unstable and perhaps delayed compared to the formation of M3G. There is no apparent...... explanation for this phenomenon and the high M3G/M6G ratios had no implications for the patient's pain experience or side effects from the morphine treatment....

  4. Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats.

    Science.gov (United States)

    Wang, Xiao-Fei; Zhao, Tai-Yun; Su, Rui-Bin; Wu, Ning; Li, Jin

    2016-12-01

    Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

  5. Metabolism and pharmacokinetics of morphine in neonates: A review

    Directory of Open Access Journals (Sweden)

    Gian Maria Pacifici

    Full Text Available Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords “morphine metabolism neonate” and “morphine pharmacokinetics neonate”. The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.

  6. Synergistic Effects of Social Isolation and Morphine Addiction on Reduced Neurogenesis and BDNF Levels and the Resultant Deficits in Cognition and Emotional State in Male Rats.

    Science.gov (United States)

    Famitafreshi, Hamidreza; Karimian, Morteza; Fatima, Sulail

    2016-01-01

    Addiction to drugs of abuse is a devastating condition which results in deterioration of brain function. On the other hand, social isolation also produces cognitive deficits such as learning and memory impairment. This study was designed to evaluate the potential negative synergistic effects of social isolation and morphine addiction on brain functions. One hundred and two Sprague-Dawley rats were randomly divided into four groups for assessing neurogenesis and behaviour: group-housed, isolated, morphine-treated group-housed and morphine-treated isolated groups. Morphine- treated animals received BrdU (50 mg/kg; i.p.) and Morphine (0.75 mg/rat; i.p.) for 14 consecutive days, whereas, control rats received BrdU (50 mg/kg; i.p.) only. At the end of the study, Morris water maze and elevated plus maze tasks were performed to assess spatial working memory and anxiety levels, respectively. Furthermore, neurogenesis and BDNF levels were studied. Reference and working memory was markedly impaired in isolated and morphine-treated isolated rats as compared to group-housed rats and morphine-treated group-housed rats, respectively. Neurogenesis and BDNF levels were reduced in isolated and morphine-treated isolated rats as compared to group-housed rats and morphine-treated group-housed rats, respectively. Furthermore, rats in both isolated groups demonstrated low anxiety levels when compared to group housed groups. Isolation during addiction imparts devastating effects on brain. Thus, socialization of addicts can minimize addiction - induce cognitive deficits and improve neurogenesis.

  7. Acute morphine activates satellite glial cells and up-regulates IL-1β in dorsal root ganglia in mice via matrix metalloprotease-9

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    Berta Temugin

    2012-03-01

    Full Text Available Abstract Background Activation of spinal cord glial cells such as microglia and astrocytes has been shown to regulate chronic opioid-induced antinociceptive tolerance and hyperalgesia, due to spinal up-regulation of the proinflammatory cytokines such as interleukin-1 beta (IL-1β. Matrix metalloprotease-9 (MMP-9 has been implicated in IL-1β activation in neuropathic pain. However, it is unclear whether acute opioid treatment can activate glial cells in the peripheral nervous system. We examined acute morphine-induced activation of satellite glial cells (SGCs and up-regulation of IL-1β in dorsal root ganglia (DRGs, and further investigated the involvement of MMP-9 in these opioid-induced peripheral changes. Results Subcutaneous morphine injection (10 mg/kg induced robust peripheral glial responses, as evidenced by increased GFAP expression in DRGs but not in spinal cords. The acute morphine-induced GFAP expression is transient, peaking at 2 h and declining after 3 h. Acute morphine treatment also increased IL-1β immunoreactivity in SGCs and IL-1β activation in DRGs. MMP-9 and GFAP are expressed in DRG neurons and SGCs, respectively. Confocal analysis revealed a close proximity of MMP-9 and GFAP immunostaining. Importantly, morphine-induced DRG up-regulation of GFAP expression and IL-1β activation was abolished after Mmp9 deletion or naloxone pre-treatment. Finally, intrathecal injections of IL-1β-selective siRNA not only reduced DRG IL-1β expression but also prolonged acute morphine-induced analgesia. Conclusions Acute morphine induces opioid receptors- and MMP-9-dependent up-regulation of GFAP expression and IL-1β activation in SGCs of DRGs. MMP-9 could mask and shorten morphine analgesia via peripheral neuron-glial interactions. Targeting peripheral glial activation might prolong acute opioid analgesia.

  8. Hippocampal GluA1-containing AMPA receptors mediate context-dependent sensitization to morphine.

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    Xia, Yan; Portugal, George S; Fakira, Amanda K; Melyan, Zara; Neve, Rachael; Lee, H Thomas; Russo, Scott J; Liu, Jie; Morón, Jose A

    2011-11-09

    Glutamatergic systems, including AMPA receptors (AMPARs), are involved in opiate-induced neuronal and behavioral plasticity, although the mechanisms underlying these effects are not fully understood. In the present study, we investigated the effects of repeated morphine administration on AMPAR expression, synaptic plasticity, and context-dependent behavioral sensitization to morphine. We found that morphine treatment produced changes of synaptic AMPAR expression in the hippocampus, a brain area that is critically involved in learning and memory. These changes could be observed 1 week after the treatment, but only when mice developed context-dependent behavioral sensitization to morphine in which morphine treatment was associated with drug administration environment. Context-dependent behavioral sensitization to morphine was also associated with increased basal synaptic transmission and disrupted hippocampal long-term potentiation (LTP), whereas these effects were less robust when morphine administration was not paired with the drug administration environment. Interestingly, some effects may be related to the prior history of morphine exposure in the drug-associated environment, since alterations of AMPAR expression, basal synaptic transmission, and LTP were observed in mice that received a saline challenge 1 week after discontinuation of morphine treatment. Furthermore, we demonstrated that phosphorylation of GluA1 AMPAR subunit plays a critical role in the acquisition and expression of context-dependent behavioral sensitization, as this behavior is blocked by a viral vector that disrupts GluA1 phosphorylation. These data provide evidence that glutamatergic signaling in the hippocampus plays an important role in context-dependent sensitization to morphine and supports further investigation of glutamate-based strategies for treating opiate addiction.

  9. Differential Changes in Expression of Stress- and Metabolic-Related Neuropeptides in the Rat Hypothalamus during Morphine Dependence and Withdrawal.

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    Bernadett Pintér-Kübler

    Full Text Available Chronic morphine treatment and naloxone precipitated morphine withdrawal activates stress-related brain circuit and results in significant changes in food intake, body weight gain and energy metabolism. The present study aimed to reveal hypothalamic mechanisms underlying these effects. Adult male rats were made dependent on morphine by subcutaneous implantation of constant release drug pellets. Pair feeding revealed significantly smaller weight loss of morphine treated rats compared to placebo implanted animals whose food consumption was limited to that eaten by morphine implanted pairs. These results suggest reduced energy expenditure of morphine-treated animals. Chronic morphine exposure or pair feeding did not significantly affect hypothalamic expression of selected stress- and metabolic related neuropeptides - corticotropin-releasing hormone (CRH, urocortin 2 (UCN2 and proopiomelanocortin (POMC compared to placebo implanted and pair fed animals. Naloxone precipitated morphine withdrawal resulted in a dramatic weight loss starting as early as 15-30 min after naloxone injection and increased adrenocorticotrophic hormone, prolactin and corticosterone plasma levels in morphine dependent rats. Using real-time quantitative PCR to monitor the time course of relative expression of neuropeptide mRNAs in the hypothalamus we found elevated CRH and UCN2 mRNA and dramatically reduced POMC expression. Neuropeptide Y (NPY and arginine vasopressin (AVP mRNA levels were transiently increased during opiate withdrawal. These data highlight that morphine withdrawal differentially affects expression of stress- and metabolic-related neuropeptides in the rat hypothalamus, while relative mRNA levels of these neuropeptides remain unchanged either in rats chronically treated with morphine or in their pair-fed controls.

  10. Implication of cyclin-dependent kinase 5 in the development of psychological dependence on and behavioral sensitization to morphine.

    Science.gov (United States)

    Narita, Minoru; Shibasaki, Masahiro; Nagumo, Yasuyuki; Narita, Michiko; Yajima, Yoshinori; Suzuki, Tsutomu

    2005-06-01

    In the present study, we investigated the role of cyclin-dependent kinase 5 (cdk5) in the brain dynamics changed by repeated in vivo treatment with morphine. The level of phosphorylated-cdk5 was significantly increased in the cingulate cortex of mice showing the morphine-induced rewarding effect. Under these conditions, roscovitine, a cdk5 inhibitor, given intracerebroventricularly (i.c.v.) caused a dose-dependent and significant inhibition of the morphine-induced rewarding effect. In addition, the dose-response effect of the morphine-induced rewarding effect was dramatically attenuated in cdk5 heterozygous (+/-) knockout mice. Furthermore, the development of behavioral sensitization by intermittent administration of morphine was virtually abolished in cdk5 (+/-) mice. These findings suggest that the induction and/or activation of cdk5 are implicated in the development of psychological dependence on morphine.

  11. The effect of various morphine weaning regimens on the sequelae of opioid tolerance involving physical dependency, anxiety and hippocampus cell neurodegeneration in rats.

    Science.gov (United States)

    Motaghinejad, Majid; Karimian, Seyed Morteza; Motaghinejad, Ozra; Shabab, Behnaz; Asadighaleni, Majid; Fatima, Sulail

    2015-06-01

    Chronic consumption of morphine induces physical dependency, anxiety, and neurodegeneration. In this study, morphine on its own has been used for the management of morphine-induced dependency, oxidative stress, and apoptosis. Forty-eight male rats were randomly divided into six groups. Rats in groups 1-5 were made morphine dependent by an increasing manner of morphine for 7 days (15-45 mg/kg). For the next 14 days, morphine was administered using the following regimen: (i) once daily 45 mg/kg (positive controls), (ii) the same dose at additional intervals (6 h longer than the previous intervals each time), (iii) 45 mg/kg of morphine at irregular intervals like of 12, 24, 36 h, (iv) decreasing dose once daily (every time 2.5 mg/kg less than the former dosage). Group 5 received 45 mg/kg of morphine and 10 mg/kg of SOD mimetic agent (M40401) injection per day. Group 6 (negative control) received saline solution only. On day 22, all animals received naloxone (3 mg/kg) and their Total Withdrawal Index (TWI) and blood cortisol levels were measured. After drug treatment, hippocampus cells were isolated, and oxidative, antioxidative, and apoptotic factors were evaluated. Various regimens of morphine reduced TWI, cortisol levels, Bax activity, caspase-3, caspase-9, TNF-α, and IL-1β and lipid peroxidation. In all treatment groups, GSH level, superoxide dismutase, glutathione peroxidase, and Bcl-2 activity were significantly increased. Furthermore, SOD mimetic agent c diminished morphine effect on SOD activity. Thus, varying the dosage regimen of morphine can reduce the severity of morphine-induced dependency and neurodegeneration. © 2015 Société Française de Pharmacologie et de Thérapeutique.

  12. PolyMorphine: an innovative biodegradable polymer drug for extended pain relief.

    Science.gov (United States)

    Rosario-Meléndez, Roselin; Harris, Carolyn L; Delgado-Rivera, Roberto; Yu, Lei; Uhrich, Kathryn E

    2012-09-28

    Morphine, a potent narcotic analgesic used for the treatment of acute and chronic pain, was chemically incorporated into a poly(anhydride-ester) backbone. The polymer termed "PolyMorphine", was designed to degrade hydrolytically releasing morphine in a controlled manner to ultimately provide analgesia for an extended time period. PolyMorphine was synthesized via melt-condensation polymerization and its structure was characterized using proton and carbon nuclear magnetic resonance spectroscopies, and infrared spectroscopy. The weight-average molecular weight and the thermal properties were determined. The hydrolytic degradation pathway of the polymer was determined by in vitro studies, showing that free morphine is released. In vitro cytocompatibility studies demonstrated that PolyMorphine is non-cytotoxic towards fibroblasts. In vivo studies using mice showed that PolyMorphine provides analgesia for 3 days, 20 times the analgesic window of free morphine. The animals retained full responsiveness to morphine after being subjected to an acute morphine challenge. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. Steady-state kinetics and dynamics of morphine in cancer patients

    DEFF Research Database (Denmark)

    Christrup, Lona Louring; Sjøgren, P; Jensen, N H

    1999-01-01

    Eighteen patients suffering from chronic pain due to cancer completed a balanced, double-blind, double-dummy, two period cross-over trial comparing the pharmacokinetics (PK) and pharmacodynamics (PD) of morphine and its metabolites, morphine-3-glucuronide and morphine-6-glucuronide, after...... samples for analysis of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were obtained. Pain intensity, sedation, and continuous reaction time (CRT) were assessed. No significant differences could be demonstrated in AUC/dose, Cmin, Cmax or fluctuation index values between the two treatments...... and the variability in the data, the statistical power of the test was only 0.074. The risk of a type II error is 0.926. These data demonstrate the PK and PD similarities and differences between CR and IR morphine. They suggest that there may be a relationship between Tmax (determined by absorption rate) and sedation...

  14. Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish.

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    Beng-Siang Khor

    Full Text Available A major obstacle in treating drug addiction is the severity of opiate withdrawal syndrome, which can lead to unwanted relapse. Mitragynine is the major alkaloid compound found in leaves of Mitragyna speciosa, a plant widely used by opiate addicts to mitigate the harshness of drug withdrawal. A series of experiments was conducted to investigate the effect of mitragynine on anxiety behavior, cortisol level and expression of stress pathway related genes in zebrafish undergoing morphine withdrawal phase. Adult zebrafish were subjected to two weeks chronic morphine exposure at 1.5 mg/L, followed by withdrawal for 24 hours prior to tests. Using the novel tank diving tests, we first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement. Morphine withdrawal also elevated whole-body cortisol levels, which confirms the phenotypic stress-like behaviors. Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole-body cortisol level. Using real-time PCR gene expression analysis, we also showed that mitragynine reduces the mRNA expression of corticotropin releasing factor receptors and prodynorphin in zebrafish brain during morphine withdrawal phase, revealing for the first time a possible link between mitragynine's ability to attenuate anxiety during opiate withdrawal with the stress-related corticotropin pathway.

  15. Modulation of memory with septal injections of morphine and glucose: effects on extracellular glucose levels in the hippocampus.

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    McNay, Ewan C; Canal, Clinton E; Sherwin, Robert S; Gold, Paul E

    2006-02-28

    The concentration of glucose in the extracellular fluid (ECF) of the hippocampus decreases substantially during memory testing on a hippocampus-dependent memory task. Administration of exogenous glucose, which enhances task performance, prevents this decrease, suggesting a relationship between hippocampal glucose availability and memory performance. In the present experiment, spontaneous alternation performance and task-related changes in hippocampal ECF glucose were assessed in rats after intraseptal administration of morphine, which impairs memory on a spontaneous alternation task, and after co-administration of intraseptal glucose, which attenuates that impairment. Consistent with previous findings, spontaneous alternation testing resulted in a decrease in hippocampal ECF glucose levels in control rats. However, rats that received intraseptal morphine prior to testing showed memory impairments and an absence of the task-related decrease in hippocampal ECF glucose levels. Intraseptal co-administration of glucose with morphine attenuated the memory impairment, and ECF glucose levels in the hippocampus decreased in a manner comparable to that seen in control rats. These data suggest that fluctuations in hippocampal ECF glucose levels may be a marker of mnemonic processing and support the view that decreases in extracellular glucose during memory testing reflect increased glucose demand during memory processing.

  16. Blockade of the Naloxone-induced Aversion in Morphine-conditioned Wistar Rats by L-Arginine Intra-central Amygdala

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    Mahnaz Rahimpour

    2011-03-01

    Full Text Available AbstractObjective(sSingle injection of naloxone, a selective antagonist of morphine, prior to the drug conditioning testing was used to investigate on morphine dependence.Materials and MethodsConditioning to morphine (2.5-10 mg/kg, s.c. was established in adult male Wistar rats (weighing 200-250 g using an unbiased procedure. Nitric oxide agents were microinjected into the central amygdala prior to naloxone-paired place conditioning testing.ResultsThe results showed that morphine produced a significant dose-dependent place preference in animals. Naloxone (0.1-0.4 mg/kg, i.p. injections pre-testing of the response to morphine (7.5 mg/kg, s.c. caused a significant aversion at the higher doses (0.4 mg/kg, i.p.. This response was reversed by microinjection of L-arginine (0.3-3 µg/rat, intra-central amygdala prior to naloxone on the day of the testing. The response to L-arginine was blocked by pre-injection of NG-nitro-L-arginine methyl ester (L-NAME (intra-central amygdala.ConclusionA single injection of naloxone on the test day of morphine place conditioning may simply reveal the occurrence of morphine dependence in rats, and that the nitric oxide in the central amygdala most likely plays a key role in this phenomenon.

  17. Morphine and oxycodone in the management of cancer pain

    International Nuclear Information System (INIS)

    Kalso, E.; Vainio, A.; Rosenberg, P.H.; Mattila, M.J.; Seppaelae, T.

    1990-01-01

    Morphine and oxycodone were administered to ten patients suffering from severe cancer pain in a double-blind cross-over study. The patients titrated themselves pain-free, first intravenously, using a patient-controlled analgesia device, and then orally. Each titration phase lasted for 48 hours. Blood samples were drawn after 36 hr of each administration phase. The plasma levels of morphine, morphine-6- and morphine-3 glucuronides were determined with high performance liquid chromatography (HPLC), whereas the oxycodone samples were assayed with gas chromatography (GC). Twin samples were analyzed for plasma opioid activity with a radioreceptor assay (RRA) using 3 H-dihydromorphien and 3 H-naloxone as radioligands. Adequate analgesia was achieved with both morphine and oxycodone. About 30% more oxycodone was needed intravenously, whereas 25% less oxycodone than morphine was consumed orally. There was a good linear correlation between the morphine concentrations measured with HPLC and RRA. The mean morphine-6-glucuronide to morphine concentration ratio was 2.3 after intravenous and 4.6 after oral administration. Results from RRA indicate that oxycodone in vivo is a potent μ-agonist and that a least part of its analgesic action is mediated by active metabolites. In vitro morphine glucuronides enhanced morphine in displacing radioligands from the opioid receptors, thus suggesting their complex interactions in vivo. (author)

  18. Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomized clinical trial.

    Science.gov (United States)

    Surran, B; Visintainer, P; Chamberlain, S; Kopcza, K; Shah, B; Singh, R

    2013-12-01

    To compare the efficacy of clonidine versus phenobarbital in reducing morphine sulfate treatment days for neonatal abstinence syndrome (NAS). Prospective, non-blinded, block randomized trial at a single level III NICU (Neonatal Intensive Care Unit). Eligible infants were treated with a combination of medications as per protocol. Primary outcome was treatment days with morphine sulfate. Secondary outcomes were the mean total morphine sulfate dose, outpatient phenobarbital days, adverse events and treatment failures. A total of 82 infants were eligible, of which 68 were randomized with 34 infants in each study group. Adjusting for covariates phenobarbital as compared with clonidine had shorter morphine sulfate treatment days (-4.6, 95% confidence interval (CI): -0.3, -8.9; P=0.037) with no difference in average morphine sulfate total dose (1.1 mg kg(-1), 95% CI: -0.1, 2.4; P=0.069). Post-discharge phenobarbital was continued for an average of 3.8 months (range 1 to 8 months). No other significant differences were noted. Phenobarbital as adjunct had clinically nonsignificant shorter inpatient but significant overall longer therapy time as compared with clonidine.

  19. Changes in lymphocyte and macrophage subsets due to morphine and ethanol treatment during a retrovirus infection causing murine AIDS

    Energy Technology Data Exchange (ETDEWEB)

    Watson, R.R.; Prabhala, R.H.; Darban, H.R.; Yahya, M.D.; Smith, T.L.

    1988-01-01

    The number of lymphocytes of various subsets were not significantly changed by the ethanol exposure except those showing activation markers which were reduced. The percentage of peripheral blood cells showing markers for macrophage functions and their activation were significantly reduced after binge use of ethanol. Ethanol retarded suppression of cells by retroviral infection. However by 25 weeks of infection there was a 8.6% survival in the ethanol fed mice infected with retrovirus which was much less than virally infected controls. Morphine treatment also increased the percentage of cells with markers for macrophages and activated macrophages in virally infected mice, while suppressing them in uninfected mice. The second and third morphine injection series suppressed lymphocyte T-helper and T-suppressor cells, but not total T cells. However, suppression by morphine was significantly less during retroviral disease than suppression caused by the virus only. At 25 weeks of infection 44.8% of morphine treated, infected mice survived.

  20. Low-dose memantine attenuated morphine addictive behavior through its anti-inflammation and neurotrophic effects in rats.

    Science.gov (United States)

    Chen, Shiou-Lan; Tao, Pao-Luh; Chu, Chun-Hsien; Chen, Shih-Heng; Wu, Hsiang-En; Tseng, Leon F; Hong, Jau-Shyong; Lu, Ru-Band

    2012-06-01

    Opioid abuse and dependency are international problems. Studies have shown that neuronal inflammation and degeneration might be related to the development of opioid addiction. Thus, using neuroprotective agents might be beneficial for treating opioid addiction. Memantine, an Alzheimer's disease medication, has neuroprotective effects in vitro and in vivo. In this study, we evaluated whether a low dose of memantine prevents opioid-induced drug-seeking behavior in rats and analyzed its mechanism. A conditioned-place-preference test was used to investigate the morphine-induced drug-seeking behaviors in rats. We found that a low-dose (0.2-1 mg/kg) of subcutaneous memantine significantly attenuated the chronic morphine-induced place-preference in rats. To clarify the effects of chronic morphine and low-dose memantine, serum and brain levels of cytokines and brain-derived neurotrophic factor (BDNF) were measured. After 6 days of morphine treatment, cytokine (IL-1β, IL-6) levels had significantly increased in serum; IL-1β and IL-6 mRNA levels had significantly increased in the nucleus accumbens and medial prefrontal cortex, both addiction-related brain areas; and BDNF levels had significantly decreased, both in serum and in addiction-related brain areas. Pretreatment with low-dose memantine significantly attenuated chronic morphine-induced increases in serum and brain cytokines. Low-dose memantine also significantly potentiated serum and brain BDNF levels. We hypothesize that neuronal inflammation and BDNF downregulation are related to the progression of opioid addiction. We hypothesize that the mechanism low-dose memantine uses to attenuate morphine-induced addiction behavior is its anti-inflammatory and neurotrophic effects.

  1. Hospital morphine preparation for abstinence syndrome in newborns exposed to buprenorphine or methadone.

    Science.gov (United States)

    Colombini, Nathalie; Elias, Riad; Busuttil, Muriel; Dubuc, Myriam; Einaudi, Marie-Ange; Bues-Charbit, Martine

    2008-06-01

    This study was undertaken to evaluate the adequacy of a hospital formulated oral morphine preparation for management of neonatal abstinence syndrome (NAS) and to compare clinical features in infants exposed to methadone or buprenorphine in utero. Between October 1998 and October 2004 all infants born to mothers treated with buprenorphine or methadone during pregnancy were enrolled into this prospective study. Morphine hydrochloride solution (0.2 mg/ml) was prepared without preservatives under a flow laminar air box (class 100). Morphine solution: quantitative and qualitative HPLC analysis and microbiological study at regular intervals during storage at 4 degrees C for 6 months. Maternal characteristics: age, opiate dose during pregnancy. Neonatal characteristics: gestational age at delivery, birth weight, Lipsitz scores. Morphine dose: daily morphine dose, maximum morphine dose, duration of NAS, and duration of treatment required to achieve stable Lipsitz scores below 4. Kruskal-Wallis test for comparison of median values. Microbiological and HPLC analysis showed that the morphine preparation remained stable for 6 months at 4 degrees C. Nine methadone-exposed infants and 13 buprenorphine-exposed infants were included in the study. All infants presented NAS requiring treatment with the morphine solution. Lipsitz scores at birth were significantly different in the methadone and buprenorphine groups (P methadone group required significantly higher doses of morphine preparation than the buprenorphine group during the first 38 days of treatment (P methadone-exposed infants (range 6-24 h) and within 48 h after birth in buprenorphine-exposed infants (range 24-168 h). Due to the possibility of delayed onset of NAS up to 7 days, infants born to mothers treated with buprenorphine should be kept in the hospital for an appropriate surveillance period. Treatment time was significantly longer (45 vs. 28 days) and the mean morphine doses were higher (1.7 fold) in methadone

  2. A Single-Dose Intra-Articular Morphine plus Bupivacaine versus Morphine Alone following Knee Arthroscopy: A Systematic Review and Meta-Analysis

    Science.gov (United States)

    Wang, Yi-lun; Li, Yu-sheng; Wei, Jie; Li, Hui; Yang, Tuo; Yang, Tu-bao; Lei, Guang-hua

    2015-01-01

    Objectives The purpose of this study was to compare the efficacy and safety of a single-dose intra-articular morphine plus bupivacaine versus morphine alone in patients undergoing arthroscopic knee surgery. Methods Randomized controlled trials comparing a combination of morphine and bupivacaine with morphine alone injected intra-articularly in the management of pain after knee arthrocopic surgery were retrieved (up to August 10, 2014) from MEDLINE, the Cochrane Library and Embase databases. The weighted mean difference (WMD), relative risk (RR) and their corresponding 95% confidence intervals (CIs) were calculated using RevMan statistical software. Results Thirteen randomized controlled trials were included. Statistically significant differences were observed with regard to the VAS values during the immediate period (0-2h) (WMD -1.16; 95% CI -2.01 to -0.31; p = 0.007) and the time to first request for rescue analgesia (WMD = 2.05; 95% CI 0.19 to 3.92; p = 0.03). However, there was no significant difference in the VAS pain score during the early period (2-6h) (WMD -0.36; 95% CI -1.13 to 0.41; p = 0.35), the late period (6-48h) (WMD 0.11; 95% CI -0.40 to 0.63; p = 0.67), and the number of patients requiring supplementary analgesia (RR = 0.78; 95% CI 0.57 to 1.05; p = 0.10). In addition, systematic review showed that intra-articular morphine plus bupivacaine would not increase the incidence of adverse effects compared with morphine alone. Conclusion The present study suggested that the administration of single-dose intra-articular morphine plus bupivacaine provided better pain relief during the immediate period (0-2h), and lengthened the time interval before the first request for analgesic rescue without increasing the short-term side effects when compared with morphine alone. Level of Evidence Level I, meta-analysis of Level I studies. PMID:26474401

  3. Role of phosphodiesterase inhibitor Ibudilast in morphine-induced hippocampal injury

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    Mohsen Zhaleh

    2014-07-01

    Full Text Available Abstract: Background: Opioid drugs are used in the treatment of acute post-surgical pain and chronic pain, such as those associated with cancer. Opioid used is associated with complications such as analgesic tolerance, dependence and opioid abuse. The molecular mechanisms of unwanted opioid responses are varied but recent advances have highlighted elevations in pro-inflammatory cytokines and pro-inflammatory glial following chronic administration of morphine. In this study we investigated the neurodegenerative effects of morphine through its effects on Toll-Like Receptor 4 (TLR4 in the male rat hippocampus and evaluated the level of Interleukin-1 beta (IL-1β. Then we compared the difference between inhibitory effects on mu opioid receptors (by β-Funaltrexamine, β-FNA and TLR4 (by Ibudilast. Subsequently, we assessed the amount of IL-1β and the number of granular cells in male rat hippocampus. Methods: Adult male rats (n=24 were treated with sucrose, morphine, Ibudilast (7.5 mg/kg and β-FNA (20 mg/kg for 30 days. Their brains were isolated and hemisected with one hippocampus for granular cell and the other used for IL-1 β immunoblotting. Results: Data showed that Ibudilast suppresses IL-1 β expression significantly more than β-FNA. The granular cell count displayed significant differences. Conclusions: Our results suggested that Ibudilast can be used for controlling and treatment of morphine-induced CNS inflammations or traumatic conditions.

  4. Effect of preemptive intra-articular morphine and ketamine on pain after arthroscopic rotator cuff repair: a prospective, double-blind, randomized controlled study.

    Science.gov (United States)

    Khashan, M; Dolkart, O; Amar, E; Chechik, O; Sharfman, Z; Mozes, G; Maman, E; Weinbroum, A A

    2016-02-01

    Rotator cuff tear is a leading etiology of shoulder pain and disability. Surgical treatment is indicated in patients with persistent pain who fail a trial of non-surgical treatment. Pain reduction following rotator cuff repair, particularly within the first 24-48 h, is a major concern to both doctors and patients. This study aimed to compare the postoperative antinociceptive additive effects of pre-incisional intra-articular (IA) ketamine when combined with morphine with two times the dose of morphine or saline. In this prospective, randomized, double blind, controlled trial patients undergoing arthroscopic rotator cuff tear repair (ARCR) under general anesthesia were enrolled. Patients were randomly assigned to one of the three intervention groups. Twenty minutes prior to incision, morphine (20 mg/10 ml), ketamine (50 mg + morphine 10 mg/10 ml), or saline (0.9 % 10 ml) (n = 15/group), were administered to all patients. First 24 h postoperative analgesia consisted of intravenous patient controlled analgesia (IV-PCA) morphine and oral rescue paracetamol 1000 mg or oxycodone 5 mg. 24-h, 2-week and 3-month patient rated pain numeric rating scale (NRS) and analgesics consumption were documented. Patients' demographic and perioperative data were similar among all groups. The 24-h and the 2-week NRSs were significantly (p pain in the first 2 weeks after arthroscopic rotator cuff repair. Further research is warranted to elucidate the optimal timing and dosing of IA ketamine and morphine for postoperative analgesic effects.

  5. Endogenous Opioid Inhibition of Chronic Low Back Pain Influences Degree of Back Pain Relief Following Morphine Administration

    Science.gov (United States)

    Bruehl, Stephen; Burns, John W.; Gupta, Rajnish; Buvanendran, Asokumar; Chont, Melissa; Schuster, Erik; France, Christopher R.

    2014-01-01

    Background and Objectives Factors underlying differential responsiveness to opioid analgesic medications used in chronic pain management are poorly understood. We tested whether individual differences in endogenous opioid inhibition of chronic low back pain were associated with magnitude of acute reductions in back pain ratings following morphine administration. Methods In randomized, counterbalanced order over three sessions, 50 chronic low back pain patients received intravenous naloxone (8mg), morphine (0.08 mg/kg), or placebo. Back pain intensity was rated pre-drug and again after peak drug activity was achieved using the McGill Pain Questionnaire-Short Form (Sensory and Affective subscales, VAS intensity measure). Opioid blockade effect measures to index degree of endogenous opioid inhibition of back pain intensity were derived as the difference between pre-to post-drug changes in pain intensity across placebo and naloxone conditions, with similar morphine responsiveness measures derived across placebo and morphine conditions. Results Morphine significantly reduced back pain compared to placebo (MPQ-Sensory, VAS; P effects of opioid blockade on back pain intensity. However, individual differences in opioid blockade effects were significantly associated with degree of acute morphine-related reductions in back pain on all measures, even after controlling for effects of age, sex, and chronic pain duration (P morphine. Conclusions Morphine appears to provide better acute relief of chronic back pain in individuals with lower natural opioidergic inhibition of chronic pain intensity. Possible implications for personalized medicine are discussed. PMID:24553304

  6. Effects of voluntary exercise on the viability, proliferation and BDNF levels of bone marrow stromal cells in rat pups born from morphine- dependent mothers during pregnancy.

    Science.gov (United States)

    Haydari, Sakineh; Safari, Manouchehr; Zarbakhsh, Sam; Bandegi, Ahmad Reza; Miladi-Gorji, Hossein

    2016-11-10

    This study was designed to investigate whether free access to a running wheel during pregnancy in morphine-dependent mothers would influence the viability, proliferation and BDNF levels of bone marrow stromal cells in rat pups. Pregnant rats were made dependent by chronic administration of morphine in drinking water simultaneously with free access to a running wheel. Male pups are weaned at 21days of birth and their bones marrows were aspirated from the femurs and tibias and also the bone marrow stromal cells (BMSCs) cultured. MTT assay was used to determine cell viability and proliferation rate. The level of BDNF was measured in the supernant of BMSCs culture by ELISA. The sedentary morphine-dependent mothers' pups showed a significant increase in the percentage cell viability and proliferation rate and also a significant decrease in the BDNF protein levels in BMSCs. The rat pups borne from exercising the control and morphine-dependent mothers exhibited an increase in the percentage viability, proliferation rate and BDNF levels of the BMSCs. This study showed that maternal exercise during pregnancy in morphine-dependent and non-dependent mothers, with increasing of BDNF levels increased the proliferation and viability of BMSCs in the rat pups. Also, chronic administration of morphine during pregnancy was able to increase the proliferation and viability of BMSCs in the rat pups. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Pharmacology of morphine and morphine-3-glucuronide at opioid, excitatory amino acid, GABA and glycine binding sites

    Energy Technology Data Exchange (ETDEWEB)

    Bartlett, S.E.; Smith, M.T. (Department of Pharmacy, The University of Queensland (Australia)); Dood, P.R. (Clinical Research Centre, Royal Brisbane Hospital Foundation, Brisbane (Australia))

    1994-07-01

    Morphine in high doses and its major metabolite, morphine-3-glucuronide, cause CNS excitation following intrathecal and intracerebroventricular administration by an unknown mechanism. This study investigated whether morphine and morphine-3-glucuronide interact at major excitatory (glutamate), major inhibitory (GABA or glycine), or opioid binding sites. Homogenate binding assays were performed using specific radioligands. At opioid receptors, morphine-3-glucuronide and morphine caused an equipotent sodium shift, consistent with morphine-3-glucuronide behaving as an agonist. This suggests that morphine-3-glucuronide-mediated excitation is not caused by an interaction at opioid receptors. Morphine-3-glucuronide and morphine caused a weak inhibition of the binding of [sup 3]H-MK801 (non-competitive antagonist) and [sup 125]I-ifenprodil (polyamine site antagonist), but at unphysiologically high concentrations. This suggests that CNS excitation would not result from an interaction of morphine-3-glucuronide and high-dose morphine with these sites on the NMDA receptor. Morphine-3-glucuronide and morphine inhibited the binding of [sup 3]H-muscimol (GABA receptor agonist), [sup 3]H-diazepam and [sup 3]H-flunitraxepam (benzodiazepine agonists) binding very weakly, suggesting the excitatory effects of morphine-3-glucuronide and high-dose morphine are not elicited through GABA[sub A] receptors. Morphine-3-glucuronide and high-dose morphine did not prevent re-uptake of glutamate into presynaptic nerve terminals. In addition, morphine-3-glucuronide and morphine did not inhibit the binding of [sup 3]H-strychnine (glycine receptor antagonist) to synaptic membranes prepared from bovine spinal cord. It is concluded that excitation caused by high-dose morphine and morphine-3-glucuronide is not mediated by an interaction with postsynaptic amino acid receptors. (au) (30 refs.).

  8. Exploration of central dopamine transporter and D2 receptor in morphine abstinent rats

    International Nuclear Information System (INIS)

    Lin Yansong; Wang Bocheng; Wang Shizhen; Ding Shiyu; Chen Zhengping; Zhang Manda

    2006-01-01

    The experiment was designed to investigate the variation of DAT and D2 receptor in morphine administered and 1,2,3 day abstinent rats. Morphine exposure was induced by repeated morphine (i.p.) treatment for 8 days. Conditioned place preference test was conducted to evaluate the drug seeking behaviour and morphine dependence of rats with morphine exposure. Biodistribution of the imaging agents 125 I-β-CIT and 125 I-IBZM was used to evaluate the central DAT and D2 receptor during morphine exposure and 1,2,3 day's abstinence. Results reveal the following facts. (1) The morphine abstinent rats showed diarrhea and body-shake 1 day after morphine withdrawal. (2) For morphine group, 125 I-β-CIT %ID/g in ST and NAC was higher than that of the 1,2,3 day's abstinent rats and control (P 0.05). (3) 125 I-IBZM %ID/g in ST, NAC and HIP in morphine rats were lower than those of the abstinent and control rats (P 125 I-IBZM %ID/g in ST and NAC gradually increased with the abstinent days. While in ST the %ID/g among the abstinent rats was all lower than that of the control rats, in NAC the %ID/g was still lower in 1 day's abstinent rats (P 0.05), indicating the reduction of hyper-activated DAT and the increase of down-regulatory D2 receptor induced by morphine during morphine withdrawal. Our results confirmed that the dopamine system, especially DAT and D2 receptor in mesolimbic and meso-striatum pathway, has been implicated in morphine treatment. The rewarding properties of morphine and the somatic expression of morphine abstinence were related to changes in mesolimbic and meso-striatum dopaminergic activity. (authors)

  9. Prognostic Significance of Pre-treatment Serum C-Reactive Protein Level in Patients with Adenocarcinoma of the Uterine Cervix.

    Science.gov (United States)

    Bodner-Adler, Barbara; Kimberger, Oliver; Schneidinger, Cora; Kölbl, Heinz; Bodner, Klaus

    2016-09-01

    To evaluate pre-treatment serum C-reactive protein (CRP) level as a prognostic parameter in patients with adenocarcinoma of the uterine cervix. Pre-treatment CRP levels were analyzed to determine potential associations with clinicopathological parameters and to assess prognostic value in 46 patients with sole adenocarcinoma of the uterine cervix. The mean (±SD) pre-treatment serum CRP level was 5.82 (7.21) mg/l. Serum CRP concentration significantly correlated positively with age at diagnosis (p=0.001), lymphovascular space invasion (p=0.0026), recurrent disease (p=0.0001) and International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.0002). In multivariate Cox regression models with age, FIGO stage, histological grade and lymph node status, elevated CRP and cancer antigen 125 levels were associated with shortened survival (pcervix. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  10. Population Pharmacokinetics of Morphine and Morphine-6-Glucuronide following Rectal Administration

    DEFF Research Database (Denmark)

    Brokjær, Anne; Kreilgaard, Mads; Olesen, Anne Estrup

    2015-01-01

    INTRODUCTION: To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: 1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), 2...... cm from the anal verge. A 2 mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid...... chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction. RESULTS: A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described...

  11. Essential role of the NO signaling pathway in the hippocampal CA1 in morphine-associated memory depends on glutaminergic receptors.

    Science.gov (United States)

    Shen, Fang; Wang, Xue-Wei; Ge, Fei-Fei; Li, Yi-Jing; Cui, Cai-Lian

    2016-03-01

    The nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP-dependent protein kinase (PKG) signaling pathway has been reported to play a key role in memory processing. However, little is known about its role in drug-associated reward memory. Here, we report the following. 1) The NO pathway in the CA1 is critical for the retrieval of morphine-associated reward memory. Specifically, the nNOS, sGC and PKG protein levels in the CA1 were increased after the expression of morphine conditioned place preference (CPP). Intra-CA1 injection of an NOS, sGC or PKG inhibitor prevented morphine CPP expression. 2) The involvement of the NO pathway in morphine CPP requires NR2B-containing NMDA receptors (NR2B-NMDARs). NR2B-NMDAR expression was elevated in the CA1 following morphine CPP expression, and intra-CA1 injection of the NR2B-NMDAR antagonist Ro25-6981 not only blocked morphine CPP expression but also inhibited the up-regulation of nNOS, sGC and PKG. Moreover, the Ro25-6981-induced blockade of morphine CPP was abolished by intra-CA1 injection of a NOS substrate or an sGC activator. 3) The NR2B-NMDAR stimulated the NO pathway by up-regulating the phosphorylation of Akt(Ser473). Morphine CPP expression enhanced the pAkt(Ser473) level, which has been corroborated to regulate nNOS activity, and this effect was reversed by intra-CA1 injection of Ro25-6981. 4) GluR1 acted downstream of the NO pathway. The membrane level of GluR1 in the CA1 was increased after morphine CPP expression, and this effect was prevented by pre-injection of a PKG inhibitor into the CA1. Additionally, co-immunoprecipitation revealed an interaction between PKG and GluR1; this result further indicated a role of PKG in regulating GluR1 trafficking. Collectively, the results of our study demonstrated that the activation of the NR2B-NMDAR/NO/sGC/PKG signaling pathway is necessary for the retrieval of morphine-associated reward memory. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. The biology of deception: emotion and morphine.

    Science.gov (United States)

    Stefano, G B; Fricchione, G L

    1995-01-01

    The biology of deception suggests that denial-like processes are at the core of the cognitive coping. In this regard, with cognitive ability, one associates or assumes that this process occurs by way of a 'rational' mind. Such a detailed cognitive process as being rational would also lead, counter intuitively, to inactivity and or major delays in conclusion reaching. Thus, our perceived rationality may also be a deceptive behavioral response. Of equal noteworthyness, man is also 'emotional'. We surmise that emotion represents the pre-cognitive short-cut to overcome this potential for excessive rationality. In this light, we may explain certain psychiatric disorders such as obsessive-compulsive behavior as emotional extremes dealing with cognitive habits used to bind anxiety operating most probably at the pre-cognitive level. Given recent discoveries in neuroimmunology and an understanding of naturally occurring morphine as both an immune and neurological down-regulatory substance we hypothesize that abnormalities associated with emotional extremes may be due, in part, to morphinergic imbalances.

  13. PolyMorphine: an innovative biodegradable polymer drug for extended pain relief

    OpenAIRE

    Rosario-Meléndez, Roselin; Harris, Carolyn L.; Delgado-Rivera, Roberto; Yu, Lei; Uhrich, Kathryn E.

    2012-01-01

    Morphine, a potent narcotic analgesic used for the treatment of acute and chronic pain, was chemically incorporated into a poly(anhydride-ester) backbone. The polymer termed “PolyMorphine”, was designed to degrade hydrolytically releasing morphine in a controlled manner to ultimately provide analgesia for an extended time period. PolyMorphine was synthesized via melt-condensation polymerization and its structure was characterized using proton and carbon nuclear magnetic resonance spectroscopi...

  14. Driving ability in cancer patients receiving long-term morphine analgesia.

    Science.gov (United States)

    Vainio, A; Ollila, J; Matikainen, E; Rosenberg, P; Kalso, E

    1995-09-09

    When given in single doses to healthy volunteers, opioid analgesics impair reaction time, muscle coordination, attention, and short-term memory sufficiently to affect driving and other skilled activities. Despite the increasing use of oral morphine daily, little is known about the effect of long-term opioid therapy on psychomotor performance. To examine the effects of continuous morphine medication, psychological and neurological tests originally designed for professional motor vehicle drivers were conducted in two groups of cancer patients who were similar apart from experience of pain. 24 were on continuous morphine (mean 209 mg oral morphine daily) for cancer pain; and 25 were pain-free without regular analgesics. Though the results were a little worse in the patients taking morphine, there were no significant differences between the groups in intelligence, vigilance, concentration, fluency of motor reactions, or division of attention. Of the neural function tests, reaction times (auditory, visual, associative), thermal discrimination, and body sway with eyes open were similar in the two groups; only balancing ability with closed eyes was worse in the morphine group. These results indicate that, in cancer patients receiving long-term morphine treatment with stable doses, morphine has only a slight and selective effect on functions related to driving.

  15. Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine

    Science.gov (United States)

    Hill, Rob; Lyndon, Abi; Withey, Sarah; Roberts, Joanne; Kershaw, Yvonne; MacLachlan, John; Lingford-Hughes, Anne; Kelly, Eamonn; Bailey, Chris; Hickman, Matthew; Henderson, Graeme

    2016-01-01

    Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO2 in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths. PMID:26171718

  16. Morphine Suppresses T helper Lymphocyte Differentiation to Th1 Type Through PI3K/AKT Pathway.

    Science.gov (United States)

    Mao, Mao; Qian, Yanning; Sun, Jie

    2016-04-01

    To investigate the effect of morphine on T helper lymphocyte differentiation and PI3K/AKT pathway mechanism, CD4+ lymphocytes were treated by phorbol-myristate-acetate (25 ng/ml) (PMA) plus ionomycin (1 μg/ml) in the presence of various concentrations of morphine (25, 50, 100, 200 ng/ml) for 4 h. Th1 and Th2 subsets, supernatant cytokines, and PI3K, AKT, and protein kinase C-theta (PKC-θ) levels were detected. The Th1 cell percentage, Th1-derived cytokines, and ratio of Th1/Th2 decreased in the presence of morphine in a concentration-dependent manner. However, Th2 cell percentage kept stable after morphine treatment. The phosphorylation of PI3K and AKT decreased, but the phosphorylation of PKC-θ did not change in the presence of morphine. The decreased percentage of Th1 cells and ratio of Th1/Th2 was recovered by naloxone concentration-dependently. Morphine can inhibit the differentiation of Th1 lymphocytes and decrease the ratio of Th1/Th2 via the pathway of PI3K/AKT. The effect can be inhibited by naloxone.

  17. Treatment of the acute sickle cell vaso-occlusive crisis in the Emergency Department: a Brazilian method of switching from intravenous to oral morphine.

    Science.gov (United States)

    Campos, Jessica; Lobo, Clarisse; Queiroz, Ana Maria Mach; do Nascimento, Emilia Matos; Lima, Carlos Bernardo; Cardoso, Gilberto; Ballas, Samir K

    2014-07-01

    Describe the treatment of patients with vaso-occlusive crises (VOC) in a Brazilian emergency department (ED) and the successful switch from intravenous to oral morphine. We analyzed records of 315 patients with sickle cell disease using two different protocols for pain: one in March 2010 prescribing intravenous morphine every 4 h throughout their stay, and another in March 2011 and 2012 prescribing one initial dose of intravenous morphine followed by equianalgesic doses of oral morphine every 4 h. Patients were triaged into three groups: mild, moderate, and severe VOC. The mild group was treated within 1 h after triage, the moderate within 30 min and the severe was treated immediately. Patients whose pain was not relieved within 6 h after the first dose of morphine were transferred into a different holding area of the ED where they continued to receive the same treatment for 48 h after which they were hospitalized if still in pain. The number of patients who stayed <24 h in the ED increased significantly from 63 in 2010 to 87 in 2012, and the number of admissions decreased from 26 in 2010 to 10 in 2012. The incidence of acute chest syndrome decreased from 8.5% in 2010 to 1.9% in 2012. Patients treated with oral morphine stayed a shorter time in the ED, had more pain relief, were admitted less frequently, and had less acute chest syndrome. These differences may be due to environmental, cultural, psychological, and pharmacogenetic factors. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Managing Postoperative Analgesic Failure: Tramadol Versus Morphine for Refractory Pain in the Post-Operative Recovery Unit.

    Science.gov (United States)

    Byrne, Kelly; Nolan, Aoife; Barnard, John; Tozer, Megan; Harris, David; Sleigh, Jamie

    2017-02-01

    This study aimed to discover whether co-analgesia with tramadol or additional morphine was more effective for patients who still had severe pain despite being given 10 mg intravenous morphine in the post-anesthesia care unit (PACU). All eligible patients were consented and recruited to the trial pre-operatively, but only a small subgroup – whose pain was not successfully controlled (pain score 6/10 or more) after receiving 10 mg of morphine in the PACU—were then randomized to enter the trial and receive, in a double blinded fashion, the analgesic study drug; which consisted of either a further 10 mg of morphine, or 100 mg of tramadol, titrated intravenously to control their pain. The groups were compared as to: the time to readiness for discharge, the patient’s pain scores over time, and the presence of side effects. There was no statistically significant difference in any of the outcomes measured. The time to readiness for discharge from PACU was 119 minutes in the morphine group and 120 minutes in the tramadol group. However in approximately half the cases who entered the trial (i.e., where pain had not been controlled with the pre-enrollment baseline 10 mg of morphine in PACU) neither a further 10 mg of morphine nor 100 mg of tramadol effectively relieved the patient’s pain. We found no difference between additional morphine and co-analgesia with tramadol in this study. Patients who don’t respond to reasonable doses of opioids in PACU are very likely to be unresponsive to further opioids, and other non-opioid analgesic techniques (such as regional anesthesia) should be considered early in this group of patients.

  19. Comparison of Patient-Controlled Analgesia Using Morphine With and Without Paracetamol in Postoperative Pain Control

    Directory of Open Access Journals (Sweden)

    Mehryar Taghavi Gilani

    2016-04-01

    Full Text Available Introduction: Postoperative pain control plays a pivotal role in reducing postoperative complications, hospitality time, and increasing satisfaction. This study aimed to evaluate the effect of paracetamol on the pain and complications caused by gastrectomy. Materials and Methods: This randomized prospective study was conducted on 60 patients (two same group who were candidate for gastrectomy in Imam Reza Hospital of Mashhad, Iran during August-September 2015. The first group received Patient-Controlled Analgesia (PCA with morphine only, and in the second group, paracetamol (1 gram infused with morphine every six hours. Level of pain, morphine intake, and side effects were evaluated in both groups. Results:No significant difference was observed in the four-scale score of pain in the patients (morphine group: 0.64±0.1, morphine-paracetamol group: 0.6±0.1 (P=0.72. During the first 24 hours after the surgery, the morphine group had lower consciousness level (2.3±0.2 compared to the morphine-paracetamol group (1.7±0.3 (P=0.001. Moreover, infusion of paracetamol with morphine to control the pain after gastrectomy reduced the need for morphine analgesia. Morphine intake was 21.4±7.7 in morphine group, while it was 14.3±5.8 in the morphine-paracetamol group within the first 24 hours after the surgery (P=0.001. However, this level had no significant effect on postoperative complications such as itching, nausea, and arterial oxygen saturation. Conclusion: According to the results of this study, intravenous paracetamol (one gram administered every six hours with PCA using morphine could decrease morphine intake leading to better consciousness level during the first 24 hours after gastrectomy without further complications.

  20. Carbamazepine potentiates the effectiveness of morphine in a rodent model of neuropathic pain.

    Directory of Open Access Journals (Sweden)

    Michael R Due

    Full Text Available Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4 may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG, we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS and over 35% of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ, a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p. were observed in TNI rodents at post-injury day (PID 7-14 and absent at PID21-28, while administration of CBZ (10 mg/kg, i.p. alone failed to produce anti-nociceptive effects at any time following TNI (PID 7-28. In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a

  1. Effects of Repeated Morphine on Intracranial Self-Stimulation in Male Rats In the Absence or Presence of a Noxious Pain Stimulus

    Science.gov (United States)

    Miller, Laurence L.; Altarifi, Ahmad A.; Negus, S. Stevens

    2015-01-01

    Research on opioid analgesics such as morphine suggests that expression of abuse-related effects increases with repeated exposure. Repeated exposure to opioids often occurs clinically in the context of pain management, and a major concern for clinicians is the risk of iatrogenic addiction and dependence in patients receiving opioids for treatment of pain. This study compared abuse-related morphine effects in male rats in an intracranial self-stimulation (ICSS) procedure after repeated treatment either with morphine alone or with morphine in combination with a repeated noxious stimulus (intraperitoneal administration of dilute acid). The study also permitted comparison of morphine potency and effectiveness to block acid-induced depression of ICSS (antinociception) and to produce enhanced facilitation of ICSS (abuse-related effect). There were three main findings. First, initial morphine exposure to drug naïve rats did not produce abuse-related ICSS facilitation. Second, repeated daily treatment with 3.2 mg/kg/day morphine for six days increased expression of ICSS facilitation. This occurred whether morphine was administered in the absence or presence of the noxious stimulus. Finally, a lower dose of 1.0 mg/kg/day morphine was sufficient to produce antinociception during repeated acid treatment, but this lower dose did not reliably increase abuse-related morphine effects. Taken together, these results suggest that prior morphine exposure can increase abuse liability of subsequent morphine treatments even when that morphine exposure occurs in the context of a pain state. However, it may be possible to relieve pain with relatively low morphine doses that do not produce increases in abuse-related morphine effects. PMID:26375515

  2. Effects of chronic morphine and morphine withdrawal on gene expression in rat peripheral blood mononuclear cells.

    Science.gov (United States)

    Desjardins, Stephane; Belkai, Emilie; Crete, Dominique; Cordonnier, Laurie; Scherrmann, Jean-Michel; Noble, Florence; Marie-Claire, Cynthia

    2008-12-01

    Chronic morphine treatment alters gene expression in brain structures. There are increasing evidences showing a correlation, in gene expression modulation, between blood cells and brain in psychological troubles. To test whether gene expression regulation in blood cells could be found in drug addiction, we investigated gene expression profiles in peripheral blood mononuclear (PBMC) cells of saline and morphine-treated rats. In rats chronically treated with morphine, the behavioral signs of spontaneous withdrawal were observed and a withdrawal score was determined. This score enabled to select the time points at which the animals displayed the mildest and strongest withdrawal signs (12 h and 36 h after the last injection). Oligonucleotide arrays were used to assess differential gene expression in the PBMCs and quantitative real-time RT-PCR to validate the modulation of several candidate genes 12 h and 36 h after the last injection. Among the 812 differentially expressed candidates, several genes (Adcy5, Htr2a) and pathways (Map kinases, G-proteins, integrins) have already been described as modulated in the brain of morphine-treated rats. Sixteen out of the twenty-four tested candidates were validated at 12 h, some of them showed a sustained modulation at 36 h while for most of them the modulation evolved as the withdrawal score increased. This study suggests similarities between the gene expression profile in PBMCs and brain of morphine-treated rats. Thus, the searching of correlations between the severity of the withdrawal and the PBMCs gene expression pattern by transcriptional analysis of blood cells could be promising for the study of the mechanisms of addiction.

  3. Venlafaxine prevents morphine antinociceptive tolerance: The role of neuroinflammation and the l-arginine-nitric oxide pathway.

    Science.gov (United States)

    Mansouri, Mohammad Taghi; Naghizadeh, Bahareh; Ghorbanzadeh, Behnam; Alboghobeish, Soheila; Amirgholami, Neda; Houshmand, Gholamreza; Cauli, Omar

    2018-05-01

    Opioid-induced neuroinflammation and the nitric oxide (NO) signal-transduction pathway are involved in the development of opioid analgesic tolerance. The antidepressant venlafaxine (VLF) modulates NO in nervous tissues, and so we investigated its effect on induced tolerance to morphine, neuroinflammation, and oxidative stress in mice. Tolerance to the analgesic effects of morphine were induced by injecting mice with morphine (50 mg/kg) once a day for three consecutive days; the effect of co-administration of VLF (5 or 40 mg/kg) with morphine was similarly tested in a separate group. To determine if the NO precursor l-arginine hydrochloride (l-arg) or NO are involved in the effects rendered by VLF, animals were pre-treated with l-arg (200 mg/kg), or the NO synthesis inhibitors N(ω)-nitro-l-arginine methyl ester (L-NAME; 30 mg/kg) or aminoguanidine hydrochloride (AG; 100 mg/kg), along with VLF (40 mg/kg) for three days before receiving morphine for another three days. Nociception was assessed with a hot-plate test on the fourth day, and the concentration of tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), interleukin-6 (IL-6), interleukin-10, brain-derived neurotrophic factor, NO, and oxidative stress factors such as total thiol, malondialdehyde content, and glutathione peroxidase (GPx) activity in the brain was also determined. Co-administration of VLF with morphine attenuated morphine-induced analgesic tolerance and prevented the upregulation of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), NO, and malondialdehyde in brains of mice with induced morphine tolerance; chronic VLF administration inhibited this decrease in brain-derived neurotrophic factor, total thiol, and GPx levels. Moreover, repeated administration of l-arg before receipt of VLF antagonized the effects induced by VLF, while L-NAME and AG potentiated these effects. VLF attenuates morphine-induced analgesic tolerance, at least partly because of its anti

  4. A pharmacokinetic-pharmacodynamic model of morphine exposure and subsequent morphine consumption in postoperative pain

    DEFF Research Database (Denmark)

    Juul, Rasmus Vestergaard; Nyberg, Joakim; Lund, Trine Meldgaard

    2016-01-01

    Purpose To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation. Methods Dose, formulation and time of morphine administration was available from a published study...

  5. Swimming reduces the severity of physical and psychological dependence and voluntary morphine consumption in morphine dependent rats.

    Science.gov (United States)

    Fadaei, Atefeh; Gorji, Hossein Miladi; Hosseini, Shahrokh Makvand

    2015-01-15

    Previous studies have indicated that voluntary exercise decreases the severity of the anxiogenic-like behaviors in both morphine-dependent and withdrawn rats. This study examined the effects of regular swimming exercise during the development of dependency and spontaneous morphine withdrawal on the anxiety-depression profile and voluntary morphine consumption in morphine dependent rats. The rats were chronically treated with bi-daily doses (10 mg/kg, at 12h intervals) of morphine over a period of 14 days. The exercising rats were allowed to swim (45 min/d, five days per a week, for 14 or 21 days) during the development of morphine dependence and withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice paradigm in animal models of craving. The results showed that withdrawal signs were decreased in swimmer morphine dependent rats than sedentary rats (Pmorphine-dependent and withdrawn rats exhibited an increase in EPM open arm time and entries (Pmorphine was less in the swimmer morphine-withdrawn rats than the sedentary groups during four periods of the intake of drug (Pmorphine dependence and voluntary morphine consumption with reducing anxiety and depression in morphine-dependent and withdrawn rats. Thus, swimming exercise may be a potential method to ameliorate some of the deleterious behavioral consequences of morphine dependence. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. The effect of post-conditioning exposure to morphine on the retention of a morphine-induced conditioned taste aversion.

    Science.gov (United States)

    Jacobs, W J; Zellner, D A; LoLordo, V M; Riley, A L

    1981-06-01

    In the following experiment, multiple injections of morphine sulfate following the acquisition of a morphine-induced taste aversion had no effect on the retention of the previously acquired aversion. Post-conditioning injections of morphine resulted in the development of physical dependence to morphine and led to a decrement in the ability of morphine to induce a subsequent aversion to a second novel taste. This failure of post-conditioning exposures to morphine to affect a previously acquired morphine-induced taste aversion even though tolerance to morphine had occurred was discussed in the context of Rescorla's event-memory model of conditioning.

  7. Intrathecal morphine plus general anesthesia in cardiac surgery: effects on pulmonary function, postoperative analgesia, and plasma morphine concentration

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    Luciana Moraes dos Santos

    2009-04-01

    Full Text Available OBJECTIVES: To evaluate the effects of intrathecal morphine on pulmonary function, analgesia, and morphine plasma concentrations after cardiac surgery. INTRODUCTION: Lung dysfunction increases morbidity and mortality after cardiac surgery. Regional analgesia may improve pulmonary outcomes by reducing pain, but the occurrence of this benefit remains controversial. METHODS: Forty-two patients were randomized for general anesthesia (control group n=22 or 400 µg of intrathecal morphine followed by general anesthesia (morphine group n=20. Postoperative analgesia was accomplished with an intravenous, patient-controlled morphine pump. Blood gas measurements, forced vital capacity (FVC, forced expiratory volume (FEV, and FVC/FEV ratio were obtained preoperatively, as well as on the first and second postoperative days. Pain at rest, profound inspiration, amount of coughing, morphine solicitation, consumption, and plasma morphine concentration were evaluated for 36 hours postoperatively. Statistical analyses were performed using the repeated measures ANOVA or Mann-Whiney tests (*p<0.05. RESULTS: Both groups experienced reduced FVC postoperatively (3.24 L to 1.38 L in control group; 2.72 L to 1.18 L in morphine group, with no significant decreases observed between groups. The two groups also exhibited similar results for FEV1 (p=0.085, FEV1/FVC (p=0.68 and PaO2/FiO2 ratio (p=0.08. The morphine group reported less pain intensity (evaluated using a visual numeric scale, especially when coughing (18 hours postoperatively: control group= 4.73 and morphine group= 1.80, p=0.001. Cumulative morphine consumption was reduced after 18 hours in the morphine group (control group= 20.14 and morphine group= 14.20 mg, p=0.037. The plasma morphine concentration was also reduced in the morphine group 24 hours after surgery (control group= 15.87 ng.mL-1 and morphine group= 4.08 ng.mL-1, p=0.029. CONCLUSIONS: Intrathecal morphine administration did not significantly alter

  8. Modulation of opiate-related signaling molecules in morphine-dependent conditioned behavior: conditioned place preference to morphine induces CREB phosphorylation.

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    Morón, José A; Gullapalli, Srinivas; Taylor, Chirisse; Gupta, Achla; Gomes, Ivone; Devi, Lakshmi A

    2010-03-01

    Opiate addiction is a chronic, relapsing behavioral disorder where learned associations that develop between the abused opiate and the environment in which it is consumed are brought about through Pavlovian (classical) conditioning processes. However, the signaling mechanisms/pathways regulating the mechanisms that underlie the responses to opiate-associated cues or the development of sensitization as a consequence of repeated context-independent administration of opiates are unknown. In this study we examined the phosphorylation levels of various classic signaling molecules in brain regions implicated in addictive behaviors after acute and repeated morphine administration. An unbiased place conditioning protocol was used to examine changes in phosphorylation that are associated with (1) the expression of the rewarding effects of morphine and (2) the sensitization that develops to this effect. We also examined the effects of a delta-receptor antagonist on morphine-induced conditioned behavior and on the phosphorylation of classic signaling molecules in view of data showing that blockade of delta-opioid receptor (deltaOR) prevents the development of sensitization to the rewarding effects of morphine. We find that CREB phosphorylation is specifically induced upon the expression of a sensitized response to morphine-induced conditioned behavior in brain areas related to memory consolidation, such as the hippocampus and cortex. A similar effect is also observed, albeit to a lesser extent, in the case of the GluR1 subunit of AMPA glutamate receptor. These increases in the phosphorylation levels of CREB and pGluR1 are significantly blocked by pretreatment with a deltaOR antagonist. These results indicate a critical role for phospho-CREB, AMPA, and deltaOR activities in mediating the expression of a sensitized response to morphine-dependent conditioned behavior.

  9. Effect of the methanolic extracts of different parts of Ferula assa-foetida on naloxone-induced withdrawal behavior in morphine-dependent mice

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    Mahnaz Khanavi

    2017-08-01

    Full Text Available Objective: Ferula assa-foetida, a native species in Iran, is used for treatment of several diseases particularly for neurological disorders in Iranian Traditional Medicine. The aim of this study is to investigate the effect of methanolic roots, fruits, and aerial parts extracts of Ferula assa-foetida on withdrawal syndrome in morphine-dependent mice. Materials and Methods: Aerial parts, roots, and fruits of the plant were separately extracted with 80% MeOH. For induction of dependence, morphine (50, 50 and 75 mg/kg was injected subcutaneously three times daily (10 am, 1 pm and 4 pm for three days and a last dose of morphine (50 mg/kg was administrated on the fourth day. Withdrawal syndrome was induced by injection of naloxone (5 mg/kg, intraperitoneal 2 hr after the final dose of morphine. Different doses of the extracts were administered i.p. 60 minutes before naloxone injection and withdrawal sign was recorded 2 minutes after naloxone injection for a period of 60 minutes.   Results: Pre-treatment of animals with different doses (2.5, 5, 10, 20 mg/kg of methanolic extract of the aerial parts of F. assa-foetida caused a significant decrease in naloxone-induced behavior. Intraperitoneal administration of different doses (10, 15, 20, 25 mg/kg of methanolic extract of the fruit significantly reduced the naloxone-induced withdrawal behavior (p

  10. Human Abuse Potential of an Abuse-Deterrent (AD), Extended-Release (ER) Morphine Product Candidate (Morphine-ADER Injection-Molded Tablets) vs Extended-Release Morphine Administered Intranasally in Nondependent Recreational Opioid Users.

    Science.gov (United States)

    Webster, Lynn R; Smith, Michael D; Lawler, John; Lindhardt, Karsten; Dayno, Jeffrey M

    2017-09-01

    To compare the relative human abuse potential after insufflation of manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine ER tablets. A randomized, double-blind, double-dummy, active- and placebo-controlled five-way crossover study was performed with adult volunteers who were experienced, nondependent, recreational opioid users. After intranasal (IN) administration of manipulated high-volume (HV) morphine-ADER-IMT (60 mg), participants were randomized (1:1:1:1) to receive IN manipulated low-volume (LV) morphine ER (60 mg), IN manipulated LV morphine-ADER-IMT, intact oral morphine-ADER-IMT (60 mg), and placebo in crossover fashion. Pharmacodynamic and pharmacokinetic assessments included peak effect of drug liking (E max ; primary endpoint) using drug liking visual analog scale (VAS) score, E max using overall drug liking, and take drug again (TDA) VASs scores, and mean abuse quotient (AQ), a pharmacokinetic parameter associated with drug liking. Forty-six participants completed the study. After insufflation of HV morphine-ADER-IMT and LV morphine-ADER-IMT, drug liking E max was significantly lower ( P  <   0.0001) compared with IN morphine ER. Overall drug liking and TDA E max values were significantly lower ( P  <   0.0001) after insufflation of HV morphine-ADER-IMT and LV morphine-ADER-IMT compared with IN morphine ER. Mean AQ was lower after insufflation of HV (9.2) and LV (2.3) morphine-ADER-IMT or ingestion of oral morphine-ADER-IMT (5.5) compared with insufflation of LV morphine ER (37.2). All drug liking, take drug again, and abuse quotient endpoints support a significantly lower abuse potential with insufflation of manipulated morphine-ADER-IMT compared with manipulated and insufflated non-AD ER morphine. © 2016 American Academy of Pain Medicine.

  11. Predicting morphine related side effects in the ED: An international cohort study.

    Science.gov (United States)

    Bounes, Vincent; Charriton-Dadone, Béatrice; Levraut, Jacques; Delangue, Cyril; Carpentier, Françoise; Mary-Chalon, Stéphanie; Houze-Cerfon, Vanessa; Sommet, Agnès; Houze-Cerfon, Charles-Henri; Ganetsky, Michael

    2017-04-01

    Morphine is the reference treatment for severe acute pain in an emergency department. The purpose of this study was to describe and analyse opioid-related ADRs (adverse drug reactions) in a large cohort of emergency department patients, and to identify predictive factors for those ADRs. In this prospective, observational, pharmaco-epidemiological international cohort study, all patients aged 18years or older who were treated with morphine were enrolled. The study was done in 23 emergency departments in the US and France. Baseline numerical rating scale score and initial and total doses of morphine titration were recorded. Logistic regression analysis was used to study the effects of demographic, clinical and medical history covariates on the occurrence of opioid-induced ADRs within 6h after treatment. A total of 1128 patients were included over 10months. Median baseline initial pain scores were 8/10 (7-10) versus 3/10 (1-4) after morphine administration. Median titration duration was 10min (IQR, 1-30). The occurrence of opioid-induced ADRs was 25% and 2% were serious. Patients experienced mainly nausea and drowsiness. Medical history of travel sickness (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.01-2.86) and history of nausea or vomiting post morphine (OR, 3.86; 95% CI, 2.29-6.51) were independent predictors of morphine related ADRs. Serious morphine related ADRs are rare and unpredictable. Prophylactic antiemetic therapy could be proposed to patients with history of travel sickness and history of nausea or vomiting in a postoperative setting or after morphine administration. Copyright © 2016. Published by Elsevier Inc.

  12. Antagonism of the morphine-induced locomotor activation of mice by fructose: comparison with other opiates and sugars, and sugar effects on brain morphine.

    Science.gov (United States)

    Brase, D A; Ward, C R; Bey, P S; Dewey, W L

    1991-01-01

    The mouse locomotor activation test of opiate action in a 2+2 dose parallel line assay was used in a repeated testing paradigm to determine the test, opiate and hexose specificities of a previously reported antagonism of morphine-induced antinocociception by hyperglycemia. In opiate specificity studies, fructose (5 g/kg, i.p.) significantly reduced the potency ratio for morphine and methadone, but not for levorphanol, meperidine or phenazocine when intragroup comparisons were made. In intergroup comparisons, fructose significantly reduced the potencies of levorphanol and phenazocine, but not methadone or meperidine. In hexose/polyol specificity studies, tagatose and fructose significantly reduced the potency ratio for morphine, whereas glucose, galactose, mannose and the polyols, sorbitol and xylitol, caused no significant decrease in potency. Fructose, tagatose, glucose and mannose (5 g/kg, i.p.) were tested for effects on brain morphine levels 30 min after morphine (60 min after sugar), and all four sugars significantly increased brain morphine relative to saline-pretreated controls. It is concluded that the antagonism of morphine by acute sugar administration shows specificity for certain sugars and occurs despite sugar-induced increases in the distribution of morphine to the brain. Furthermore, the effects of fructose show an opiate specificity similar to that of glucose on antinociception observed previously in our laboratory, except that methadone was also significantly inhibited in the present study, when a repeated-testing experimental design was used.

  13. Maternal swimming exercise during pregnancy attenuates anxiety/depressive-like behaviors and voluntary morphine consumption in the pubertal male and female rat offspring born from morphine dependent mothers.

    Science.gov (United States)

    Torabi, Masoumeh; Pooriamehr, Alireza; Bigdeli, Imanollah; Miladi-Gorji, Hossein

    2017-10-17

    This study was designed to examine whether maternal swimming exercise during pregnancy would attenuate prenatally morphine-induced anxiety, depression and voluntary consumption of morphine in the pubertal male and female rat offspring. Pregnant rats during the development of morphine dependence were allowed to swim (30-45min/d, 3days per a week) on gestational days 11-18. Then, the pubertal male and female rat offspring were tested for the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that male and female rat offspring born of the swimmer morphine-dependent mothers exhibited an increase in EPM open arm time and entries, higher levels of sucrose preference than their sedentary control mothers. Voluntary consumption of morphine was less in the male and female rat offspring born of the swimmer morphine-dependent mothers as compared with their sedentary control mothers during three periods of the intake of drug. Thus, swimming exercise in pregnant morphine dependent mothers decreased anxiety, depressive-like behavior and also the voluntary morphine consumption in the pubertal male and female offspring, which may prevent prenatally morphine-induced behavioral sensitization in offspring. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Phenobarbital versus morphine in the management of neonatal abstinence syndrome, a randomized control trial.

    Science.gov (United States)

    Nayeri, Fatemeh; Sheikh, Mahdi; Kalani, Majid; Niknafs, Pedram; Shariat, Mamak; Dalili, Hosein; Dehpour, Ahmad-Reza

    2015-05-15

    Evaluating the efficacy of the loading and tapering dose of Phenobarbital versus oral Morphine in the management of NAS. This randomized, open-label, controlled trial was conducted on 60 neonates born to illicit drugs dependent mothers at Vali-Asr and Akbar-Abadi hospitals, Tehran, Iran, who exhibited NAS requiring medical therapy. The neonates were randomized to receive either: Oral Morphine Sulfate or a loading dose of Phenobarbital followed by a tapering dose. The duration of treatment required for NAS resolution, the total hospital stay and the requirement for additional second line treatment were compared between the treatment groups. The Mean ± Standard Deviation for the duration of treatment required for the resolution of NAS was 8.5 ± 5 days in the Morphine group and 8.5 ± 4 days in the Phenobarbital group (P = 0.9). The duration of total hospital stay was 12.6 ± 5.6 days in the Morphine group and 12.5 ± 5.3 days in the Phenobarbital group (P = 0.7). 3.3 % in the Morphine group versus 6.6 % in the Phenobarbital group required adjunctive treatment (P = 0.5). There were no significant differences in the duration of treatment, duration of hospital stay, and the requirement for adjunctive treatment, between the neonates with NAS who received Morphine Sulfate and neonates who received a loading and tapering dose of Phenobarbital. This study is registered at the Iranian Registry of Clinical Trials ( www.irct.ir ) which is a Primary Registry in the WHO Registry Network. (Registration Number =  IRCT201406239568N8 ).

  15. Determination of μ-, δ- and κ-opioid receptors in forebrain cortex of rats exposed to morphine for 10 days: Comparison with animals after 20 days of morphine withdrawal.

    Science.gov (United States)

    Ujcikova, Hana; Hlouskova, Martina; Cechova, Kristina; Stolarova, Katerina; Roubalova, Lenka; Svoboda, Petr

    2017-01-01

    Chronic exposure of mammalian organism to morphine results in adaption to persistent high opioid tone through homeostatic adjustments. Our previous results indicated that in the frontal brain cortex (FBC) of rats exposed to morphine for 10 days, such a compensatory adjustment was detected as large up-regulation of adenylylcyclases I (8-fold) and II (2.5-fold). The other isoforms of AC (III-IX) were unchanged. Importantly, the increase of ACI and ACII was reversible as it disappeared after 20 days of morphine withdrawal. Changes of down-stream signaling molecules such as G proteins and adenylylcyclases should respond to and be preceded by primary changes proceeding at receptor level. Therefore in our present work, we addressed the problem of reversibility of the long-term morphine effects on μ-, δ- and κ-OR protein levels in FBC. Rats were exposed to increasing doses of morphine (10-40 mg/kg) for 10 days and sacrificed either 24 h (group +M10) or 20 days (group +M10/-M20) after the last dose of morphine in parallel with control animals (groups -M10 and -M10/-M20). Post-nuclear supernatant (PNS) fraction was prepared from forebrain cortex, resolved by 1D-SDS-PAGE under non-dissociated (-DTT) and dissociated (+DTT) conditions, and analyzed for the content of μ-, δ- and κ-OR by immunoblotting with C- and N-terminus oriented antibodies. Significant down-regulation of δ-OR form exhibiting Mw ≈ 60 kDa was detected in PNS prepared from both (+M10) and (+M10/-M20) rats. However, the total immunoblot signals of μ-, δ- and κ-OR, respectively, were unchanged. Plasma membrane marker Na, K-ATPase, actin and GAPDH were unaffected by morphine in both types of PNS. Membrane-domain marker caveolin-1 and cholesterol level increased in (+M10) rats and this increase was reversed back to control level in (+M10/-M20) rats. In FBC, prolonged exposure of rats to morphine results in minor (δ-OR) or no change (μ- and κ-OR) of opioid receptor content. The reversible increases

  16. Determination of μ-, δ- and κ-opioid receptors in forebrain cortex of rats exposed to morphine for 10 days: Comparison with animals after 20 days of morphine withdrawal.

    Directory of Open Access Journals (Sweden)

    Hana Ujcikova

    Full Text Available Chronic exposure of mammalian organism to morphine results in adaption to persistent high opioid tone through homeostatic adjustments. Our previous results indicated that in the frontal brain cortex (FBC of rats exposed to morphine for 10 days, such a compensatory adjustment was detected as large up-regulation of adenylylcyclases I (8-fold and II (2.5-fold. The other isoforms of AC (III-IX were unchanged. Importantly, the increase of ACI and ACII was reversible as it disappeared after 20 days of morphine withdrawal. Changes of down-stream signaling molecules such as G proteins and adenylylcyclases should respond to and be preceded by primary changes proceeding at receptor level. Therefore in our present work, we addressed the problem of reversibility of the long-term morphine effects on μ-, δ- and κ-OR protein levels in FBC.Rats were exposed to increasing doses of morphine (10-40 mg/kg for 10 days and sacrificed either 24 h (group +M10 or 20 days (group +M10/-M20 after the last dose of morphine in parallel with control animals (groups -M10 and -M10/-M20. Post-nuclear supernatant (PNS fraction was prepared from forebrain cortex, resolved by 1D-SDS-PAGE under non-dissociated (-DTT and dissociated (+DTT conditions, and analyzed for the content of μ-, δ- and κ-OR by immunoblotting with C- and N-terminus oriented antibodies.Significant down-regulation of δ-OR form exhibiting Mw ≈ 60 kDa was detected in PNS prepared from both (+M10 and (+M10/-M20 rats. However, the total immunoblot signals of μ-, δ- and κ-OR, respectively, were unchanged. Plasma membrane marker Na, K-ATPase, actin and GAPDH were unaffected by morphine in both types of PNS. Membrane-domain marker caveolin-1 and cholesterol level increased in (+M10 rats and this increase was reversed back to control level in (+M10/-M20 rats.In FBC, prolonged exposure of rats to morphine results in minor (δ-OR or no change (μ- and κ-OR of opioid receptor content. The reversible increases

  17. Attenuation by dextromethorphan on the higher liability to morphine-induced reward, caused by prenatal exposure of morphine in rat offspring

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    Tao Pao-Luh

    2009-11-01

    Full Text Available Abstract Co-administration of dextromethorphan (DM with morphine during pregnancy and throughout lactation has been found to reduce morphine physical dependence and tolerance in rat offspring. No evidence was presented, however, for the effect of DM co-administered with morphine during pregnancy on morphine-induced reward and behavioral sensitization (possibly related to the potential to induce morphine addiction in morphine-exposed offspring. Conditioned place preference and locomotor activity tests revealed that the p60 male offspring of chronic morphine-treated female rats were more vulnerable to morphine-induced reward and behavioral sensitization. The administration of a low dose of morphine (1 mg/kg, i.p. in these male offspring also increased the dopamine and serotonin turnover rates in the nucleus accumbens, which implied that they were more sensitive to morphine. Co-administration of DM with morphine in the dams prevented this adverse effect of morphine in the offspring rats. Thus, DM may possibly have a great potential in the prevention of higher vulnerability to psychological dependence of morphine in the offspring of morphine-addicted mothers.

  18. μ Opioid Receptor Expression after Morphine Administration Is Regulated by miR-212/132 Cluster.

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    Adrian Garcia-Concejo

    Full Text Available Since their discovery, miRNAs have emerged as a promising therapeutical approach in the treatment of several diseases, as demonstrated by miR-212 and its relation to addiction. Here we prove that the miR-212/132 cluster can be regulated by morphine, through the activation of mu opioid receptor (Oprm1. The molecular pathways triggered after morphine administration also induce changes in the levels of expression of oprm1. In addition, miR-212/132 cluster is actively repressing the expression of mu opioid receptor by targeting a sequence in the 3' UTR of its mRNA. These findings suggest that this cluster is closely related to opioid signaling, and function as a post-transcriptional regulator, modulating morphine response in a dose dependent manner. The regulation of miR-212/132 cluster expression is mediated by MAP kinase pathway, CaMKII-CaMKIV and PKA, through the phosphorylation of CREB. Moreover, the regulation of both oprm1 and of the cluster promoter is mediated by MeCP2, acting as a transcriptional repressor on methylated DNA after prolonged morphine administration. This mechanism explains the molecular signaling triggered by morphine as well as the regulation of the expression of the mu opioid receptor mediated by morphine and the implication of miR-212/132 in these processes.

  19. Chronic intracerebroventricular morphine and lactation in rats: dependence and tolerance in relation to oxytocin neurones.

    Science.gov (United States)

    Rayner, V C; Robinson, I C; Russell, J A

    1988-02-01

    1. Acutely, opioids inhibit oxytocin secretion. To study the responses of oxytocin neurones during chronic opioid exposure, forty-five lactating rats were infused continuously from a subcutaneous osmotically driven mini-pump via a lateral cerebral ventricle with morphine sulphate solution from day 2 post-partum for 5-7 days; the infusion rate was increased 2- or 2.5-fold each 40 h from 10 micrograms/h initially up to 50 micrograms/h; controls were infused with vehicle (1 microliter/h, twenty-eight rats) or were untreated (eight rats). 2. Maternal behaviour was disrupted in 27% of the morphine-treated rats; in rats that remained maternal morphine did not affect body weight or water intake but increased rectal temperature by 0.82 +/- 0.14 degrees C (mean +/- S.E.M.) across the first 4 days. 3. Weight gain of the litters of maternal morphine-treated rats was reduced by 32% during 7 days, predominantly in the first day of treatment when milk transfer was also reduced. Observation of pup behaviour during suckling showed decreased frequency of milk ejections on only the second day of morphine treatment. Plasma concentration of prolactin after 6 days was similar in maternal morphine-treated and control rats, but reduced by 90% in non-maternal morphine-treated rats, indicating normal control of prolactin secretion by suckling in morphine-treated rats. 4. Oxytocin and vasopressin contents, measured by radioimmunoassay, in the supraoptic and paraventricular nuclei and in the neurohypophysis were similar between fourteen maternal morphine-treated, twelve vehicle-treated and eight untreated lactating rats; thus exposure to morphine did not involve increased production and storage of oxytocin. 5. Distribution of [3H]morphine infused intracerebroventricularly into six virgin female rats for 6 days was measured by scintillation counting of tissue extracts. Morphine concentration in the hypothalamus and neurohypophysis was 2.7 and 12.8 micrograms/g, respectively, and in blood

  20. Hippocampal GluA1-containing AMPA receptors mediate context-dependent sensitization to morphine

    OpenAIRE

    Xia, Yan; Portugal, George S.; Fakira, Amanda K.; Melyan, Zara; Neve, Rachael; Lee, H. Thomas; Russo, Scott J.; Liu, Jie; Morón, Jose A.

    2011-01-01

    Glutamatergic systems, including α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are involved in opiate-induced neuronal and behavioral plasticity, although the mechanisms underlying these effects are not fully understood. In the present study, we investigated the effects of repeated morphine administration on AMPAR expression, synaptic plasticity, and context-dependent behavioral sensitization to morphine. We found that morphine treatment produced changes of synaptic...

  1. Influence of renal function on the elimination of morphine and morphine glucuronides

    DEFF Research Database (Denmark)

    Wolff, Jesper; Bigler, Dennis Richard; Christensen, C B

    1988-01-01

    plasma. No significant correlation was found between total body clearance of unconjugated morphine and 51Cr-EDTA clearance. However, patients with renal insufficiency had impaired elimination of morphine glucuronides, and the apparent clearance was significantly correlated with the 51Cr-EDTA clearance (r...... = 0.94, p less than 0.001). A relatively long terminal elimination of half-life of morphine was found in all patients (mean +/- SD: 9.2 +/- 2.5 h), irrespective of glomerular function....

  2. Importance of GluA1 subunit-containing AMPA glutamate receptors for morphine state-dependency.

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    Teemu Aitta-aho

    Full Text Available In state-dependency, information retrieval is most efficient when the animal is in the same state as it was during the information acquisition. State-dependency has been implicated in a variety of learning and memory processes, but its mechanisms remain to be resolved. Here, mice deficient in AMPA-type glutamate receptor GluA1 subunits were first conditioned to morphine (10 or 20 mg/kg s.c. during eight sessions over four days using an unbiased procedure, followed by testing for conditioned place preference at morphine states that were the same as or different from the one the mice were conditioned to. In GluA1 wildtype littermate mice the same-state morphine dose produced the greatest expression of place preference, while in the knockout mice no place preference was then detected. Both wildtype and knockout mice expressed moderate morphine-induced place preference when not at the morphine state (saline treatment at the test; in this case, place preference was weaker than that in the same-state test in wildtype mice. No correlation between place preference scores and locomotor activity during testing was found. Additionally, as compared to the controls, the knockout mice showed unchanged sensitization to morphine, morphine drug discrimination and brain regional μ-opioid receptor signal transduction at the G-protein level. However, the knockout mice failed to show increased AMPA/NMDA receptor current ratios in the ventral tegmental area dopamine neurons of midbrain slices after a single injection of morphine (10 mg/kg, s.c., sliced prepared 24 h afterwards, in contrast to the wildtype mice. The results indicate impaired drug-induced state-dependency in GluA1 knockout mice, correlating with impaired opioid-induced glutamate receptor neuroplasticity.

  3. Antagonism of morphine-induced central respiratory depression by donepezil in the anesthetized rabbit

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    MIKI TSUJITA

    2007-01-01

    Full Text Available Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C0(2. In the other experiment, apneic threshold PaC0(2 was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit

  4. Geraniin attenuates Naloxone-Precipitated Morphine Withdrawal and Morphine-Induced Tolerance in Mice

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    Ella Anle Kasanga

    2017-06-01

    Conclusion: Geraniin does not produce any tolerant effects like morphine and also reduced the signs associated with naloxone-precipitated morphine withdrawal in mice. [J Complement Med Res 2017; 6(2.000: 199-205

  5. Role of music in morphine rewarding effects in mice using conditioned place preference method.

    Science.gov (United States)

    Tavakoli, Farnaz; Hoseini, Seyed Ebrahim; Mokhtari, Mokhtar; Vahdati, Akbar; Razmi, Nematollah; Vessal, Mahmood

    2012-01-01

    This research aims at studying the neuroendocrine effects of music on creating morphine dependence in mice using conditioned place preference (CPP). The mice treated with 10 mg/kg morphine subcutaneously, fast music and slow music. Morphine was used to create dependence. In order to recognize the morphine rewarding effects, CPP technique was used. In the conditioning stage that lasted for 8 days, different groups of mice, after receiving the treatment were randomly placed in compartment for 30 minutes. The post-conditioning stage included the fourth day, the ninth day, the 12th day and the 16th day. Comparing place preference between morphine group and the control group, a significant increase (pmusic group compared with morphine group alone. In addition morphine + alone in the rain music group demonstrated a significantly increased conditioned place preference (pmusic acts as a positive pleasant emotion increasing the dopaminergic activity in the Nucleus Accumbens (NAc) and Ventral Tegmental Area (VTA) and through associated learning mechanisms of reward-related behavior increases morphine addiction. However, taxi girl music may act as unpleasant experiences producing negative emotions and reducing morphine addiction.

  6. Comparison of Intravenous Morphine Versus Paracetamol in Sciatica: A Randomized Placebo Controlled Trial.

    Science.gov (United States)

    Serinken, Mustafa; Eken, Cenker; Gungor, Faruk; Emet, Mucahit; Al, Behcet

    2016-06-01

    The objective was to compare intravenous morphine and intravenous acetaminophen (paracetamol) for pain treatment in patients presenting to the emergency department with sciatica. Patients, between the ages of 21 and 65 years, suffering from pain in the sciatic nerve distribution and a positive straight leg-raise test composed the study population. Study patients were assigned to one of three intravenous interventions: morphine (0.1 mg/kg), acetaminophen (1 g), or placebo. Physicians, nurses, and patients were blinded to the study drug. Changes in pain intensity were measured at 15 and 30 minutes using a visual analog scale. Rescue drug (fentanyl) use and adverse effects were also recorded. Three-hundred patients were randomized. The median change in pain intensity between treatment arms at 30 minutes were as follows: morphine versus acetaminophen 25 mm (95% confidence interval [CI] = 20 to 29 mm), morphine versus placebo 41 mm (95% CI = 37 to 45 mm), and acetaminophen versus placebo 16 mm (95% CI = 12 to 20 mm). Eighty percent of the patients in the placebo group (95% CI = 63.0% to 99%), 18% of the patients in the acetaminophen group (95% CI = 10.7% to 28.5%), and 6% of those in the morphine group (95% CI = 2.0% to 13.2%) required a rescue drug. Adverse effects were similar between the morphine and acetaminophen groups. Morphine and acetaminophen are both effective for treating sciatica at 30 minutes. However, morphine is superior to acetaminophen. © 2016 by the Society for Academic Emergency Medicine.

  7. Variation in pre-treatment count lead time and its effect on baseline estimates of cage-level sea lice abundance.

    Science.gov (United States)

    Gautam, R; Boerlage, A S; Vanderstichel, R; Revie, C W; Hammell, K L

    2016-11-01

    Treatment efficacy studies typically use pre-treatment sea lice abundance as the baseline. However, the pre-treatment counting window often varies from the day of treatment to several days before treatment. We assessed the effect of lead time on baseline estimates, using historical data (2010-14) from a sea lice data management programme (Fish-iTrends). Data were aggregated at the cage level for three life stages: (i) chalimus, (ii) pre-adult and adult male and (iii) adult female. Sea lice counts were log-transformed, and mean counts by lead time relative to treatment day were computed and compared separately for each life stage, using linear mixed models. There were 1,658 observations (treatment events) from 56 sites in 5 Bay Management Areas. Our study showed that lead time had a significant effect on the estimated sea lice abundance, which was moderated by season. During the late summer and autumn periods, counting on the day of treatment gave significantly higher values than other days and would be a more appropriate baseline estimate, while during spring and early summer abundance estimates were comparable among counts within 5 days of treatment. A season-based lead time window may be most appropriate when estimating baseline sea lice levels. © 2016 John Wiley & Sons Ltd.

  8. Morphine regulates Argonaute 2 and TH expression and activity but not miR-133b in midbrain dopaminergic neurons.

    Science.gov (United States)

    García-Pérez, Daniel; López-Bellido, Roger; Hidalgo, Juana M; Rodríguez, Raquel E; Laorden, Maria Luisa; Núñez, Cristina; Milanés, Maria Victoria

    2015-01-01

    Epigenetic changes such as microRNAs (miRs)/Ago2-induced gene silencing represent complex molecular signature that regulate cellular plasticity. Recent studies showed involvement of miRs and Ago2 in drug addiction. In this study, we show that changes in gene expression induced by morphine and morphine withdrawal occur with concomitant epigenetic modifications in the mesolimbic dopaminergic (DA) pathway [ventral tegmental area (VTA)/nucleus accumbens (NAc) shell], which is critically involved in drug-induced dependence. We found that acute or chronic morphine administration as well as morphine withdrawal did not modify miR-133b messenger RNA (mRNA) expression in the VTA, whereas Ago2 protein levels were decreased and increased in morphine-dependent rats and after morphine withdrawal, respectively. These changes were paralleled with enhanced and decreased NAc tyrosine hydroxylase (TH) protein (an early DA marker) in morphine-dependent rats and after withdrawal, respectively. We also observed changes in TH mRNA expression in the VTA that could be related to Ago2-induced translational repression of TH mRNA during morphine withdrawal. However, the VTA number of TH-positive neurons suffered no alterations after the different treatment. Acute morphine administration produced a marked increase in TH activity and DA turnover in the NAc (shell). In contrast, precipitated morphine withdrawal decreased TH activation and did not change DA turnover. These findings provide new information into the possible correlation between Ago2/miRs complex regulation and DA neurons plasticity during opiate addiction. © 2013 Society for the Study of Addiction.

  9. Attenuation of morphine-induced delirium in palliative care by substitution with infusion of oxycodone.

    Science.gov (United States)

    Maddocks, I; Somogyi, A; Abbott, F; Hayball, P; Parker, D

    1996-09-01

    We have observed among patients of the Southern Community Hospice Programme that up to 25% experience acute delirium when treated with morphine and improve when the opioid is changed to oxycodone or fentanyl. This study aimed to confirm by a prospective trial that oxycodone produces less delirium than morphine in such patients. Oxycodone was administered by a continuous subcutaneous infusion, as this allowed more flexible and reliable dosing, and patients were monitored for any adverse reactions to the drug. Thirteen patients completed the study. Statistically significant improvements in mental state and nausea and vomiting occurred following a change from morphine to oxycodone. Pain scores improved but did not reach a level of statistical significance. The phenotype status of the patients was tested to establish their capacity to metabolize oxycodone. One patient who did not achieve adequate pain control proved to be a poor metabolizer. These results show that oxycodone administered by the subcutaneous route can provide effective analgesia without significant side effects in patients with morphine-induced delirium. This treatment allows patients to remain more comfortable and lucid in their final days. A small proportion of patients who do not metabolize oxycodone effectively may not receive this benefit.

  10. Fatal versus non-fatal heroin "overdose": blood morphine concentrations with fatal outcome in comparison to those of intoxicated drivers.

    Science.gov (United States)

    Meissner, Christoph; Recker, Sabine; Reiter, Arthur; Friedrich, Hans Juergen; Oehmichen, Manfred

    2002-11-05

    The study was performed to distinguish fatal from non-fatal blood concentrations of morphine. For this purpose, blood levels of free morphine and total morphine (free morphine plus morphine conjugates) in 207 cases of heroin-related deaths were compared to those in 27 drivers surviving opiate intoxication. The majority of both survivors and non-survivors were found to show a concomitant use of depressants including alcohol or stimulants. Blood morphine levels in both groups varied widely, with a large area of overlap between survivors (free morphine: 0-128 ng/ml, total morphine: 10-2,110 ng/ml) and non-survivors (free morphine: 0-2,800 ng/ml, total morphine: 33-5,000 ng/ml). Five (18.5%) survivors and 87 (42.0%) non-survivors exhibit intoxication only by morphine. In these cases, too, both groups overlapped (survivors-free morphine: 28-93 ng/ml, total morphine: 230-1,451 ng/ml; non-survivors-free morphine: 0-2,800 ng/ml, total morphine: 119-4,660 ng/ml). Although the blood levels of free or total morphine do not allow a reliable prediction of survival versus non-survival, the ratio of free/total morphine may be a criterion to distinguish lethal versus survived intoxication. The mean of the ratio of free to total morphine for all lethal cases (N=207) was 0.293, for those that survived (N=27) 0.135, in cases of intoxication only by morphine 0.250 (N=87) and 0.080 (N=5), respectively. Applying a cut-off of 0.12 for free/total morphine and performing ROC analyses, fatal outcome can be predicted in 80% of the cases correctly, whereas 16% of the survivors were classified as dead. Nevertheless, in this study, all cases with a blood concentration of 200 ng/ml and more of free morphine displayed a fatal outcome.

  11. Comparative bioavailability of a morphine suppository given rectally and in a colostomy

    DEFF Research Database (Denmark)

    Højsted, J; Rubeck-Petersen, K; Rask, H

    1990-01-01

    In eight patients with a colostomy, plasma morphine levels were followed for 8 h after administration of 20 mg morphine chloride as a suppository, first rectally and after at least 48 h via the colostomy. The bioavailability after administration in the colostomy showed very great variation......; the mean value compared to rectal bioavailability was only 43% (range 0.1-127%). In four patients the plasma concentrations of morphine after colostomy administration were lower at all times than after rectal administration, and in three only small amounts of morphine were detectable. One patient showed...... higher plasma concentrations after colostomy application than after rectal administration. It is concluded that administration of morphine suppositories in a colostomy cannot be recommended....

  12. Delayed postoperative gastric emptying following intrathecal morphine and intrathecal bupivacaine.

    LENUS (Irish Health Repository)

    Lydon, A M

    2012-02-03

    PURPOSE: A decrease in the rate of gastric emptying can delay resumption of enteral feeding, alter bioavailability of orally administered drugs, and result in larger residual gastric volumes, increasing the risk of nausea and vomiting. We compared the effects of 1) intrathecal bupivacaine (17.5 mg) and 2) the combination of intrathecal morphine (0.6 mg) and intrathecal bupivacaine (17.5 mg) on the rate of gastric emptying in patients undergoing elective hip arthroplasty. METHODS: Twenty four fasting ASA 1-3 patients were randomly assigned, in a double blind manner, to receive intrathecal hyperbaric bupivacaine (17.5 mg), either alone (group 1), or followed by intrathecal morphine (0.6 mg) (group 2). Gastric emptying was measured (using an acetaminophen absorption technique), twice in each patient; preoperatively, and approximately one hour postoperatively. Gastric emptying parameters are: AUC (area under the plasma acetaminophen concentration time curve), maximum plasma acetaminophen concentration (Cmax), and time to Cmax (tCmax), analyzed using paired Student\\'s t tests. RESULTS: Gastric emptying rates were reduced in both group 1 (AUC = 14.98 (3.8) and 11.05 (4.6) pre- and postoperatively, respectively) and group 2 (AUC = 13.93 (3.59) and 6.4 (3.42) pre- and postoperatively, respectively); the magnitude of the reduction was greater in group 2 [AUC (P = 0.04), Cmax (P = 0.05), tCmax (P = 0.13)]. CONCLUSION: The combination of intrathecal morphine (0.6 mg) and intrathecal bupivacaine (17.5 mg) delays gastric emptying postoperatively.

  13. The effectiveness of Patient Controlled Analgesia (PCA morphine-ketamine compared to Patient Controlled Analgesia (PCA morphine to reduce total dose of morphine and Visual Analog Scale (VAS in postoperative laparotomy surgery

    Directory of Open Access Journals (Sweden)

    I Gusti Ngurah Mahaalit Aribawa

    2017-05-01

    Full Text Available Background: Laparotomy may cause moderate to severe after surgery pain, thus adequate pain management is needed. The addition of ketamine in patient controlled analgesia (PCA morphine after surgery can be the option. This study aims to evaluate the effectiveness of PCA morphine-ketamine compared to PCA morphine in patient postoperative laparotomy surgery to reduce total dose of morphine requirement and pain intensity evaluated with visual analog scale (VAS. Methods: This study was a double-blind RCT in 58 patients of ASA I and II, age 18-64 years, underwent an elective laparotomy at Sanglah General Hospital. Patients were divided into 2 groups. Group A, got addition of ketamine (1mg/ml in PCA morphine (1mg/ml and patients in group B received morphine (1mg/ml by PCA. Prior to surgical incision both group were given a bolus ketamine 0,15mg/ kg and ketorolac 0,5mg/kg. The total dose of morphine and VAS were measured at 6, 12, and 24 hours postoperatively. Result: Total dose of morphine in the first 24 hours postoperatively at morphine-ketamine group (5,1±0,8mg is lower than morphine only group (6,5±0,9mg p<0,001. VAS (resting 6 and 12 hour postoperative in morphine-ketamine group (13,4±4,8 mm and (10,7±2,6 mm are lower than morphine (17,9±4,1mm p≤0,05 and (12,8±5,3mm p≤0,05. VAS (moving 6, 12, and 24 hour postoperative morphineketamine group (24,8±5,1mm, (18±5,6mm and (9±5,6mm are lower than morphine (28,7±5,2mm p≤0,05, (23,1±6,0mm p≤0,05, and (12,8±5,3mm p≤0,05. Conclusions: Addition of ketamine in PCA morphine for postoperative laparotomy surgery reduces total morphine requirements in 24 hours compared to PCA morphine alone.

  14. Unusual pattern of leukoencephalopathy after morphine sulphate intoxication

    Energy Technology Data Exchange (ETDEWEB)

    Nanan, R.; Stockhausen, H.B. von; Petersen, B. [Children' s Hospital, University of Wuerzburg (Germany); Solymosi, L.; Warmuth-Metz, M. [Department for Neuroradiology, University of Wuerzburg (Germany)

    2000-11-01

    We report a 14-year-old girl with an unusual pattern of leukoencephalopathy after intentional intoxication with morphine sulphate tablets. Toxicological analysis showed exceedingly high levels of morphine and its metabolites. MRI disclosed a leukoencephalopathy with high signal from the centrum semiovale, corpus callosum and cerebellar white matter on T2-weighted images. These findings could be only partially explained by a hypoxic-ischaemic event; neurotoxic effects must be considered in this atypical leukoencephalopathy. (orig.)

  15. Unusual pattern of leukoencephalopathy after morphine sulphate intoxication

    International Nuclear Information System (INIS)

    Nanan, R.; Stockhausen, H.B. von; Petersen, B.; Solymosi, L.; Warmuth-Metz, M.

    2000-01-01

    We report a 14-year-old girl with an unusual pattern of leukoencephalopathy after intentional intoxication with morphine sulphate tablets. Toxicological analysis showed exceedingly high levels of morphine and its metabolites. MRI disclosed a leukoencephalopathy with high signal from the centrum semiovale, corpus callosum and cerebellar white matter on T2-weighted images. These findings could be only partially explained by a hypoxic-ischaemic event; neurotoxic effects must be considered in this atypical leukoencephalopathy. (orig.)

  16. Perinatal protein deprivation facilitates morphine cross-sensitization to cocaine and enhances ΔFosB expression in adult rats.

    Science.gov (United States)

    Perondi, María Cecilia; Gutiérrez, María Cecilia; Valdomero, Analía; Cuadra, Gabriel Ricardo

    2017-08-30

    Previous studies have indicated that neural changes induced by early nutritional insult cause an altered response to pharmacological treatments, including addictive drugs. This study evaluates the influence of perinatal protein malnutrition in developing cross-sensitization to cocaine-induced rewarding effects in animals pre-exposed to morphine. Different groups of well-nourished (C-rats) and protein-deprived animals (D-rats) were treated twice a day for three days with increasing doses of morphine or with saline. After 3days, the incentive motivational effects of cocaine were assessed in a Conditioned Place Preference paradigm in both groups. In saline pre-treated animals, dose-response curves to cocaine revealed a conditioning effect in D-rats at doses of 5, 7.5 and 10mg/kg, while this effect was observed in C-rats only with 10 and 15mg/kg. Furthermore, when animals of both groups were pre-treated with escalating doses of morphine, cross-sensitization to the conditioning effect of cocaine was elicited only in D-rats with low doses of cocaine (5 and 7.5mg/kg). In contrast, under the same experimental conditions, C-rats show no cross-sensitization. To correlate this differential rewarding response with a molecular substrate linked to the behavioral changes observed after repeated drug exposure, ΔFosB expression was assessed in different brain regions. D-rats showed a significant increase in this transcription factor in the nucleus accumbens, amygdala and medial prefrontal cortex. These results demonstrated that perinatal protein deprivation facilitates rewarding effects and the development of cross-sensitization to cocaine, which correlates with an upregulation of ΔFosB in brain areas related to the reward circuitry. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Distribution of 14C-morphine and macromolecules in the brain and liver and their nuclei in pregnant rats and their foetuses after infusion of morphine into pregnant rats at near-term

    International Nuclear Information System (INIS)

    Steele, W.J.; Johannesson, T.

    1975-01-01

    Timed-pregnant (day 21 or 22) Sprague-Dawley rats were administered 14 C-morphine (2.85 mci/mmol) 5 mg/kg/hr, or saline in equivalent volumes, by continuous intravenous infusion for periods of up to 4hrs. The brains and livers of the maternal rats and of their foetuses were collected and their nuclei were isolated. The tissues and nuclei isolated from them were analyzed for DNA, RNA, protein content and radioactivity. Morphine infused maternal rats exhibited no significant difference in the total amount of DNA, RNA and protein in the brain or in the concentration of these constituents in brain nuclei. The concentration of nuclear RNA in foetal brain of morphine infused mothers was significantly lower at 4 hrs than that of saline infused controls. It was concluded that RNA synthesis in the foetal brain must be much more sensitive to the inhibitory effect of morphine on macromolecular synthesis than that in maternal brain. The change in nuclear RNA concentration in foetal brain became significantly different when morphine reached its highest level in foetal brain nuclei. The morphine concentration (pmol 14 C-morphine equivalents per mg DNA) in the brain of foetal and maternal rats was the same at each time period, whereas the maternal liver levels were at least eight times greater than those in foetal liver. The concentrations in foetal brain nuclei were 2-14 times greater than those in maternal brain nuclei, whereas levels in the latter were found to be low and virtually constant at all time periods tested. It was concluded that foetal brain nuclei have a greater capacity to bind or retain morphine than maternal brain nuclei. (author)

  18. Reversal effect of intra-central amygdala microinjection of L-arginine on place aversion induced by naloxone in morphine conditioned rats.

    Science.gov (United States)

    Karimi, Sara; Karami, Manizheh; Sahraei, Hedayat; Rahimpour, Mahnaz

    2011-01-01

    Role of nitric oxide (NO) on expression of morphine conditioning using a solely classic task has been proposed previously. In this work, the involvement of NO on the expression of opioid-induced conditioning in the task paired with an injection of naloxone was investigated. Conditioning was established in adult male Wistar rats (weighing 200-250 g) using an unbiased procedure. Naloxone (0.05-0.4 mg/kg, i.p.), a selective antagonist of mu-opioid receptor, was administered once prior to morphine response testing. NO agents were administered directly into the central amygdala (CeA) prior to naloxone injection pre-testing. Morphine (2.5-10 mg/kg, s.c.) produced a significant dose-dependent place preference in experimental animals. When naloxone (0.05-0.4 mg/kg, i.p.) was injected before testing of morphine (5 mg/kg, s.c.) response, the antagonist induced a significant aversion. This response was reversed due to injection of L-arginine (0.3-3 microg/rat), intra-CeA prior to naloxone administration. However, pre-injection of L-NAME (intra-CeA), an inhibitor of NO production, blocked this effect. The finding may reflect that NO in the nucleus participates in morphine plus naloxone interaction.

  19. Distribution of /sup 14/C-morphine and macromolecules in the brain and liver and their nuclei in pregnant rats and their foetuses after infusion of morphine into pregnant rats at near-term

    Energy Technology Data Exchange (ETDEWEB)

    Steele, W J; Johannesson, T [Iowa Univ., Iowa City (USA)

    1975-01-01

    Timed-pregnant (day 21 or 22) Sprague-Dawley rats were administered /sup 14/C-morphine (2.85 mci/mmol) 5 mg/kg/hr, or saline in equivalent volumes, by continuous intravenous infusion for periods of up to 4hrs. The brains and livers of the maternal rats and of their foetuses were collected and their nuclei were isolated. The tissues and nuclei isolated from them were analyzed for DNA, RNA, protein content and radioactivity. Morphine infused maternal rats exhibited no significant difference in the total amount of DNA, RNA and protein in the brain or in the concentration of these constituents in brain nuclei. The concentration of nuclear RNA in foetal brain of morphine infused mothers was significantly lower at 4 hrs than that of saline infused controls. It was concluded that RNA synthesis in the foetal brain must be much more sensitive to the inhibitory effect of morphine on macromolecular synthesis than that in maternal brain. The change in nuclear RNA concentration in foetal brain became significantly different when morphine reached its highest level in foetal brain nuclei. The morphine concentration (pmol /sup 14/C-morphine equivalents per mg DNA) in the brain of foetal and maternal rats was the same at each time period, whereas the maternal liver levels were at least eight times greater than those in foetal liver. The concentrations in foetal brain nuclei were 2-14 times greater than those in maternal brain nuclei, whereas levels in the latter were found to be low and virtually constant at all time periods tested. It was concluded that foetal brain nuclei have a greater capacity to bind or retain morphine than maternal brain nuclei.

  20. Comparison of Electroacupuncture and Morphine-Mediated Analgesic Patterns in a Plantar Incision-Induced Pain Model

    Directory of Open Access Journals (Sweden)

    Yen-Jing Zeng

    2014-01-01

    Full Text Available Electroacupuncture (EA is a complementary therapy to improve morphine analgesia for postoperative pain, but underlying mechanism is not well-known. Herein, we investigated EA-induced analgesic effect in a plantar incision (PI model in male Sprague-Dawley rats. PI was performed at the left hind paw. EA of 4 Hz and high intensity or sham needling was conducted at right ST36 prior to PI and repeated for another 2 days. Behavioral responses to mechanical and thermal stimuli, spinal phospho-ERK, and Fos expression were all analyzed. In additional groups, naloxone and morphine were administered to elucidate involvement of opioid receptors and for comparison with EA. EA pretreatment significantly reduced post-PI tactile allodynia for over 1 day; repeated treatments maintained analgesic effect. Intraperitoneal naloxone could reverse EA analgesia. Low-dose subcutaneous morphine (1 mg/kg had stronger inhibitory effect on PI-induced allodynia than EA for 1 h. However, analgesic tolerance appeared after repeated morphine injections. Both EA and morphine could equally inhibit PI-induced p-ERK and Fos inductions. We conclude that though EA and morphine attenuate postincision pain through opioid receptor activations, daily EA treatments result in analgesic accumulation whereas daily morphine injections develop analgesic tolerance. Discrepant pathways and mechanisms underlying two analgesic means may account for the results.

  1. Long-term morphine delivery via slow release morphine pellets or osmotic pumps: Plasma concentration, analgesia, and naloxone-precipitated withdrawal.

    Science.gov (United States)

    McLane, Virginia D; Bergquist, Ivy; Cormier, James; Barlow, Deborah J; Houseknecht, Karen L; Bilsky, Edward J; Cao, Ling

    2017-09-15

    Slow-release morphine sulfate pellets and osmotic pumps are common routes of chronic morphine delivery in mouse models, but direct comparisons of these drug delivery systems are lacking. In this study, we assessed the efficacy of slow-release pellets versus osmotic pumps in delivering morphine to adult mice. Male C57BL/6NCr mice (8weeksold) were implanted subcutaneously with slow-release pellets (25mg morphine sulfate) or osmotic pumps (64mg/mL, 1.0μL/h). Plasma morphine concentrations were quantified via LC-MS/MS, analgesic efficacy was determined by tail flick assay, and dependence was assessed with naloxone-precipitated withdrawal behaviors (jumping) and physiological effects (excretion, weight loss). Morphine pellets delivered significantly higher plasma drug concentrations compared to osmotic pumps, which were limited by the solubility of the morphine sulfate and pump volume/flow rate. Within 96h post-implantation, plasma morphine concentrations were indistinguishable in pellet vs. pump-treated samples. While osmotic pump did not have an antinociceptive effect in the tail flick assay, pumps and pellets induced comparable dependence symptoms (naloxone-precipitated jumping behavior) from 24-72h post-implantation. In this study, we compared slow-release morphine pellets to osmotic minipumps for morphine delivery in mice. We found that osmotic pumps and subcutaneous morphine sulfate pellets yielded significantly different pharmacokinetics over a 7-day period, and as a result significantly different antinociceptive efficacy. Nonetheless, both delivery methods induced dependence as measured by naloxone-precipitated withdrawal. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Effects of maropitant, acepromazine, and electroacupuncture on vomiting associated with administration of morphine in dogs.

    Science.gov (United States)

    Koh, Ronald B; Isaza, Natalie; Xie, Huisheng; Cooke, Kirsten; Robertson, Sheilah A

    2014-04-01

    To evaluate effects of maropitant, acepromazine, and electroacupuncture on morphine-related signs of nausea and vomiting in dogs and assess sedative effects of the treatments. Randomized controlled clinical trial. 222 dogs. Dogs received 1 of 6 treatments: injection of saline (0.9% NaCl) solution, maropitant citrate, or acepromazine maleate or electroacupuncture treatment at 1 acupoint, 5 acupoints, or a sham acupoint. Morphine was administered after 20 minutes of electroacupuncture treatment or 20 minutes after injectable treatment. Vomiting and retching events and signs of nausea and sedation were recorded. Incidence of vomiting and retching was significantly lower in the maropitant (14/37 [37.8%]) group than in the saline solution (28/37 [75.7%]) and sham-acupoint electroacupuncture (32/37 [86.5%]) groups. The number of vomiting and retching events in the maropitant (21), acepromazine (38), 1-acupoint (35), and 5-acupoint (34) groups was significantly lower than in the saline solution (88) and sham-acupoint electroacupuncture (109) groups. Incidence of signs of nausea was significantly lower in the acepromazine group (3/37 [8.1%]) than in the sham-acupoint group (15/37 [40.5%]). Mean nausea scores for the saline solution, maropitant, and sham-acupoint electroacupuncture groups increased significantly after morphine administration, whereas those for the acepromazine, 1-acupoint electroacupuncture, and 5-acupoint electroacupuncture groups did not. Mean sedation scores after morphine administration were significantly higher in dogs that received acepromazine than in dogs that received saline solution, maropitant, and sham-acupoint electroacupuncture treatment. Maropitant treatment was associated with a lower incidence of vomiting and retching, compared with control treatments, and acepromazine and electroacupuncture appeared to prevent an increase in severity of nausea following morphine administration in dogs.

  3. Perioperative analgesia after intrathecal fentanyl and morphine or morphine alone for cesarean section: A randomized controlled study.

    Science.gov (United States)

    Weigl, Wojciech; Bieryło, Andrzej; Wielgus, Monika; Krzemień-Wiczyńska, Świetlana; Kołacz, Marcin; Dąbrowski, Michał J

    2017-12-01

    Intrathecal morphine is used in the postoperative management of pain after caesarean section (CS), but might not be optimal for intraoperative analgesia. We hypothesized that intrathecal fentanyl could supplement intraoperative analgesia when added to a local anesthetic and morphine without affecting management of postoperative pain. This prospective, randomized, double-blind, parallel-group study included 60 parturients scheduled for elective CS. Spinal anesthesia consisted of bupivacaine with either morphine 100 μg (M group), or fentanyl 25 μg and morphine 100 μg (FM group). The frequency of intraoperative pain and pethidine consumption in the 24 hours postoperatively was recorded. Fewer patients in the FM group required additional intraoperative analgesia (P fentanyl and morphine may provide better perioperative analgesia than morphine alone in CS and could be useful when the time from anesthesia to skin incision is short. However, an increase in PONV and possible acute spinal opioid tolerance after addition of intrathecal fentanyl warrants further investigation using lower doses of fentanyl.

  4. Brain receptors for thyrotropin releasing hormone in morphine tolerant-dependent rats

    Energy Technology Data Exchange (ETDEWEB)

    Bhargava, H.N.; Das, S.

    1986-03-01

    The effect of chronic treatment of rats with morphine and its subsequent withdrawal on the brain receptors for thyrotropin releasing hormone (TRH) labeled with /sup 3/H-(3MeHis/sup 2/)TRH (MeTRH). Male Sprague Dawley rats were implanted with 4 morphine pellets (each containing 75 mg morphine base) during a 3-day period. Placebo pellet implanted rats served as controls. Both tolerance to and dependence on morphine developed as a result of this procedure. For characterization of brain TRH receptors, the animals were sacrificed 72 h after the implantation of first pellet. In another set of animals the pellets were removed and were sacrificed 24 h later. The binding of /sup 3/H-MeTRH to membranes prepared from brain without the cerebellum was determined. /sup 3/H-MeTRH bound to brain membranes prepared from placebo pellet implanted rats at a single high affinity site with a B/sub max/ value of 33.50 +/- 0.97 fmol/mg protein and a K/sub d/ of 5.18 +/- 0.21 nM. Implantation of morphine pellets did not alter the B/sub max/ value of /sup 3/H-MeTRH but decreased the K/sub d/ value significantly. Abrupt or naloxone precipitated withdrawal of morphine did not alter B/sub max/ or the K/sub d/ values. The binding of /sup 3/H-MeTRH to brain areas was also determined. The results suggest that the development of tolerance to morphine is associated with enhanced sensitivity of brain TRH receptors, however abrupt withdrawal of morphine does not change the characteristics of brain TRH receptors.

  5. Long-term Morphine-treated Rats are more Sensitive to Antinociceptive Effect of Diclofenac than the Morphine-naive rats

    OpenAIRE

    Akbari, Esmaeil; Mirzaei, Ebrahim; Shahabi Majd, Naghi

    2013-01-01

    This study investigates the effectiveness of the antinociceptive effects of diclofenac, an NSAID, on the nociceptive behavior of morphine-treated rats on formalin test. Rats were treated with morphine-containing drinking water for twenty one days, which induced morphine dependence. The antinociceptive effects of 8, 16, and 32 mg/kg doses of diclofenac were then evaluated and compared with distilled water in a formalin-based model of pain. Diclofenac potentiated pain suppression in morphine-de...

  6. Comparison of pre-treatment and post-treatment use of selenium in retinal ischemia reperfusion injury

    Directory of Open Access Journals (Sweden)

    Alper Yazici

    2015-04-01

    Full Text Available AIM: To investigate the effects of selenium in rat retinal ischemia reperfusion (IR model and compare pre-treatment and post-treatment use. METHODS: Selenium pre-treatment group (n=8 was treated with intraperitoneal (i.p. selenium 0.5 mg/kg for 7d and terminated 24h after the IR injury. Selenium post-treatment group (n=8 was treated with i.p. selenium 0.5 mg/kg for 7d after the IR injury with termination at the end of the 7d period. Sham group (n=8 received i.p. saline injections identical to the selenium volume for 7d with termination 24h after the IR injury. Control group (n=8 received no intervention. Main outcome measures were retina superoxide dismutase (SOD, glutathione (GSH, total antioxidant status (TAS, malondialdehyde (MDA, DNA fragmentation levels, and immunohistological apoptosis evaluation. RESULTS: Compared to the Sham group, selenium pre-treatment had a statistical difference in all parameters except SOD. Post-treatment selenium also resulted in statistical differences in all parameters except the MDA levels. When comparing selenium groups, the pre-treatment selenium group had a statistically higher success in reduction of markers of cell damage such as MDA and DNA fragmentation. In contrast, the post-selenium treatment group had resulted in statistically higher levels of GSH. Histologically both selenium groups succeeded to limit retinal thickening and apoptosis. Pre-treatment use was statistically more successful in decreasing apoptosis in ganglion cell layer compared to post-treatment use. CONCLUSION: Selenium was successful in retinal protection in IR injuries. Pre-treatment efficacy was superior in terms of prevention of tissue damage and apoptosis.

  7. Oxytocin receptor antagonist treatments alter levels of attachment to mothers and central dopamine activity in pre-weaning mandarin vole pups.

    Science.gov (United States)

    He, Zhixiong; Hou, Wenjuan; Hao, Xin; Dong, Na; Du, Peirong; Yuan, Wei; Yang, Jinfeng; Jia, Rui; Tai, Fadao

    2017-10-01

    Oxytocin (OT) is known to be important in mother-infant bonding. Although the relationship between OT and filial attachment behavior has been studied in a few mammalian species, the effects on infant social behavior have received little attention in monogamous species. The present study examined the effects of OT receptor antagonist (OTA) treatment on attachment behavior and central dopamine (DA) activity in male and female pre-weaning mandarin voles (Microtus mandarinus). Our data showed that OTA treatments decreased the attachment behavior of pups to mothers, measured using preference tests at postnatal day 14, 16, 18 and 20. OTA treatments reduced serum OT concentration in pre-weaning pups and decreased tyrosine hydroxylase (TH) levels in the ventral tegmental area (VTA), indicating a decrease in central DA activity. In male and female pups, OTA reduced DA levels, DA 1-type receptor (D1R) and DA 2-type receptor (D2R) protein expression in the nucleus accumbens (NAcc). Our results indicate that OTA treatment inhibits the attachment of pre-weaning pups to mothers. This inhibition is possibly associated with central DA activity and levels of two types of dopamine receptor in the NAcc. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Effect of prenatal restraint stress and morphine co-administration on plasma vasopressin concentration and anxiety behaviors in adult rat offspring.

    Science.gov (United States)

    Nakhjiri, Elnaz; Saboory, Ehsan; Roshan-Milani, Shiva; Rasmi, Yousef; Khalafkhani, Davod

    2017-03-01

    Stressful events and exposure to opiates during gestation have important effects on the later mental health of the offspring. Anxiety is among the most common mental disorders. The present study aimed to identify effects of prenatal restraint stress and morphine co-administration on plasma vasopressin concentration (PVC) and anxiety behaviors in rats. Pregnant rats were divided into four groups (n = 6, each): saline, morphine, stress + saline and stress + morphine treatment. The stress procedure consisted of restraint twice per day, two hours per session, for three consecutive days starting on day 15 of pregnancy. Rats in the saline and morphine groups received either 0.9% saline or morphine intraperitoneally on the same days. In the morphine/saline + stress groups, rats were exposed to restraint stress and received either morphine or saline intraperitoneally. All offspring were tested in an elevated plus maze (EPM) on postnatal day 90 (n = 6, each sex), and anxiety behaviors of each rat were recorded. Finally, blood samples were collected to determine PVC. Prenatal morphine exposure reduced anxiety-like behaviors. Co-administration of prenatal stress and morphine increased locomotor activity (LA) and PVC. PVC was significantly lower in female offspring of the morphine and morphine + stress groups compared with males in the same group, but the opposite was seen in the saline + stress group. These data emphasize the impact of prenatal stress and morphine on fetal neuroendocrine development, with long-term changes in anxiety-like behaviors and vasopressin secretion. These changes are sex specific, indicating differential impact of prenatal stress and morphine on fetal neuroendocrine system development. Lay Summary Pregnant women are sometimes exposed to stressful and painful conditions which may lead to poor outcomes for offspring. Opiates may provide pain and stress relief to these mothers. In this study, we used an experimental model of

  9. Comparison of Intravenous Morphine with Sublingual Buprenorphine in Management of Postoperative Pain after Closed Reduction Orthopedic Surgery.

    Science.gov (United States)

    Soltani, Ghasem; Khorsand, Mahmood; Shamloo, Alireza Sepehri; Jarahi, Lida; Zirak, Nahid

    2015-10-01

    Postoperative pain is a common side effect following surgery that can significantly reduce surgical quality and patient's satisfaction. Treatment options are morphine and buprenorphine. We aimed to compare the efficacy of a single dose of intravenous morphine with sublingual buprenorphine in postoperative pain control following closed reduction surgery. This triple blind clinical trial was conducted on 90 patients referred for closed reduction orthopedic surgery. They were older than 18 years and in classes I and II of the American Society of Anesthesiologists (ASA) with an operation time of 30-90 minutes. Patients were divided into two groups of buprenorphine (4.5µg/kg sublingually) and morphine (0.2mg/kg intravenously). Baseline characteristics, vital signs, pain score, level of sedation and pharmacological side effects were recorded in the recovery room (at 0 and 30 minutes), and in the ward (at 3, 6 and 12 hours). SPSS version 19 software was used for data analysis and the significance level was set at P<0.05. Ninety patients were studied, 60 males and 30 females with a mean age of 37.7±16.2 years. There was no significant difference between the two groups in terms of baseline characteristics. Pain score in the morphine group was significantly higher than the buprenorphine group with an average score of 2.5 (P<0.001). Postoperative mean heart rate in the buprenorphine group was four beats lower than the morphine group (P<0.001). Also, in the buprenorphine 48.6% and in the morphine group 86.7% of cases were conscious in recovery (P=0.001) with a higher rate of pruritus in the latter group (P=0.001). Sublingual buprenorphine administration before anesthesia induction in closed reduction surgery can lead to better postoperative pain control in comparison to intravenous morphine. Due to simple usage and longer postoperative sedation, sublingual buprenorphine is recommended as a suitable drug in closed reduction surgery.

  10. Interactive effects of morphine and dopaminergic compounds on spatial working memory in rhesus monkeys

    Institute of Scientific and Technical Information of China (English)

    Jian-Hong Wang; Joshua Dominie Rizak; Yan-Mei Chen; Liang Li; Xin-Tian Hu; Yuan-Ye Ma

    2013-01-01

    Opiates and dopamine (DA) play key roles in learning and memory in humans and animals.Although interactions between these neurotransmitters have been found,their functional roles remain to be fully elucidated,and their dysfunction may contribute to human diseases and addiction.Here we investigated the interactions of morphine and dopaminergic neurotransmitter systems with respect to learning and memory in rhesus monkeys by using the Wisconsin General Test Apparatus (WGTA) delayed-response task.Morphine and DA agonists (SKF-38393,apomorphine and bromocriptine) or DA antagonists (SKF-83566,haloperidol and sulpiride) were co-administered to the monkeys 30 min prior to the task.We found that dose-patterned co-administration of morphine with D1 or D2 antagonists or agonists reversed the impaired spatial working memory induced by morphine or the compounds alone.For example,morphine at 0.01 mg/kg impaired spatial working memory,while morphine (0.01 mg/kg) and apomorphine (0.01 or 0.06 mg/kg) co-treatment ameliorated this effect.Our findings suggest that the interactions between morphine and dopaminergic compounds influence spatial working memory in rhesus monkeys.A better understanding of these interactive relationships may provide insights into human addiction.

  11. Effects of morphine on replication of herpes simplex virus type 1 and 2

    African Journals Online (AJOL)

    Several drugs are being used in treatment of HSV (Herpesviridae) infection in human but still introducing an effective safe drug is desirable. We investigated the inhibitory effect of morphine on replication of HSV in vitro. The results indicated that a concentration of up to 200 ìg/ml morphine had a limited effect on Vero cell ...

  12. Comparison of Intravenous Morphine with Sublingual Buprenorphine in Management of Postoperative Pain after Closed Reduction Orthopedic Surgery

    Directory of Open Access Journals (Sweden)

    Ghasem Soltani

    2015-09-01

    Full Text Available Background: Postoperative pain is a common side effect following surgery that can significantly reduce surgical quality and patient’s satisfaction. Treatment options are morphine and buprenorphine. We aimed to compare the efficacy of a single dose of intravenous morphine with sublingual buprenorphine in postoperative pain control following closed reduction surgery. Methods: This triple blind clinical trial was conducted on 90 patients referred for closed reduction orthopedic surgery. They were older than 18 years and in classes I and II of the American Society of Anesthesiologists (ASA with an operation time of 30-90 minutes. Patients were divided into two groups of buprenorphine (4.5μg/kg sublingually and morphine (0.2mg/kg intravenously. Baseline characteristics, vital signs, pain score, level of sedation and pharmacological side effects were recorded in the recovery room (at 0 and 30 minutes, and in the ward (at 3, 6 and 12 hours. SPSS version 19 software was used for data analysis and the significance level was set at P Results: Ninety patients were studied, 60 males and 30 females with a mean age of 37.7±16.2 years. There was no significant difference between the two groups in terms of baseline characteristics.Pain score in the morphine group was significantly higher than the buprenorphine group with an average score of 2.5 (P

  13. Comparison of Intravenous Morphine with Sublingual Buprenorphine in Management of Postoperative Pain after Closed Reduction Orthopedic Surgery

    Directory of Open Access Journals (Sweden)

    Ghasem Soltani

    2015-10-01

    Full Text Available Background: Postoperative pain is a common side effect following surgery that can significantly reduce surgical quality and patient’s satisfaction. Treatment options are morphine and buprenorphine. We aimed to compare the efficacy of a single dose of intravenous morphine with sublingual buprenorphine in postoperative pain control following closed reduction surgery. Methods: This triple blind clinical trial was conducted on 90 patients referred for closed reduction orthopedic surgery. They were older than 18 years and in classes I and II of the American Society of Anesthesiologists (ASA with an operation time of 30-90 minutes. Patients were divided into two groups of buprenorphine (4.5μg/kg sublingually and morphine (0.2mg/kg intravenously. Baseline characteristics, vital signs, pain score, level of sedation and pharmacological side effects were recorded in the recovery room (at 0 and 30 minutes, and in the ward (at 3, 6 and 12 hours. SPSS version 19 software was used for data analysis and the significance level was set at P Results: Ninety patients were studied, 60 males and 30 females with a mean age of 37.7±16.2 years. There was no significant difference between the two groups in terms of baseline characteristics.Pain score in the morphine group was significantly higher than the buprenorphine group with an average score of 2.5 (P

  14. Biphasic Effect of Curcumin on Morphine Tolerance: A Preliminary Evidence from Cytokine/Chemokine Protein Array Analysis

    Directory of Open Access Journals (Sweden)

    Jui-An Lin

    2011-01-01

    Full Text Available The aim of this study was to evaluate the effect of curcumin on morphine tolerance and the corresponding cytokine/chemokine changes. Male ICR mice were made tolerant to morphine by daily subcutaneous injection for 7 days. Intraperitoneal injections of vehicle, low-dose or high-dose curcumin were administered 15 min after morphine injection, either acutely or chronically for 7 days to test the effect of curcumin on morphine-induced antinociception and development of morphine tolerance. On day 8, cumulative dose-response curves were generated and the 50% of maximal analgesic dose values were calculated and compared among groups. Corresponding set of mice were used for analyzing the cytokine responses by antibody-based cytokine protein array. Acute, high-dose curcumin enhanced morphine-induced antinociception. While morphine tolerance was attenuated by administration of low-dose curcumin following morphine injections for 7 days, it was aggravated by chronic high-dose curcumin following morphine injection, suggesting a biphasic effect of curcumin on morphine-induced tolerance. Of the 96 cytokine/chemokines analyzed by mouse cytokine protein array, 14 cytokines exhibited significant changes after the different 7-day treatments. Mechanisms for the modulatory effects of low-dose and high-dose curcumin on morphine tolerance were discussed. Even though curcumin itself is a neuroprotectant and low doses of the compound serve to attenuate morphine tolerance, high-doses of curcumin might cause neurotoxicity and aggravate morphine tolerance by inhibiting the expression of antiapoptotic cytokines and neuroprotective factors. Our results indicate that the effect of curcumin on morphine tolerance may be biphasic, and therefore curcumin should be used cautiously.

  15. Aloe vera Aqueous Extract Effect on Morphine Withdrawal Syndrome in Morphine-Dependent Female Rats.

    Science.gov (United States)

    Shahraki, Mohammad Reza; Mirshekari, Hamideh; Sabri, Azame

    2014-09-01

    Aloe vera is a medicinal herb used as an anti-inflammatory and sedative agent. The current study aimed to evaluate the effect of Aloe vera aqueous extract on morphine withdrawal symptoms in morphine-dependent female rats. The current research was performed on 40 female Wista-Albino rats which were made dependent on morphine using Houshyar protocol and were randomly divided into five groups (A, B, C, D, and E). Group A did not receive any agent in the period of handling but other groups (B, C, D and E) received 5, 10, 20 and 40 mg/kg of Aloe vera aqueous extract by gavage, three times daily for a week, respectively. Withdrawal symptoms, stool form, agitation, disparity, floppy eyelids, and body mass variations were checked for 10 days. The obtained data were analyzed using SPSS v.11 software, and Friedman, Kruskal-Wallis, and Mann-Whitney statistical tests. Statistical difference was considered significant (P E were significantly higher than those of others groups; however, these symptoms in group C were significantly lower than those of the other groups. The results of the present study revealed that the Aloe vera aqueous extract had various effects on morphine withdrawal syndrome in morphine-dependent female rats .

  16. The Effect of Acepromazine Alone or in Combination with Methadone, Morphine, or Tramadol on Sedation and Selected Cardiopulmonary Variables in Sheep

    Directory of Open Access Journals (Sweden)

    Lilian Toshiko Nishimura

    2017-01-01

    Full Text Available The sedative and selected cardiopulmonary effects of acepromazine alone or in combination with methadone, morphine, or tramadol were compared in sheep. Six ewes were randomly assigned to treatments: A (0.05 mg/kg acepromazine, AM (A plus 0.5 mg/kg methadone, AMO (A plus 0.5 mg/kg morphine, and AT (A plus 5 mg/kg tramadol. Parameters were assessed before sedative drug administration (baseline and every 15 minutes thereafter, for two hours. Treatments A and AM were associated with increases in sedation score for 60 minutes and treatments AMO and AT for 30 minutes; however, there were no significant differences between treatments. There was a decrease in mean arterial pressure compared to baseline values in treatment A at 15, 45, 60, and 90 minutes, in treatment AM at 15 minutes, and in treatment AT from 45 to 120 minutes. Arterial blood carbon dioxide pressure increased at all time points in all treatments. Arterial oxygen pressure decreased in treatment AMO at 15, 30, and 120 minutes and in treatment AT at 15–45, 105, and 120 minutes, compared to baseline. Acepromazine alone causes a level of sedation similar to that observed when it is coadministered with opioids methadone, morphine, and tramadol. These combinations did not cause clinical cardiopulmonary changes.

  17. Opiate sensitization induces FosB/ΔFosB expression in prefrontal cortical, striatal and amygdala brain regions.

    Directory of Open Access Journals (Sweden)

    Gary B Kaplan

    Full Text Available Sensitization to the effects of drugs of abuse and associated stimuli contributes to drug craving, compulsive drug use, and relapse in addiction. Repeated opiate exposure produces behavioral sensitization that is hypothesized to result from neural plasticity in specific limbic, striatal and cortical systems. ΔFosB and FosB are members of the Fos family of transcription factors that are implicated in neural plasticity in addiction. This study examined the effects of intermittent morphine treatment, associated with motor sensitization, on FosB/ΔFosB levels using quantitative immunohistochemistry. Motor sensitization was tested in C57BL/6 mice that received six intermittent pre-treatments (on days 1, 3, 5, 8, 10, 12 with either subcutaneous morphine (10 mg/kg or saline followed by a challenge injection of morphine or saline on day 16. Mice receiving repeated morphine injections demonstrated significant increases in locomotor activity on days 8, 10, and 12 of treatment (vs. day 1, consistent with development of locomotor sensitization. A morphine challenge on day 16 significantly increased locomotor activity of saline pre-treated mice and produced even larger increases in motor activity in the morphine pre-treated mice, consistent with the expression of opiate sensitization. Intermittent morphine pre-treatment on these six pre-treatment days produced a significant induction of FosB/ΔFosB, measured on day 16, in multiple brain regions including prelimbic (PL and infralimbic (IL cortex, nucleus accumbens (NAc core, dorsomedial caudate-putamen (CPU, basolateral amygdala (BLA and central nucleus of the amygdala (CNA but not in a motor cortex control region. Opiate induced sensitization may develop via Fos/ΔFosB plasticity in motivational pathways (NAc, motor outputs (CPU, and associative learning (PL, IL, BLA and stress pathways (CNA.

  18. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part I.

    Science.gov (United States)

    Armstrong, Scott C; Cozza, Kelly L

    2003-01-01

    Pharmacokinetic drug-drug interactions with morphine, hydromorphone, and oxymorphone are reviewed in this column. Morphine is a naturally occurring opiate that is metabolized chiefly through glucuronidation by uridine diphosphate glucuronosyl transferase (UGT) enzymes in the liver. These enzymes produce an active analgesic metabolite and a potentially toxic metabolite. In vivo drug-drug interaction studies with morphine are few, but they do suggest that inhibition or induction of UGT enzymes could alter morphine and its metabolite levels. These interactions could change analgesic efficacy. Hydromorphone and oxymorphone, close synthetic derivatives of morphine, are also metabolized primarily by UGT enzymes. Hydromorphone may have a toxic metabolite similar to morphine. In vivo drug-drug interaction studies with hydromorphone and oxymorphone have not been done, so it is difficult to make conclusions with these drugs.

  19. Human gliomas contain morphine

    DEFF Research Database (Denmark)

    Olsen, Peter; Rasmussen, Mads; Zhu, Wei

    2005-01-01

    BACKGROUND: Morphine has been found in cancer cell lines originating from human and animal cells. Thus, it became important to demonstrate whether or not actual tumours contain this opiate alkaloid. MATERIAL/METHODS: Human glioma tissues were biochemically treated to isolate and separate endogeno...... of the solutions used in the study nor was it present as a residual material in blank HPLC runs. CONCLUSIONS: Morphine is present in human gliomas, suggesting that it may exert an action that effects tumour physiology/pathology.......BACKGROUND: Morphine has been found in cancer cell lines originating from human and animal cells. Thus, it became important to demonstrate whether or not actual tumours contain this opiate alkaloid. MATERIAL/METHODS: Human glioma tissues were biochemically treated to isolate and separate endogenous...

  20. False-positive buprenorphine EIA urine toxicology results due to high dose morphine: a case report.

    Science.gov (United States)

    Tenore, Peter L

    2012-01-01

    In monitoring a patient with chronic pain who was taking high-dose morphine and oxycodone with weekly urine enzymatic immunoassay (EIA) toxicology testing, the authors noted consistent positives for buprenorphine. The patient was not taking buprenorphine, and gas chromatography/mass spectroscopy (GCMS) testing on multiple samples revealed no buprenorphine, indicating a case of false-positive buprenorphine EIAs in a high-dose opiate case. The authors discontinued oxycodone for a period of time and then discontinued morphine. Urine monitoring with EIAs and GCMS revealed false-positive buprenorphine EIAs, which remained only when the patient was taking morphine. When taking only oxycodone and no morphine, urine samples became buprenorphine negative. When morphine was reintroduced, false-positive buprenorphine results resumed. Medical practitioners should be aware that high-dose morphine (with morphine urine levels turning positive within the 15,000 to 28,000 mg/mL range) may produce false-positive buprenorphine EIAs with standard urine EIA toxicology testing.

  1. Immediate and prolonged effects of pre- versus postoperative epidural analgesia with bupivacaine and morphine on pain at rest and during mobilisation after total knee arthroplasty

    DEFF Research Database (Denmark)

    Dahl, J B; Daugaard, J J; Rasmussen, B

    1994-01-01

    with bupivacaine 7.5 mg.ml-1, 2 ml. General anaesthesia was induced with thiopentone, pancuronium or atracurium, and fentanyl 0.1-0.3 mg, and maintained with N2O/O2 and enflurane. The epidural regimen consisted of a bolus of 16 ml of bupivacaine 7.5 mg.ml-1 plus morphine 2 mg, and continuous infusion...... of bupivacaine 1.25 mg.ml-1 plus morphine 0.05 mg.ml-1, 4 ml.h-1 for the first 24 h, and bupivacaine 0.625 mg.ml-1 plus morphine 0.05 mg.ml-1, 4 ml.h-1, for the next 24 h after operation. Additional morphine 2.5-5 mg was administered i.v. or i.m. for the first 24 h postoperatively, and ketobemidone or morphine 5...

  2. Effects of tramadol or morphine in dogs undergoing castration on intra-operative electroencephalogram responses and post-operative pain.

    Science.gov (United States)

    Kongara, K; Chambers, J P; Johnson, C B; Dukkipati, V S R

    2013-11-01

    To compare the effects of pre-operatively administered tramadol with those of morphine on electroencephalographic responses to surgery and post-operative pain in dogs undergoing castration. Dogs undergoing castration were treated with either pre-operative morphine (0.5 mg/kg S/C, n = 8) or tramadol (3 mg/kg S/C, n = 8). All dogs also received 0.05 mg/kg acepromazine and 0.04 mg/kg atropine S/C in addition to the test analgesic. Anaesthesia was induced with thiopentone administered I/V to effect and maintained with halothane in oxygen. Respiratory rate, heart rate, end-tidal halothane tension (EtHal) and end-tidal CO2 tension (EtCO2) were monitored throughout surgery. Electroencephalograms (EEG) were recorded continuously using a three electrode montage. Median frequency (F50), total power (Ptot) and 95% spectral edge frequency (F95) derived from EEG power spectra recorded before skin incision (baseline) were compared with those recorded during ligation of the spermatic cords of both testicles. Post-operatively, pain was assessed after 1, 3, 6 and 9 h using the short form of the Glasgow composite measure pain scale (CMPS-SF). Dogs premedicated with tramadol had higher mean F50 (12.2 (SD 0.2) Hz) and lower Ptot (130.39 (SD 12.1) µv(2)) compared with those premedicated with morphine (11.5 (SD 0.2) Hz and 161.8 (SD 15.1) µv(2), respectively; p0.05). The F95 of the EEG did not differ between the two groups during the ligation of either testicle (p > 0.05). Post-operatively, no significant differences in the CMPS-SF score were found between animals premedicated with tramadol and morphine at any time during the post-operative period. No dog required rescue analgesia. Tramadol and morphine administered pre-operatively provided a similar degree of post-operative analgesia in male dogs at the doses tested.

  3. Pavlovian conditioning analysis of morphine tolerance.

    Science.gov (United States)

    Siegel, S

    1978-01-01

    It has been demonstrated that many conditional responses to a variety of drugs are opposite in direction to the unconditional effects of the drug, and the conditioning analysis of morphine tolerance emphasizes the fact that subjects with a history of morphine administration display morphine-compensatory conditional responses when confronted with the usual administration procedure but without the drug. Thus, when the drug is presented in the context of the usual administration cues, these conditional morphine-compensatory responses would be expected to attenuate the drug-induced unconditional responses, thereby decreasing the observed response to the drug. Research has been summarized which supports this compensatory conditioning model of tolerance by demonstrating that the display of tolerance is specific to the environment in which the drug has been previously administered. Further evidence supporting this theory of tolerance has been provided by studies establishing that extinction, partial reinforcement, and latent inhibition--non-pharmacological manipulations known to be effective in generally affecting the display of conditional responses--similarly affect the display of morphine tolerance. Additional research has suggested many parallels between learning and morphine tolerance: Both processes exhibit great retention, both are disrupted by electroconvulsive shock and frontal cortical stimulation, both are retarded by inhibitors of protein synthesis, and both are facilitated by antagonists of these metabolic inhibitors.

  4. Role of morphine preconditioning and nitric oxide following brain ischemia reperfusion injury in mice

    Directory of Open Access Journals (Sweden)

    Maedeh Arabian

    2015-01-01

    Full Text Available Objective(s: Morphine dependence (MD potently protects heart against ischemia reperfusion (IR injury through specific signaling mechanisms, which are different from the pathways involved in acute morphine treatment or classical preconditioning. Since opioid receptor density changes post cerebral ischemia strongly correlated with brain histological damage, in the present study, we tried to elucidate the possible role of opioid receptors in IR injury among morphine-dependent mice. Materials and Methods: Accordingly, incremental doses (10 mg/kg/day to 30 mg/kg/day of morphine sulphate were subcutaneously administered for 5 days before global brain ischemia induction through bilateral common carotid artery occlusion. Animals were received naloxone (5 mg/kg or L-NAME (20 mg/kg 30 min after the last morphine dose. Twenty four hr after the ischemia induction, Retention trial of passive avoidance test and western blot analysis were done. histological analysis (TUNEL and NISSL staining performed 72 hr after ischemia. Results: MD improved post ischemia memory performance (P

  5. Administration of the glial cell modulator, minocycline, in the nucleus accumbens attenuated the maintenance and reinstatement of morphine-seeking behavior.

    Science.gov (United States)

    Arezoomandan, Reza; Haghparast, Abbas

    2016-03-01

    Relapse to drug use is one of the most difficult clinical problems in treating addiction. Glial activation has been linked with the drug abuse, and the glia modulators such as minocycline can modulate the drug abuse effects. The aim of the present study was to determine whether minocycline could attenuate the maintenance and reinstatement of morphine. Conditioned place preference (CPP) was induced by subcutaneous injection of morphine (5 mg/kg) for 3 days. Following the acquisition of the CPP, the rats were given daily bilateral intra-NAc injections of either minocycline (1, 5, and 10 μg/0.5 μL) or saline (0.5 μL). The animals were tested for conditioning score 60 min after each injection. To induce the reinstatement, a priming dose of morphine (1 mg/kg) was injected 1 day after the final extinction day. The morphine-induced CPP lasted for 7 days after cessation of morphine treatment. Our data revealed that a priming dose of morphine could reinstate the extinguished morphine-induced CPP. Daily intra-accumbal injection of minocycline during the extinction period blocked the maintenance of morphine CPP and also attenuated the priming-induced reinstatement. Our findings indicated that minocycline could facilitate the extinction and attenuate the reinstatement of morphine. These results provided new evidence that minocycline might be considered as a promising therapeutic agent for the treatment of several symptoms associated with morphine abuse.

  6. Cholecystokinin octapeptide induces endogenous opioid-dependent anxiolytic effects in morphine-withdrawal rats.

    Science.gov (United States)

    Wen, D; Sun, D; Zang, G; Hao, L; Liu, X; Yu, F; Ma, C; Cong, B

    2014-09-26

    Cholecystokinin octapeptide (CCK-8), a brain-gut peptide, plays an important role in several opioid addictive behaviors. We previously reported that CCK-8 attenuated the expression and reinstatement of morphine-induced conditioned place preference. The possible effects of CCK-8 on the negative affective components of drug abstinence are not clear. There are no studies evaluating the effect of CCK-8 on emotional symptoms, such as anxiety, in morphine-withdrawal animals. We investigated the effects of CCK-8 on the anxiety-like behavior in morphine-withdrawal rats using an elevated plus-maze. Morphine withdrawal elicited time-dependent anxiety-like behaviors with peak effects on day 10 (5 days after induction of morphine dependence). Treatment with CCK-8 (0.1 and 1 μg, i.c.v.) blocked this anxiety in a dose-dependent fashion. A CCK1 receptor antagonist (L-364,718, 10 μg, i.c.v.) blocked the effect of CCK-8. Mu-opioid receptor antagonism with CTAP (10 μg, i.c.v.) decreased the 'anxiolytic' effect. CCK-8 inhibited anxiety-like behaviors in morphine-withdrawal rats by up-regulating endogenous opioids via the CCK1 receptor in rats. This study clearly identifies a distinct function of CCK-8 and a potential medication target of central CCK1 receptors for drugs aimed at ameliorating drug addiction. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. Usefulness of MR cholangiopancreatography after intravenous morphine administration

    International Nuclear Information System (INIS)

    Lee, So Jung; Ko, Ji Ho; Cho, Young Duk; Jung, Mi Hee; Yoon, Byung Chull

    2007-01-01

    We wanted to assess the usefulness of MRCP after intravenous morphine administration in the evaluation of the hepatopancreatic pancreatico-biliary ductal system. We studied 15 patients who were suspected of having disease of hepatopancreatic ductal system and they did not have any obstructive lesion on ultrasonography and/or CT. MRCP was acquired before and after morphine administration (0.04 mg/kg, intravenously). Three radiologists scored the quality of the images of the anatomic structures in the hepatopancreatic ductal system. We directly compared the quality of the images obtained with using the two methods and the improvement of the artifacts by pulsatile vascular compression. The MRCP images obtained after intravenous morphine administration were better than those obtained before morphine administration for visualizing the hepatopancreatic ductal system. On direct comparison, the MRCP images obtained after morphine administration were better in 12 cases, equivocal in two cases, and the images before morphine administration were better in only one case. In three patients, MRCP before morphine injection showed signal loss at the duct across the pulsatile hepatic artery. In two of three patients, MRCP after morphine injection showed no signal loss in this ductal area. MRCP after intravenous morphine administration enables physicians to see the hepatopancreatic ductal system significantly better and the artifacts caused by pulsation of the hepatic artery can be avoided

  8. Investigation of Surface Pre-Treatment Methods for Wafer-Level Cu-Cu Thermo-Compression Bonding

    Directory of Open Access Journals (Sweden)

    Koki Tanaka

    2016-12-01

    Full Text Available To increase the yield of the wafer-level Cu-Cu thermo-compression bonding method, certain surface pre-treatment methods for Cu are studied which can be exposed to the atmosphere before bonding. To inhibit re-oxidation under atmospheric conditions, the reduced pure Cu surface is treated by H2/Ar plasma, NH3 plasma and thiol solution, respectively, and is covered by Cu hydride, Cu nitride and a self-assembled monolayer (SAM accordingly. A pair of the treated wafers is then bonded by the thermo-compression bonding method, and evaluated by the tensile test. Results show that the bond strengths of the wafers treated by NH3 plasma and SAM are not sufficient due to the remaining surface protection layers such as Cu nitride and SAMs resulting from the pre-treatment. In contrast, the H2/Ar plasma–treated wafer showed the same strength as the one with formic acid vapor treatment, even when exposed to the atmosphere for 30 min. In the thermal desorption spectroscopy (TDS measurement of the H2/Ar plasma–treated Cu sample, the total number of the detected H2 was 3.1 times more than the citric acid–treated one. Results of the TDS measurement indicate that the modified Cu surface is terminated by chemisorbed hydrogen atoms, which leads to high bonding strength.

  9. Morphine

    African Journals Online (AJOL)

    'it's a bad drug it can kill and even its side effect(s) are very dangerous'. ... the use of oral morphine in the palliative care management of HIV/AIDS and .... State Medical Boards definition of addiction as 'psychological dependence on the use of ...

  10. Changes in adaptability following perinatal morphine exposure in juvenile and adult rats.

    Science.gov (United States)

    Klausz, Barbara; Pintér, Ottó; Sobor, Melinda; Gyarmati, Zsuzsa; Fürst, Zsuzsanna; Tímár, Júlia; Zelena, Dóra

    2011-03-05

    The problem of drug abuse among pregnant women causes a major concern. The aim of the present study was to examine the adaptive consequences of long term maternal morphine exposure in offspring at different postnatal ages, and to see the possibility of compensation, as well. Pregnant rats were treated daily with morphine from the day of mating (on the first two days 5mg/kgs.c. than 10mg/kg) until weaning. Male offspring of dams treated with physiological saline served as control. Behavior in the elevated plus maze (EPM; anxiety) and forced swimming test (FST; depression) as well as adrenocorticotropin and corticosterone hormone levels were measured at postpartum days 23-25 and at adult age. There was only a tendency of spending less time in the open arms of the EPM in morphine treated rats at both ages, thus, the supposed anxiogenic impact of perinatal exposure with morphine needs more focused examination. In response to 5min FST morphine exposed animals spent considerable longer time with floating and shorter time with climbing at both ages which is an expressing sign of depression-like behavior. Perinatal morphine exposure induced a hypoactivity of the stress axis (adrenocorticotropin and corticosterone elevations) to strong stimulus (FST). Our results show that perinatal morphine exposure induces long term depression-like changes. At the same time the reactivity to the stress is failed. These findings on rodents presume that the progenies of morphine users could have lifelong problems in adaptive capability and might be prone to develop psychiatric disorders. Copyright © 2010 Elsevier B.V. All rights reserved.

  11. Presurgical ketoprofen, but not morphine, dipyrone, diclofenac or tenoxicam, preempts post-incisional mechanical allodynia in rats

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    Prado W.A.

    2002-01-01

    Full Text Available The treatment of pain before it initiates may prevent the persistent pain-induced changes in the central nervous system that amplify pain long after the initial stimulus. The effects of pre- or postoperative intraperitoneal administration of morphine (2 to 8 mg/kg, dipyrone (40 and 80 mg/kg, diclofenac (2 to 8 mg/kg, ketoprofen (10 and 20 mg/kg, and tenoxicam (10 and 20 mg/kg were studied in a rat model of post-incisional pain. Groups of 5 to 8 male Wistar rats (140-160 g were used to test each drug dose. An incision was made on the plantar surface of a hind paw and the changes in the withdrawal threshold to mechanical stimulation were evaluated with Von Frey filaments at 1, 2, 6 and 24 h after the surgery. Tenoxicam was given 12 or 6 h preoperatively, whereas the remaining drugs were given 2 h or 30 min preoperatively. Postoperative drugs were all given 5 min after surgery. No drug abolished allodynia when injected before or after surgery, but thresholds were significantly higher than in control during up to 2 h following ketoprofen, 6 h following diclofenac, and 24 h following morphine, dipyrone or tenoxicam when drugs were injected postoperatively. Significant differences between pre- and postoperative treatments were obtained only with ketoprofen administered 30 min before surgery. Preoperative (2 h intraplantar, but not intrathecal, ketoprofen reduced the post-incisional pain for up to 24 h after surgery. It is concluded that stimuli generated in the inflamed tissue, rather than changes in the central nervous system are relevant for the persistence of pain in the model of post-incisional pain.

  12. P-glycoprotein Modulates Morphine Uptake into the CNS: A Role for the Non-steroidal Anti-inflammatory Drug Diclofenac

    Science.gov (United States)

    Sanchez-Covarrubias, Lucy; Slosky, Lauren M.; Thompson, Brandon J.; Zhang, Yifeng; Laracuente, Mei-Li; DeMarco, Kristin M.; Ronaldson, Patrick T.; Davis, Thomas P.

    2014-01-01

    Our laboratory has previously demonstrated that peripheral inflammatory pain (PIP), induced by subcutaneous plantar injection of λ-carrageenan, results in increased expression and activity of the ATP-dependent efflux transporter P-glycoprotein (P-gp) that is endogenously expressed at the blood-brain barrier (BBB). The result of increased P-gp functional expression was a significant reduction in CNS uptake of morphine and, subsequently, reduced morphine analgesic efficacy. A major concern in the treatment of acute pain/inflammation is the potential for drug-drug interactions resulting from P-gp induction by therapeutic agents co-administered with opioids. Such effects on P-gp activity can profoundly modulate CNS distribution of opioid analgesics and alter analgesic efficacy. In this study, we examined the ability of diclofenac, a non-steroidal anti-inflammatory drug (NSAID) that is commonly administered in conjunction with the opioids during pain therapy, to alter BBB transport of morphine via P-gp and whether such changes in P-gp morphine transport could alter morphine analgesic efficacy. Administration of diclofenac reduced paw edema and thermal hyperalgesia in rats subjected to PIP, which is consistent with the known mechanism of action of this NSAID. Western blot analysis demonstrated an increase in P-gp expression in rat brain microvessels not only following PIP induction but also after diclofenac treatment alone. Additionally, in situ brain perfusion studies showed that both PIP and diclofenac treatment alone increased P-gp efflux activity resulting in decreased morphine brain uptake. Critically, morphine analgesia was significantly reduced in animals pretreated with diclofenac (3 h), as compared to animals administered diclofenac and morphine concurrently. These novel findings suggest that administration of diclofenac and P-gp substrate opioids during pain pharmacotherapy may result in a clinically significant drug-drug interaction. PMID:24520393

  13. P-glycoprotein modulates morphine uptake into the CNS: a role for the non-steroidal anti-inflammatory drug diclofenac.

    Science.gov (United States)

    Sanchez-Covarrubias, Lucy; Slosky, Lauren M; Thompson, Brandon J; Zhang, Yifeng; Laracuente, Mei-Li; DeMarco, Kristin M; Ronaldson, Patrick T; Davis, Thomas P

    2014-01-01

    Our laboratory has previously demonstrated that peripheral inflammatory pain (PIP), induced by subcutaneous plantar injection of λ-carrageenan, results in increased expression and activity of the ATP-dependent efflux transporter P-glycoprotein (P-gp) that is endogenously expressed at the blood-brain barrier (BBB). The result of increased P-gp functional expression was a significant reduction in CNS uptake of morphine and, subsequently, reduced morphine analgesic efficacy. A major concern in the treatment of acute pain/inflammation is the potential for drug-drug interactions resulting from P-gp induction by therapeutic agents co-administered with opioids. Such effects on P-gp activity can profoundly modulate CNS distribution of opioid analgesics and alter analgesic efficacy. In this study, we examined the ability of diclofenac, a non-steroidal anti-inflammatory drug (NSAID) that is commonly administered in conjunction with the opioids during pain therapy, to alter BBB transport of morphine via P-gp and whether such changes in P-gp morphine transport could alter morphine analgesic efficacy. Administration of diclofenac reduced paw edema and thermal hyperalgesia in rats subjected to PIP, which is consistent with the known mechanism of action of this NSAID. Western blot analysis demonstrated an increase in P-gp expression in rat brain microvessels not only following PIP induction but also after diclofenac treatment alone. Additionally, in situ brain perfusion studies showed that both PIP and diclofenac treatment alone increased P-gp efflux activity resulting in decreased morphine brain uptake. Critically, morphine analgesia was significantly reduced in animals pretreated with diclofenac (3 h), as compared to animals administered diclofenac and morphine concurrently. These novel findings suggest that administration of diclofenac and P-gp substrate opioids during pain pharmacotherapy may result in a clinically significant drug-drug interaction.

  14. P-glycoprotein modulates morphine uptake into the CNS: a role for the non-steroidal anti-inflammatory drug diclofenac.

    Directory of Open Access Journals (Sweden)

    Lucy Sanchez-Covarrubias

    Full Text Available Our laboratory has previously demonstrated that peripheral inflammatory pain (PIP, induced by subcutaneous plantar injection of λ-carrageenan, results in increased expression and activity of the ATP-dependent efflux transporter P-glycoprotein (P-gp that is endogenously expressed at the blood-brain barrier (BBB. The result of increased P-gp functional expression was a significant reduction in CNS uptake of morphine and, subsequently, reduced morphine analgesic efficacy. A major concern in the treatment of acute pain/inflammation is the potential for drug-drug interactions resulting from P-gp induction by therapeutic agents co-administered with opioids. Such effects on P-gp activity can profoundly modulate CNS distribution of opioid analgesics and alter analgesic efficacy. In this study, we examined the ability of diclofenac, a non-steroidal anti-inflammatory drug (NSAID that is commonly administered in conjunction with the opioids during pain therapy, to alter BBB transport of morphine via P-gp and whether such changes in P-gp morphine transport could alter morphine analgesic efficacy. Administration of diclofenac reduced paw edema and thermal hyperalgesia in rats subjected to PIP, which is consistent with the known mechanism of action of this NSAID. Western blot analysis demonstrated an increase in P-gp expression in rat brain microvessels not only following PIP induction but also after diclofenac treatment alone. Additionally, in situ brain perfusion studies showed that both PIP and diclofenac treatment alone increased P-gp efflux activity resulting in decreased morphine brain uptake. Critically, morphine analgesia was significantly reduced in animals pretreated with diclofenac (3 h, as compared to animals administered diclofenac and morphine concurrently. These novel findings suggest that administration of diclofenac and P-gp substrate opioids during pain pharmacotherapy may result in a clinically significant drug-drug interaction.

  15. Comparison of Morphine and Tramadol in Transforaminal Epidural Injections for Lumbar Radicular Pain

    Science.gov (United States)

    2013-01-01

    Background Transforaminal epidural steroid injections are known to reduce inflammation by inhibiting synthesis of various proinflammatory mediators and have been used increasingly. The anti-inflammatory properties of opioids are not as fully understood but apparently involve antagonism sensory neuron excitability and pro-inflammatory neuropeptide release. To date, no studies have addressed the efficacy of transforaminal epidural morphine in patients with radicular pain, and none have directly compared morphine with a tramadol for this indication. The aim of this study was to compare morphine and tramadol analgesia when administered via epidural injection to patients with lumbar radicular pain. Methods A total of 59 patients were randomly allocated to 1 of 2 treatment groups and followed for 3 months after procedure. Each patient was subjected to C-arm guided transforaminal epidural injection (TFEI) of an affected nerve root. As assigned, patients received either morphine sulfate (2.5 mg/2.5 ml) or tramadol (25 mg/0.5 ml) in combination with 0.2% ropivacaine (1 ml). Using numeric rating scale was subsequently rates at 2 weeks and 3 months following injection for comparison with baseline. Results Both groups had significantly lower mean pain scores at 2 weeks and at 3 months after treatment, but outcomes did not differ significantly between groups. Conclusions TFEI of an opioid plus local anesthetic proved effective in treating radicular pain. Although morphine surpassed tramadol in pain relief scores, the difference was not statistically significant. PMID:23862000

  16. Mitochondrial events responsible for morphine's cardioprotection against ischemia/reperfusion injury

    International Nuclear Information System (INIS)

    He, Haiyan; Huh, Jin; Wang, Huihua; Kang, Yi; Lou, Jianshi; Xu, Zhelong

    2016-01-01

    Morphine may induce cardioprotection by targeting mitochondria, but little is known about the exact mitochondrial events that mediate morphine's protection. We aimed to address the role of the mitochondrial Src tyrosine kinase in morphine's protection. Isolated rat hearts were subjected to 30 min ischemia and 2 h of reperfusion. Morphine was given before the onset of ischemia. Infarct size and troponin I release were measured to evaluate cardiac injury. Oxidative stress was evaluated by measuring mitochondrial protein carbonylation and mitochondrial ROS generation. HL-1 cells were subjected to simulated ischemia/reperfusion and LDH release and mitochondrial membrane potential (ΔΨm) were measured. Morphine reduced infarct size as well as cardiac troponin I release which were aborted by the selective Src tyrosine kinase inhibitors PP2 and Src-I1. Morphine also attenuated LDH release and prevented a loss of ΔΨm at reperfusion in a Src tyrosine kinase dependent manner in HL-1 cells. However, morphine failed to reduce LDH release in HL-1 cells transfected with Src siRNA. Morphine increased mitochondrial Src phosphorylation at reperfusion and this was abrogated by PP2. Morphine attenuated mitochondrial protein carbonylation and mitochondrial superoxide generation at reperfusion through Src tyrosine kinase. The inhibitory effect of morphine on the mitochondrial complex I activity was reversed by PP2. These data suggest that morphine induces cardioprotection by preventing mitochondrial oxidative stress through mitochondrial Src tyrosine kinase. Inhibition of mitochondrial complex I at reperfusion by Src tyrosine kinase may account for the prevention of mitochondrial oxidative stress by morphine. - Highlights: • Morphine induced mito-Src phosphorylation and reduced infarct size in rat hearts. • Morphine failed to reduce I/R-induced LDH release in Src-silencing HL-1 cells. • Morphine prevented mitochondria damage caused by I/R through Src. • Morphine reduced

  17. Neural mechanisms underlying morphine withdrawal in addicted patients: a review

    Directory of Open Access Journals (Sweden)

    Nima Babhadiashar

    2015-06-01

    Full Text Available Morphine is one of the most potent alkaloid in opium, which has substantial medical uses and needs and it is the first active principle purified from herbal source. Morphine has commonly been used for relief of moderate to severe pain as it acts directly on the central nervous system; nonetheless, its chronic abuse increases tolerance and physical dependence, which is commonly known as opiate addiction. Morphine withdrawal syndrome is physiological and behavioral symptoms that stem from prolonged exposure to morphine. A majority of brain regions are hypofunctional over prolonged abstinence and acute morphine withdrawal. Furthermore, several neural mechanisms are likely to contribute to morphine withdrawal. The present review summarizes the literature pertaining to neural mechanisms underlying morphine withdrawal. Despite the fact that morphine withdrawal is a complex process, it is suggested that neural mechanisms play key roles in morphine withdrawal.

  18. "Detection of Morphine in Opioid Abusers Hair by GC/MS "

    Directory of Open Access Journals (Sweden)

    Khosrou Abdi

    2004-07-01

    Full Text Available Thirty hair samples were collected from the male opioid abusers in which the presence of morphine in their urine samples was confirmed by Thin Layer Chromatography (TLC analyses. The hair samples were washed, cut into small pieces and extracted in a mixture of methanol-triflouroacetic acid (9:1. The methanolic phase was evaporated to dryness under nitrogen stream and derivitized by addition of N-methyl-N-trimethylsilyl triflouroacetamide (MSTFA and 1% trimethyl iodosilane (TMIS with sonication. One micro liter of each derivitized sample was injected into a Gas Chromatograph-Mass Spectrometer (GC/MS system consisting of a capillary column and finnigan MS with selective ion monitoring (SIM mode. The selected mass for ions codeine and morphine were 370 and 429, respectively. The limit of detection (LOD was set at 0.03ng/mg of the hair. By using the above procedure, morphine was detectable in all of the examined samples and this method is capable to detec low levels of morphine in hair for a long period of time following the last intake of the drug

  19. Effect of morphine on the growth rate of Calliphora stygia (Fabricius) (Diptera: Calliphoridae) and possible implications for forensic entomology.

    Science.gov (United States)

    George, Kelly A; Archer, Melanie S; Green, Lauren M; Conlan, Xavier A; Toop, Tes

    2009-12-15

    Insect specimens collected from decomposing bodies enable forensic entomologists to estimate the minimum post-mortem interval (PMI). Drugs and toxins within a corpse may affect the development rate of insects that feed on them and it is vital to quantify these effects to accurately calculate minimum PMI. This study investigated the effects of morphine on growth rates of the native Australian blowfly, Calliphora stygia (Fabricius) (Diptera: Calliphoridae). Several morphine concentrations were incorporated into pet mince to simulate post-mortem concentrations in morphine, codeine and/or heroin-dosed corpses. There were four treatments for feeding larvae; T 1: control (no morphine); T 2: 2 microg/g morphine; T 3: 10 microg/g morphine; and T 4: 20 microg/g morphine. Ten replicates of 50 larvae were grown at 22 degrees C for each treatment and their development was compared at four comparison intervals; CI 1: 4-day-old larvae; CI 2: 7-day-old larvae; CI 3: pupae; and CI 4: adults. Length and width were measured for larvae and pupae, and costae and tibiae were measured for adults. Additionally, day of pupariation, day of adult eclosion, and survivorship were calculated for each replicate. The continued presence of morphine in meat was qualitatively verified using high-performance liquid chromatography with acidic potassium permanganate chemiluminescence detection. Growth rates of C. stygia fed on morphine-spiked mince did not differ significantly from those fed on control mince for any comparison interval or parameter measured. This suggests that C. stygia is a reliable model to use to accurately age a corpse containing morphine at any of the concentrations investigated.

  20. Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat

    Science.gov (United States)

    Lilius, T O; Jokinen, V; Neuvonen, M S; Niemi, M; Kalso, E A; Rauhala, P V

    2015-01-01

    Background and Purpose The effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal. Experimental Approach Morphine minipumps (6 mg·day–1) induced tolerance during 5 days in Sprague–Dawley rats, after which s.c. ketamine (10 mg·kg–1) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine-3-glucuronide, ketamine and norketamine were measured using HPLC-tandem mass spectrometry. Key Results In morphine-naïve rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine-tolerant ketamine-treated rats, the morphine, ketamine and norketamine concentrations were 2.1-, 1.4- and 3.4-fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine-tolerant ketamine-treated rats, ketamine concentration was sixfold compared with morphine-naïve rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed. Conclusions and Implications The ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans. PMID:25297798

  1. Neuroplastic alteration of TTX-resistant sodium channel with visceral pain and morphine-induced hyperalgesia

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    Chen J

    2012-11-01

    Full Text Available Jinghong Chen,1,2,4 Ze-hui Gong,4 Hao Yan,2 Zhijun Qiao,3 Bo-yi Qin41Department of Internal Medicine, Neuroscience Program, The University of Texas Medical Branch, Galveston, TX, USA; 2The Divisions of Pharmacy, Pharmacology core lab, MD Anderson Cancer Center, Houston, TX, USA; 3University of Texas-Pan American, Edinburg, TX, USA; 4Beijing Institute of Pharmacology and Toxicology, Beijing, China Abstract: The discovery of the tetrodotoxin-resistant (TTX-R Na+ channel in nociceptive neurons has provided a special target for analgesic intervention. In a previous study we found that both morphine tolerance and persistent visceral inflammation resulted in visceral hyperalgesia. It has also been suggested that hyperexcitability of sensory neurons due to altered TTX-R Na+ channel properties and expression contributes to hyperalgesia; however, we do not know if some TTX-R Na+ channel property changes can be triggered by visceral hyperalgesia and morphine tolerance, or whether there are similar molecular or channel mechanisms in both situations. To evaluate the effects of morphine tolerance and visceral inflammation on the channel, we investigated the dorsal root ganglia (DRG neuronal change following these chronic treatments. Using whole-cell patch clamp recording, we recorded TTX-R Na+ currents in isolated adult rat lumbar and sacral (L6-S2 DRG neurons from normal and pathologic rats with colon inflammatory pain or chronic morphine treatment. We found that the amplitudes of TTX-R Na+ currents were signiflcantly increased in small-diameter DRG neurons with either morphine tolerance or visceral inflammatory pain. Meanwhile, the result also showed that those treatments altered the kinetics properties of the electrical current (ie, the activating and inactivating speed of the channel was accelerated. Our current results suggested that in both models, visceral chronic inflammatory pain and morphine tolerance causes electrophysiological changes in voltage

  2. Degradation of morphine and codeine by gamma radiation in methanol solution

    International Nuclear Information System (INIS)

    Kantoglu, Oemer; Ergun, Ece

    2015-01-01

    The high concentrations of opiate and solvent in wastewater are toxic to biological life and affect the aquatic environment. Therefore, it must be treated by an advanced treatment process such as ionizing radiation. Effect of organic media on morphine and codeine during gamma irradiation was determined for the first time in this paper. Samples were irradiated at ambient temperature and in air environment at various doses (0, 10, 20, 30, 40, 50 and 60 kGy). Gamma irradiation-induced changes in the molecular structure of morphine and codeine were monitored by direct infusion electrospray ionization mass spectrometry in positive ion mode. The mass of the by-products were appeared to be more than the mass of the original alkaloids. Molecular structures of the by-products and reaction pathways were proposed. Oxygenated morphine and oxygenated codeine were identified in the presence of oxygen. However, solvent radical addition reactions were observed as the main mechanism for the by-product formation in oxygen-free irradiation. The results indicated that 89% of morphine and 98% of codeine were degraded at dose of 50 kGy. In addition, alkaloids and their by-products were not detected above 50 kGy. Here, we demonstrated that ionizing radiation process is a promising method to remove morphine and codeine in solvent/opiate rich industrial wastewater.

  3. Degradation of morphine and codeine by gamma radiation in methanol solution

    Energy Technology Data Exchange (ETDEWEB)

    Kantoglu, Oemer; Ergun, Ece [TAEA, Saraykoey Nuclear Research and Training Center, Ankara (Turkey)

    2015-05-01

    The high concentrations of opiate and solvent in wastewater are toxic to biological life and affect the aquatic environment. Therefore, it must be treated by an advanced treatment process such as ionizing radiation. Effect of organic media on morphine and codeine during gamma irradiation was determined for the first time in this paper. Samples were irradiated at ambient temperature and in air environment at various doses (0, 10, 20, 30, 40, 50 and 60 kGy). Gamma irradiation-induced changes in the molecular structure of morphine and codeine were monitored by direct infusion electrospray ionization mass spectrometry in positive ion mode. The mass of the by-products were appeared to be more than the mass of the original alkaloids. Molecular structures of the by-products and reaction pathways were proposed. Oxygenated morphine and oxygenated codeine were identified in the presence of oxygen. However, solvent radical addition reactions were observed as the main mechanism for the by-product formation in oxygen-free irradiation. The results indicated that 89% of morphine and 98% of codeine were degraded at dose of 50 kGy. In addition, alkaloids and their by-products were not detected above 50 kGy. Here, we demonstrated that ionizing radiation process is a promising method to remove morphine and codeine in solvent/opiate rich industrial wastewater.

  4. Neither pre-operative education or a minimally invasive procedure have any influence on the recovery time after total hip replacement.

    Science.gov (United States)

    Biau, David Jean; Porcher, Raphael; Roren, Alexandra; Babinet, Antoine; Rosencher, Nadia; Chevret, Sylvie; Poiraudeau, Serge; Anract, Philippe

    2015-08-01

    The purpose of this study was to evaluate pre-operative education versus no education and mini-invasive surgery versus standard surgery to reach complete independence. We conducted a four-arm randomized controlled trial of 209 patients. The primary outcome criterion was the time to reach complete functional independence. Secondary outcomes included the operative time, the estimated total blood loss, the pain level, the dose of morphine, and the time to discharge. There was no significant effect of either education (HR: 1.1; P = 0.77) or mini-invasive surgery (HR: 1.0; 95 %; P = 0.96) on the time to reach complete independence. The mini-invasive surgery group significantly reduced the total estimated blood loss (P = 0.0035) and decreased the dose of morphine necessary for titration in the recovery (P = 0.035). Neither pre-operative education nor mini-invasive surgery reduces the time to reach complete functional independence. Mini-invasive surgery significantly reduces blood loss and the need for morphine consumption.

  5. Role of the NO/sGC/PKG signaling pathway of hippocampal CA1 in morphine-induced reward memory.

    Science.gov (United States)

    Shen, Fang; Li, Yi-Jing; Shou, Xiao-Jing; Cui, Cai-Lian

    2012-09-01

    Evidence suggests that the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP dependent protein kinase (PKG) signaling pathway plays a key role in memory processing, but the actual participation of this signaling cascade in the hippocampal CA1 during morphine-induced reward memory remains unknown. In this study, we investigated the role of the NO/sGC/PKG signaling pathway in the CA1 on morphine-induced reward memory using a conditioned place preference (CPP) paradigm. We found that rats receiving an intraperitoneal (i.p.) injection of 4mg/kg morphine exhibited CPP, whereas rats treated with only 0.2mg/kg morphine failed to produce CPP. Intra-CA1 injection of the neuronal NO synthase (nNOS) inhibitor 7-NI, the sGC inhibitor ODQ or the PKG inhibitor Rp-8-Br-PET-cGMPS had no effect on the acquisition of CPP by 4mg/kg morphine. Intra-CA1 injection of 7-NI blocked the consolidation of CPP induced by 4mg/kg morphine, and this amnesic effect of 7-NI was mimicked by ODQ and Rp-8-Br-PET-cGMPS. Intra-CA1 injection of the NOS substrate L-arg or the sGC activator YC-1 with an ineffective dose of morphine (0.2mg/kg, i.p.) elicited CPP. This response induced by L-arg or YC-1 was reversed by pre-microinjection of Rp-8-Br-PET-cGMPS in the CA1. These results indicated that the activation of the NO/sGC/PKG signaling pathway in the CA1 is necessary for the consolidation of morphine-related reward memory. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Degradation of morphine in opium poppy processing waste composting.

    Science.gov (United States)

    Wang, Yin Quan; Zhang, Jin Lin; Schuchardt, Frank; Wang, Yan

    2014-09-01

    To investigate morphine degradation and optimize turning frequency in opium poppy processing waste composting, a pilot scale windrow composting trial was run for 55 days. Four treatments were designed as without turning (A1), every 5 days turning (A2), every 10 days turning (A3) and every 15 days turning (A4). During composting, a range of physicochemical parameters including the residual morphine degradation, temperature, pH, and the contents of total C, total N, total P and total K were investigated. For all treatments, the residual morphine content decreased below the detection limit and reached the safety standards after day 30 of composting, the longest duration of high temperature (⩾50 °C) was observed in A3, pH increased 16.9-17.54%, total carbon content decreased 15.5-22.5%, C/N ratio reduced from 46 to 26, and the content of total phosphorus and total potassium increased slightly. The final compost obtained by a mixture of all four piles was up to 55.3% of organic matter, 3.3% of total nutrient (N, P2O5 and K2O) and 7.6 of pH. A turning frequency of every ten days for a windrow composting of opium poppy processing waste is recommended to produce homogenous compost. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Mechanisms of morphine enhancement of spontaneous seizure activity.

    Science.gov (United States)

    Saboory, Ehsan; Derchansky, Miron; Ismaili, Mohammed; Jahromi, Shokrollah S; Brull, Richard; Carlen, Peter L; El Beheiry, Hossam

    2007-12-01

    High-dose opioid therapy can precipitate seizures; however, the mechanism of such a dangerous adverse effect remains poorly understood. The aim of our study was to determine whether the neuroexcitatory activity of high-dose morphine is mediated by selective stimulation of opioid receptors. Mice hippocampi were resected intact and bathed in low magnesium artificial cerebrospinal fluid to induce spontaneous seizure-like events recorded from CA1 neurons. Application of morphine had a biphasic effect on the recorded spontaneous seizure-like events. In a low concentration (10 microM), morphine depressed electrographic seizure activity. Higher morphine concentrations (30 and 100 microM) enhanced seizure activity in an apparent dose-dependent manner. Naloxone, a nonselective opiate antagonist blocked the proconvulsant action of morphine. Selective mu and kappa opiate receptor agonists and antagonists enhanced and suppressed the spontaneous seizure activity, respectively. On the contrary, delta opioid receptor ligands did not have an effect. The proseizure effect of morphine is mediated through selective stimulation of mu and kappa opiate receptors but not the activation of the delta receptor system. The observed dose-dependent mechanism of morphine neuroexcitation underscores careful adjustment and individualized opioid dosing in the clinical setting.

  8. Morphine tolerance offers protection from radiogenic performance deficits

    International Nuclear Information System (INIS)

    Mickley, G.A.; Stevens, K.E.; Burrows, J.M.; White, G.A.; Gibbs, G.L.

    1983-01-01

    When rats are exposed to a sufficiently large dose of ionizing radiation they exhibit lethargy, hypokinesia, and deficits in performance. These and other behavioral changes parallel those often observed in this species after a large dose of morphine. Since the release of endogenous opiates has been implicated in some stress reactions, we sought to determine if they might play a part in radiogenic behavioral deficits. Rats were trained to criterion on a signaled avoidance task. Some subjects were then implanted with a pellet containing 75 mg of morphine. Other animals received placebo implants. Over a number of days, morphine tolerance was evaluated by measurement of body temperature changes. Prior to 2500 rad 60 Co exposure or sham irradiation, morphine (or placebo) pellets were removed. Twenty-four hours later rats were retested to assess their performance on the avoidance task. Morphine-tolerant subjects performed significantly better than the irradiated placebo-implanted group and no differently than morphine-tolerant/sham-irradiated animals. Morphine tolerance seems to provide a degree of behavioral radiation resistance. These data are consistent with the hypothesis that endogenous opiate hyperexcretion may play some part in the behavioral deficits often observed after irradiation

  9. The Comparison of Intrathecal Morphine and IV Morphine PCA on Pain Control, Patient Satisfaction, Morphine Consumption, and Adverse Effects in Patients Undergoing Reduction Mammoplasty

    OpenAIRE

    Karamese, Mehtap; Akda?, Osman; Kara, ?nci; Y?ld?ran, Gokce Unal; Tosun, Zekeriya

    2015-01-01

    Background: Following breast reduction procedures, the level of postoperative pain can be severe, and sufficient pain control influences a patient's physiological, immunological, and psychological status. Objective: The aim of this study was to examine the use of intrathecal morphine (ITM) in breast reduction surgery with patient-controlled analgesia (PCA). Methods: Sixty-two female patients who underwent breast reductions with the same technique participated in this study. The study group (I...

  10. Music therapy inhibits morphine-seeking behavior via GABA receptor and attenuates anxiety-like behavior induced by extinction from chronic morphine use.

    Science.gov (United States)

    Kim, Ki Jin; Lee, Sang Nam; Lee, Bong Hyo

    2018-05-01

    Morphine is a representative pain killer. However, repeated use tends to induce addiction. Music therapy has been gaining interest as a useful type of therapy for neuropsychiatric diseases. The present study examined whether Korean traditional music (KT) could suppress morphine-seeking behavior and anxiety-like behavior induced by extinction from chronic morphine use and additionally investigated a possible neuronal mechanism. Male Sprague-Dawley rats were trained to intravenously self-administer morphine hydrochloride (1.0 mg/kg) using a fixed ratio 1 schedule in daily 2 h session during 3 weeks. After training, rats who established baseline (variation less than 20% of the mean of infusion for 3 consecutive days) underwent extinction. Music was played twice a day during extinction. In the second experiment, the selective antagonists of GABA A and GABA B receptors were treated before the last playing to investigate the neuronal mechanism focusing on the GABA receptor pathway. Another experiment of elevated plus maze was performed to investigate whether music therapy has an anxiolytic effect at the extinction phase. KT but not other music (Indian road or rock music) reduced morphine-seeking behavior induced by a priming challenge with morphine. And, this effect was blocked by the GABA receptor antagonists. In addition, KT showed anxiolytic effects against withdrawal from morphine. Results of this study suggest that KT suppresses morphine-seeking behavior via GABA receptor pathway. In addition, KT showed to have anxiolytic effects, suggesting it has bi-directional effects on morphine. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Morphine overdose

    Science.gov (United States)

    ... tests Chest x-ray EKG (electrocardiogram, or heart tracing) Fluids through a vein (IV) Laxative Naloxone, a ... Toxicology Data Network. Morphine. Toxnet.nlm.nih.gov Web site. toxnet.nlm.nih.gov/cgi-bin/sis/ ...

  12. Ghrelin receptor antagonism of morphine-induced conditioned place preference and behavioral and accumbens dopaminergic sensitization in rats.

    Science.gov (United States)

    Jerabek, Pavel; Havlickova, Tereza; Puskina, Nina; Charalambous, Chrysostomos; Lapka, Marek; Kacer, Petr; Sustkova-Fiserova, Magdalena

    2017-11-01

    An increasing number of studies over the past few years have demonstrated ghrelin's role in alcohol, cocaine and nicotine abuse. However, the role of ghrelin in opioid effects has rarely been examined. Recently we substantiated in rats that ghrelin growth hormone secretagogue receptors (GHS-R1A) appear to be involved in acute opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing. The aim of the present study was to ascertain whether a ghrelin antagonist (JMV2959) was able to inhibit morphine-induced biased conditioned place preference and challenge-morphine-induced accumbens dopaminergic sensitization and behavioral sensitization in adult male rats. In the place preference model, the rats were conditioned for 8 days with morphine (10 mg/kg s.c.). On the experimental day, JMV2959 (3 and 6 mg/kg i.p.) or saline were administered before testing. We used in vivo microdialysis to determine changes of dopamine and its metabolites in the nucleus accumbens in rats following challenge-morphine dose (5 mg/kg s.c.) with or without JMV2959 (3 and 6 mg/kg i.p.) pretreatment, administered on the 12th day of spontaneous abstinence from morphine repeated treatment (5 days, 10-40 mg/kg). Induced behavioral changes were simultaneously monitored. Pretreatment with JMV2959 significantly and dose dependently reduced the morphine-induced conditioned place preference and significantly and dose dependently reduced the challenge-morphine-induced dopaminergic sensitization and affected concentration of by-products associated with dopamine metabolism in the nucleus accumbens. JMV2959 pretreatment also significantly reduced challenge-morphine-induced behavioral sensitization. Our present data suggest that GHS-R1A antagonists deserve to be further investigated as a novel treatment strategy for opioid addiction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Acute food deprivation reverses morphine-induced locomotion deficits in M5 muscarinic receptor knockout mice.

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    Steidl, Stephan; Lee, Esther; Wasserman, David; Yeomans, John S

    2013-09-01

    Lesions of the pedunculopontine tegmental nucleus (PPT), one of two sources of cholinergic input to the ventral tegmental area (VTA), block conditioned place preference (CPP) for morphine in drug-naïve rats. M5 muscarinic cholinergic receptors, expressed by midbrain dopamine neurons, are critical for the ability of morphine to increase nucleus accumbens dopamine levels and locomotion, and for morphine CPP. This suggests that M5-mediated PPT cholinergic inputs to VTA dopamine neurons critically contribute to morphine-induced dopamine activation, reward and locomotion. In the current study we tested whether food deprivation, which reduces PPT contribution to morphine CPP in rats, could also reduce M5 contributions to morphine-induced locomotion in mice. Acute 18-h food deprivation reversed the phenotypic differences usually seen between non-deprived wild-type and M5 knockout mice. That is, food deprivation increased morphine-induced locomotion in M5 knockout mice but reduced morphine-induced locomotion in wild-type mice. Food deprivation increased saline-induced locomotion equally in wild-type and M5 knockout mice. Based on these findings, we suggest that food deprivation reduces the contribution of M5-mediated PPT cholinergic inputs to the VTA in morphine-induced locomotion and increases the contribution of a PPT-independent pathway. The contributions of cholinergic, dopaminergic and GABAergic neurons to the effects of acute food deprivation are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Systemic synergism between codeine and morphine in three pain models in mice.

    Science.gov (United States)

    Miranda, Hugo F; Noriega, Viviana; Zepeda, Ramiro J; Sierralta, Fernando; Prieto, Juan C

    2013-01-01

    The combination of two analgesic agents offers advantages in pain treatment. Codeine and morphine analgesia is due to activation of opioid receptor subtypes. This study, performed in mice using isobolographic analysis, evaluated the type of interaction in intraperitoneal (ip) or intrathecal (it) coadministration of codeine and morphine, in three nociceptive behavioral models. Intrathecal morphine resulted to be 7.5 times more potent than ip morphine in the writhing test, 55.6 times in the tail flick test and 1.7 times in phase II of the orofacial formalin test; however, in phase I of the same test ip was 1.2 times more potent than it morphine. Intrathecal codeine resulted being 3.4 times more potent than ip codeine in the writhing test, 1.6 times in the tail flick test, 2.5 times in phase I and 6.7 times in phase II of the orofacial formalin test. Opioid coadministration had a synergistic effect in the acute tonic pain (acetic acid writhing test), acute phasic pain (tail flick test) and inflammatory pain (orofacial formalin test). The interaction index ranged between 0.284 (writhing ip) and 0.440 (orofacial formalin phase II ip). This synergy may relate to the different pathways of pain transmission and to the different intracellular signal transduction. The present findings also raise the possibility of potential clinical advantages in combining opioids in pain management.

  15. Opiate and non-opiate aspects of morphine induced seizures.

    Science.gov (United States)

    Frenk, H; Liban, A; Balamuth, R; Urca, G

    1982-12-16

    The intraperitoneal administration of morphine hydrochloride at doses of 300 mg/kg produced analgesia, catalepsy, and electrographic spiking in rats that developed into electrographic seizure patterns after approximately 2.5 h. Whereas naltrexone (12 mg/kg) reversed analgesia and catalepsy, and diminished electrographic spiking, it precipitated electrographic seizure activity similar to that observed following intraperitoneal morphine alone. These seizures were accompanied by behavioral convulsions. No tolerance to these seizures developed with repeated paired administration of morphine and naltrexone or in morphine tolerant rats, but rather potentiation was observed. The epileptogenic effects were found to be potentiated in amygdaloid kindled rats, as well. It was concluded that morphine at these doses activates two different epileptogenic mechanisms, one mediated by opiate receptors, the other not. The possibility of the simultaneous activation of a morphine sensitive anticonvulsant mechanism is discussed.

  16. Comparison of morphine and carprofen administered alone or in combination for analgesia in dogs undergoing ovariohysterectomy.

    Science.gov (United States)

    Dzikiti, T B; Joubert, K E; Venter, L J; Dzikiti, L N

    2006-09-01

    In this study the analgesic efficacy of the pure agonistic opioid morphine and the cyclo-oxygenase type-2-selective carprofen were compared since there is no previous specific comparative study for these two common analgesics. Forty-five bitches undergoing elective ovariohysterectomy were randomly assigned to one of three groups; receiving morphine 0.4 mg/kg bodyweight pre-operatively and 0.2 mg/kg every 4-6 hours thereafter (Morphine group), receiving a once-off carprofen 4 mg/kg injection (Carprofen group) or receiving both morphine and carprofen (MorphCarp group). The dogs were premedicated with acepromazine 0.01 mg/kg and induced with either thiopentone 5-10 mg/kg or propofol 4-6 mg/kg. General anaesthesia was maintained with halothane in oxygen. The degree of pain was assessed over a 24-hour period under blinded conditions using a pain scale modified from the University of Melbourne pain scale and the Glasgow composite pain tool. Physiological parameters such as respiratory rate, pulse rate and body temperature were also assessed over the same time period. There was no significant difference in pain-scores and thus analgesia offered by the three analgesia protocols at any assessment point across the three groups, but there were differences within groups across time points. Baseline total pain-scores were lower than scores at all post-operative points within all three groups. Both morphine and carprofen provided good analgesia without any obvious adverse effects. This study indicates that at the dosages indicated above, carprofen administered on its own produces analgesia equal to that produced by morphine and that the two drugs administered together do not produce better analgesia than either drug administered on its own.

  17. Dexketoprofen-induced antinociception in animal models of acute pain: synergy with morphine and paracetamol.

    Science.gov (United States)

    Miranda, Hugo F; Puig, Margarita M; Dursteler, Christian; Prieto, Juan Carlos; Pinardi, Gianni

    2007-02-01

    The antinociceptive activity of dexketoprofen was studied in mice using the acetic acid writhing test (acute tonic pain), the tail flick test (acute phasic pain) and the formalin assay (inflammatory pain). Isobolographic analysis was used to study the antinociceptive interactions between morphine and paracetamol co-administered with dexketoprofen. In the writhing test, the intraperitoneal administration of dexketoprofen or ketoprofen resulted in parallel dose-response curves with equal efficacy, but higher relative potency for dexketoprofen. In the tail flick test, the curves were parallel with similar efficacy and potency. The administration of morphine or paracetamol in both tests resulted in dose-response curves not parallel with that of dexketoprofen, which showed a potency between morphine and paracetamol. In the formalin assay, the antinociceptive activity of morphine during phase I was 122, 295 and 1695 times higher than dexketoprofen, ketoprofen and paracetamol, respectively. Isobolographic analysis demonstrated that the combination of sub-analgesic doses of dexketoprofen with morphine or with paracetamol was strongly synergic in all three tests. Synergistic drug combinations should improve effective pharmacological treatment of pain, minimizing drug specific adverse effects. These findings are undoubtedly worthy of additional controlled clinical trials in severe pain syndromes.

  18. Oral Morphine Use in South India: A Population-Based Study.

    Science.gov (United States)

    Rajagopal, M R; Karim, Safiya; Booth, Christopher M

    2017-12-01

    Purpose Access to opioids for pain control is recognized as an urgent issue in low- and middle-income countries. Here we report temporal and regional trends in morphine use in Kerala, India. Methods Oral morphine use data for the State of Kerala (2012 to 2015) was used to describe temporal trends, regional variation, and provider characteristics. Total morphine use was calculated for each district of Kerala to derive an annual per capita use rate (milligrams per capita). Each provider was classified as government, private, nongovernment organization (NGO), or NGO partnership. Results Oral morphine use for Kerala was 1.32 mg/capita and increased over the study period 27% (from 1.23 mg/capita to 1.56 mg/capita). There was substantial variation in morphine use across districts (range, 0.49 mg/capita to 2.97 mg/capita; six-fold difference). This variation increased over time (19-fold difference in 2015). In 2015, 31% of morphine providers (51 of 167) were government institutions; they delivered 48% of total morphine in Kerala. Corresponding data for other providers are private institutions, 23% of centers and 13% of morphine; NGOs, 41% of centers and 34% of morphine; and NGO partnerships, 5% of centers and 4% of morphine. From 2012 to 2015, the total number of centers increased by 35%, from 124 to 167. Conclusion Oral morphine use has increased over time in Kerala but remains substantially lower than estimated need. There is significant geographic variation of use. Efforts are needed to improve palliative care in Kerala and to reduce regional disparities in access to opioids.

  19. Effect of Morphine Withdrawal Syndrome on Cerebral Ischemia

    Directory of Open Access Journals (Sweden)

    Mohammad Allahtavakoli

    2011-01-01

    Full Text Available Objective(sOpioid abuse is still remained a major mental health problem, a criminal legal issue and may cause ischemic brain changes including stroke and brain edema. In the present study, we investigated whether spontaneously withdrawal syndrome might affect stroke outcomes.Materials and MethodsAddiction was induced by progressive incremental doses of morphine over 7 days. Behavioral signs of withdrawal were observed 24, 48 and 72 hr after morphine deprivation and total withdrawal score was determined. Cerebral ischemia was induced 18-22 hr after the last morphine injection by placing a natural clot into the middle cerebral artery (MCA. Neurological deficits were evaluated at 2, 24 and 48 hr after ischemia induction, and infarct size and brain edema were determined at 48 hr after stroke.ResultsMorphine withdrawal animals showed a significant increase in total withdrawal score and decrease of weight gain during the 72 hr after the last morphine injection. Compared to the addicted and control animals, infarct volume and brain edema were significantly increased in the morphine deprived animals (P< 0.05 at 48 hr after cerebral ischemia. Also, neurological deficits were higher in the morphine-withdrawn rats at 48 hr after stroke (P< 0.05. ConclusionOur data indicates that spontaneous withdrawal syndrome may worsen stroke outcomes. Further investigations are necessary to elucidate mechanisms of opiate withdrawal syndrome on stroke.

  20. High concentrations of morphine sensitize and activate mouse dorsal root ganglia via TRPV1 and TRPA1 receptors

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    Messlinger Karl

    2009-04-01

    Full Text Available Abstract Background Morphine and its derivatives are key drugs in pain control. Despite its well-known analgesic properties morphine at high concentrations may be proalgesic. Particularly, short-lasting painful sensations have been reported upon dermal application of morphine. To study a possible involvement of TRP receptors in the pro-nociceptive effects of morphine (0.3 – 10 mM, two models of nociception were employed using C57BL/6 mice and genetically related TRPV1 and TRPA1 knockout animals, which were crossed and generated double knockouts. Hindpaw skin flaps were used to investigate the release of calcitonin gene-related peptide indicative of nociceptive activation. Results Morphine induced release of calcitonin gene-related peptide and sensitized the release evoked by heat or the TRPA1 agonist acrolein. Morphine activated HEK293t cells transfected with TRPV1 or TRPA1. Activation of C57BL/6 mouse dorsal root ganglion neurons in culture was investigated with calcium imaging. Morphine induced a dose-dependent rise in intracellular calcium in neurons from wild-type animals. In neurons from TRPV1 and TRPA1 knockout animals activation by morphine was markedly reduced, in the TRPV1/A1 double knockout animals this morphine effect was abrogated. Naloxone induced an increase in calcium levels similar to morphine. The responses to both morphine and naloxone were sensitized by bradykinin. Conclusion Nociceptor activation and sensitization by morphine is conveyed by TRPV1 and TRPA1.

  1. Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats

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    Chen HH

    2015-03-01

    Full Text Available Hwei-Hsien Chen,1,2,* Yao-Chang Chiang,3,4,* Zung Fan Yuan,5,6 Chung-Chih Kuo,5,6 Mei-Dan Lai,2 Tsai-Wei Hung,1 Ing-kang Ho,1,3,4 Shao-Tsu Chen2,7 1Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan; 2Master and PhD Program in Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan; 3Center for Drug Abuse and Addiction, China Medical University Hospital, 4Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; 5Master Program in Physiological and Anatomical Medicine, 6Department of Physiology, School of Medicine, Tzu Chi University, 7Department of Psychiatry, Buddhist Tzu Chi General Hospital, Hualien, Taiwan *These authors contributed equally to this work Abstract: Methadone and buprenorphine are widely used for treating people with opioid dependence, including pregnant women. Prenatal exposure to opioids has devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. This study aimed at comparing the behavioral outcomes of young rats prenatally exposed to buprenorphine, methadone, and morphine. Pregnant Sprague-Dawley rats were administered saline, morphine, methadone, and buprenorphine during embryonic days 3–20. The cognitive function, social interaction, anxiety-like behaviors, and locomotor activity of offsprings were examined by novel object recognition test, social interaction test, light–dark transition test, elevated plus-maze, and open-field test between 6 weeks and 10 weeks of age. Prenatal exposure to methadone and buprenorphine did not affect locomotor activity, but significantly impaired novel object recognition and social interaction in both male and female offsprings in the same manner as morphine. Although prenatal exposure to methadone or buprenorphine increased anxiety-like behaviors in the light–dark transition in both male and female

  2. Locomotor activity: A distinctive index in morphine self-administration in rats.

    Science.gov (United States)

    Zhang, Jian-Jun; Kong, Qingyao

    2017-01-01

    Self-administration of addictive drugs is a widely used tool for studying behavioral, neurobiological, and genetic factors in addiction. However, how locomotor activity is affected during self-administration of addictive drugs has not been extensively studied. In our present study, we tested the locomotor activity levels during acquisition, extinction and reinstatement of morphine self-administration in rats. We found that compared with saline self-administration (SA), rats that trained with morphine SA had higher locomotor activity. Rats that successfully acquired SA also showed higher locomotor activity than rats that failed in acquiring SA. Moreover, locomotor activity was correlated with the number of drug infusions but not with the number of inactive pokes. We also tested the locomotor activity in the extinction and the morphine-primed reinstatement session. Interestingly, we found that in the first extinction session, although the number of active pokes did not change, the locomotor activity was significantly lower than in the last acquisition session, and this decrease can be maintained for at least six days. Finally, morphine priming enhanced the locomotor activity during the reinstatement test, regardless of if the active pokes were significantly increased or not. Our results clearly suggest that locomotor activity, which may reflect the pharmacological effects of morphine, is different from drug seeking behavior and is a distinctive index in drug self-administration.

  3. Locomotor activity: A distinctive index in morphine self-administration in rats

    Science.gov (United States)

    Kong, Qingyao

    2017-01-01

    Self-administration of addictive drugs is a widely used tool for studying behavioral, neurobiological, and genetic factors in addiction. However, how locomotor activity is affected during self-administration of addictive drugs has not been extensively studied. In our present study, we tested the locomotor activity levels during acquisition, extinction and reinstatement of morphine self-administration in rats. We found that compared with saline self-administration (SA), rats that trained with morphine SA had higher locomotor activity. Rats that successfully acquired SA also showed higher locomotor activity than rats that failed in acquiring SA. Moreover, locomotor activity was correlated with the number of drug infusions but not with the number of inactive pokes. We also tested the locomotor activity in the extinction and the morphine-primed reinstatement session. Interestingly, we found that in the first extinction session, although the number of active pokes did not change, the locomotor activity was significantly lower than in the last acquisition session, and this decrease can be maintained for at least six days. Finally, morphine priming enhanced the locomotor activity during the reinstatement test, regardless of if the active pokes were significantly increased or not. Our results clearly suggest that locomotor activity, which may reflect the pharmacological effects of morphine, is different from drug seeking behavior and is a distinctive index in drug self-administration. PMID:28380023

  4. Inhibition of Histone Deacetylases Attenuates Morphine Tolerance and Restores MOR Expression in the DRG of BCP Rats

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    Xiao-Tao He

    2018-05-01

    Full Text Available The easily developed morphine tolerance in bone cancer pain (BCP significantly hindered its clinical use. Increasing evidence suggests that histone deacetylases (HDACs regulate analgesic tolerance subsequent to continuous opioid exposure. However, whether HDACs contribute to morphine tolerance in the pathogenesis of BCP is still unknown. In the current study, we explored the possible engagement of HDACs in morphine tolerance during the pathogenesis of BCP. After intra-tibia tumor cell inoculation (TCI, we found that the increased expression of HDACs was negatively correlated with the decreased expression of MOR in the DRG following TCI. The paw withdrawal threshold (PWT and percentage maximum possible effects (MPEs decreased rapidly in TCI rats when morphine was used alone. In contrast, the concomitant use of SAHA and morphine significantly elevated the PWT and MPEs of TCI rats compared to morphine alone. Additionally, we found that SAHA administration significantly elevated MOR expression in the DRG of TCI rats with or without morphine treatment. Moreover, the TCI-induced increase in the co-expression of MOR and HDAC1 in neurons was significantly decreased after SAHA administration. These results suggest that HDACs are correlated with the downregulation of MOR in the DRG during the pathogenesis of BCP. Inhibition of HDACs using SAHA can be used to attenuate morphine tolerance in BCP.

  5. Selective brain lesions reduce morphine- and radiation-induced locomotor hyperactivity of the C57BL/6J mouse

    International Nuclear Information System (INIS)

    Mickley, G.A.; Stevens, K.E.; White, G.A.; Gibbs, G.L.

    1984-01-01

    The apparent resemblance between the stereotypic locomotor hyperactivity observed after either an injection of morphine or irradiation of the C57BL/6J mouse has suggested the possibility of similar biochemical and neuroanatomical substrates of these behaviors. In this study the authors made selective brain lesions in an attempt to reverse the locomotor response observed after morphine (30 mg/kg) or radiation (1500 rads /sup 60/Co) treatments. Lesions impinging on both the dorso-medial caudate and lateral septal nuclei caused a significant decrease in morphine-induced and radiogenic locomotion. Lesions of the individual brain areas did not significantly alter the opiate locomotor response. This reduction in locomotion could not be attributed to a generalized post-surgical lethargy since other brain lesions of similar size did not significantly suppress these behaviors. These data suggest the possibility of some common central nervous system mechanisms which may support the stereotypic locomotor hyperactivity observed in the C57BL/6J mouse after either morphine or radiation treatment

  6. The effects of acute morphine treatment on the incorporation of [3H]L-lysine by normal and regenerating facial nucleus neurons

    International Nuclear Information System (INIS)

    Sinatra, R.S.; Ford, D.H.; Rhines, R.K.

    1979-01-01

    The effect of morphine on the incorporation of [ 3 H]L-lysine into proteins of facial nucleus neurons was examined by light microscopic radioautography. Silver grains present within various compartments of normal and regenerating (3-, 7-. 14- and 21 days post-axotomy) neurons from saline-treated Wistar rats were compared with the amount present in similar cells from animals receiving 40 mg/kg morphine sulfate i.v. At 14- and 21-days post-axotomy, regenerating neurons were larger and the grain count in the emulsion over these cells was greater than that observed in normal (unoperated) neurons. In normal facial neurons, the accumulation of lysine into the nucleus and nucleolus was significantly lower 60 min after morphine adminstration. However, morphine's inhibition of lysine incorporation was even more pronounced in regenerating neurons. In these cells, nuclear lysine uptake was depressed at 3 and 7 days, while maximum inhibition of cytoplasmic incorporation occurred at 14-days post-axotomy. Morphine adminstration decreased nucleolar lysine incorporation at all survival intervals. (Auth.)

  7. [Effect of Corydalis yanhusuo and L-THP on Gastrointestinal Dopamine System in Morphine-Dependent Rats].

    Science.gov (United States)

    Xu, Jing-yu; Bai, Wei-feng; Qiu, Cheng-kai; Tu, Ping; Yu, Shou-yang; Luo, Su-yuan

    2015-12-01

    To investigate the protective mechanism of Corydalis yanhuso and L-THP in morphine-dependent gastrointestinal injury rats. 180 male rats were randomly divided into nine groups, 20 rats for each group: saline group (N), model group (M), NS treatment group and three different dosage of Corydalis yanhusuo and L-THP groups (low dose group,middle dose group and high dose group). The rat CPP (conditioned place preference) model was established by injecting the rats with an increasing dosage of morphine, all groups received CPP training in a black compartments and white ones (drug-paired compartment) for ten days. At 48 h after the final training, the performance of CPP models were assessed to make sure all models were exported correctly. Then the treatment groups were administered with different concentration of Corydalis yanhuso (0.5, 1 and 2 g/kg) and L-THP (0.94, 1.88 and 3.76 mg/kg) for six days. All rats were immediately killed after finish the last CPP test. For each group, ten rats were killed to detect the contents of DA in the stomach and duodenum through the fluorescence spectrophotometer. The expression levels of D2 receptor( D2R) in different tissues (gastric cardia, gastric body, pylorus and duodenum) were checked by Western-blot in the other rats. In the NS treatment group, the time when rats stay in the white ones were significantly decreased compared with the Corydalis yanhusuo treated groups (1 and 2 g/kg) and L-THP treated groups (1.88 and 3.76 mg/kg) (P THP. This is one of mechanism underlying the protective effects of gastrointestinal tract in morphine-dependent rats.

  8. A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, Exertion And Morphine Sulfate (BEAMS) study protocol.

    Science.gov (United States)

    Currow, David; Watts, Gareth John; Johnson, Miriam; McDonald, Christine F; Miners, John O; Somogyi, Andrew A; Denehy, Linda; McCaffrey, Nicola; Eckert, Danny J; McCloud, Philip; Louw, Sandra; Lam, Lawrence; Greene, Aine; Fazekas, Belinda; Clark, Katherine C; Fong, Kwun; Agar, Meera R; Joshi, Rohit; Kilbreath, Sharon; Ferreira, Diana; Ekström, Magnus

    2017-07-17

    Chronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended- release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, parallel-arm, placebo-controlled, multisite, factorial, block-randomised study evaluating regular ER morphine for chronic breathlessness in people with COPD. The primary question is what effect regular ER morphine has on worst breathlessness, measured daily on a 0-10 numerical rating scale. Uniquely, the coprimary outcome will use a FitBit to measure habitual physical activity. Secondary questions include safety and, whether upward titration after initial benefit delivers greater net symptom reduction. Substudies include longitudinal driving simulation, sleep, caregiver, health economic and pharmacogenetic studies. Seventeen centres will recruit 171 participants from respiratory and palliative care. The study has five phases including three randomisation phases to increasing doses of ER morphine. All participants will receive placebo or active laxatives as appropriate. Appropriate statistical analysis of primary and secondary outcomes will be used. Ethics approval has been obtained. Results of the study will be submitted for publication in peer-reviewed journals, findings presented at relevant conferences and potentially used to inform registration of ER morphine for chronic breathlessness. NCT02720822; Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  9. Comparison of Intravenous Ketamine with Morphine in Pain Relief of Long Bones Fractures: a Double-Blind Randomized Clinical Trial

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    Saeed Majidinejad

    2014-03-01

    Full Text Available Introduction: The selective medication for pain control in many clinical situations is morphine but its complications prevent its widespread use. Ketamine has been introduced as an alternative for morphine in some studies. However, the efficacy of its solitary use has not yet been evaluated. Therefore, the present study was undertaken to evaluate the effect of ketamine alone in relieving pain in trauma patients referring to an emergency unit. Methods: In this double-blind clinical trial, patients with long bone fractures were randomly divided into two groups of treatment with intravenous (IV morphine at a dose of 0.1 mg/kg and treatment with IV ketamine at a dose of 0.5 mg/kg. Pain severity of the patients was recorded before and 10 minutes after injection based on numeric rating scale. The means in the two groups were compared using independent t-test. Then the Kaplan-Meier curve and log rank analysis were used to evaluate the success of treatment. Results: A total of 126 patients were included in this study. The mean ages of the patients in the morphine and ketamine groups were 33.6±14.3 and 35.1±13.5 years, respectively (P=0.54. After therapeutic intervention, the pain severity significantly decreased in ketamine (2.7±1.8; P<0.0001 and morphine (2.4±1.5; P<0.0001 groups, with a similar effect of both medications on alleviating pain (P=0.28. The success rate of the treatment at 10-minute interval in groups receiving ketamine and morphine were 59 (93.65% and 61 (96.8% patients, respectively (P=0.62. Conclusion: The results of the present study showed that administration of ketamine at a low dose (0.5 mg/kg results in a significant decrease in the severity of acute pain in patients with fractures of long bones. This palliative effect is very similar to that of morphine

  10. Epidural morphine for postoperative pain relief in children

    DEFF Research Database (Denmark)

    Henneberg, S W; Hole, P; Haas, Inge Madsen De

    1993-01-01

    Epidural morphine for postoperative pain relief is in general use, and has proved to be very efficient in adults. The epidural technique and the use of epidural morphine are much less frequent in children. For 2 years we have prospectively followed 76 children who had epidural morphine...... for postoperative pain relief after major abdominal surgery. The age distribution was from newborn to 13 years, with a median age of 12 months. It was estimated that 94% of the patients had good analgesia for the first 24 postoperative hours and no other opioids were given. The side effects were few, but one case...... the investigation. We observed a change in the sleeping pattern with an increased number of sleep-induced myoclonia during the administration of epidural morphine. In conclusion, the use of epidural morphine in children for postoperative pain relief is very efficient. The minimal effective dose has not been...

  11. Pre-hospital treatment of acute poisonings in Oslo

    Science.gov (United States)

    Heyerdahl, Fridtjof; Hovda, Knut E; Bjornaas, Mari A; Nore, Anne K; Figueiredo, Jose CP; Ekeberg, Oivind; Jacobsen, Dag

    2008-01-01

    Background Poisoned patients are often treated in and discharged from pre-hospital health care settings. Studies of poisonings should therefore not only include hospitalized patients. Aims: To describe the acutely poisoned patients treated by ambulance personnel and in an outpatient clinic; compare patients transferred to a higher treatment level with those discharged without transfer; and study the one-week mortality after pre-hospital discharge. Methods A one-year multi-centre study with prospective inclusion of all acutely poisoned patients ≥ 16 years of age treated in ambulances, an outpatient clinic, and hospitals in Oslo. Results A total of 3757 health service contacts from 2997 poisoning episodes were recorded: 1860 were treated in ambulances, of which 15 died and 750 (40%) were discharged without transfer; 956 were treated in outpatient clinic, of which 801 (84%) were discharged without transfer; and 941 episodes were treated in hospitals. Patients discharged alive after ambulance treatment were mainly poisoned by opiates (70%), were frequently comatose (35%), had respiratory depression (37%), and many received naloxone (49%). The majority of the patients discharged from the outpatient clinic were poisoned by ethanol (55%), fewer were comatose (10%), and they rarely had respiratory depression (4%). Among the hospitalized, pharmaceutical poisonings were most common (58%), 23% were comatose, and 7% had respiratory depression. Male patients comprised 69% of the pre-hospital discharges, but only 46% of the hospitalized patients. Except for one patient, who died of a new heroin overdose two days following discharge from an ambulance, there were no deaths during the first week after the poisonings in the 90% of the pre-hospital discharged patients with known identity. Conclusion More than half of the poisoned patients treated in pre-hospital treatment settings were discharged without transfer to higher levels. These poisonings were more often caused by drug and

  12. Pre-hospital treatment of acute poisonings in Oslo

    Directory of Open Access Journals (Sweden)

    Nore Anne K

    2008-11-01

    Full Text Available Abstract Background Poisoned patients are often treated in and discharged from pre-hospital health care settings. Studies of poisonings should therefore not only include hospitalized patients. Aims: To describe the acutely poisoned patients treated by ambulance personnel and in an outpatient clinic; compare patients transferred to a higher treatment level with those discharged without transfer; and study the one-week mortality after pre-hospital discharge. Methods A one-year multi-centre study with prospective inclusion of all acutely poisoned patients ≥ 16 years of age treated in ambulances, an outpatient clinic, and hospitals in Oslo. Results A total of 3757 health service contacts from 2997 poisoning episodes were recorded: 1860 were treated in ambulances, of which 15 died and 750 (40% were discharged without transfer; 956 were treated in outpatient clinic, of which 801 (84% were discharged without transfer; and 941 episodes were treated in hospitals. Patients discharged alive after ambulance treatment were mainly poisoned by opiates (70%, were frequently comatose (35%, had respiratory depression (37%, and many received naloxone (49%. The majority of the patients discharged from the outpatient clinic were poisoned by ethanol (55%, fewer were comatose (10%, and they rarely had respiratory depression (4%. Among the hospitalized, pharmaceutical poisonings were most common (58%, 23% were comatose, and 7% had respiratory depression. Male patients comprised 69% of the pre-hospital discharges, but only 46% of the hospitalized patients. Except for one patient, who died of a new heroin overdose two days following discharge from an ambulance, there were no deaths during the first week after the poisonings in the 90% of the pre-hospital discharged patients with known identity. Conclusion More than half of the poisoned patients treated in pre-hospital treatment settings were discharged without transfer to higher levels. These poisonings were more often

  13. Oral Morphine Use in South India: A Population-Based Study

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    M.R. Rajagopal

    2017-12-01

    Full Text Available Purpose: Access to opioids for pain control is recognized as an urgent issue in low- and middle-income countries. Here we report temporal and regional trends in morphine use in Kerala, India. Methods: Oral morphine use data for the State of Kerala (2012 to 2015 was used to describe temporal trends, regional variation, and provider characteristics. Total morphine use was calculated for each district of Kerala to derive an annual per capita use rate (milligrams per capita. Each provider was classified as government, private, nongovernment organization (NGO, or NGO partnership. Results: Oral morphine use for Kerala was 1.32 mg/capita and increased over the study period 27% (from 1.23 mg/capita to 1.56 mg/capita. There was substantial variation in morphine use across districts (range, 0.49 mg/capita to 2.97 mg/capita; six-fold difference. This variation increased over time (19-fold difference in 2015. In 2015, 31% of morphine providers (51 of 167 were government institutions; they delivered 48% of total morphine in Kerala. Corresponding data for other providers are private institutions, 23% of centers and 13% of morphine; NGOs, 41% of centers and 34% of morphine; and NGO partnerships, 5% of centers and 4% of morphine. From 2012 to 2015, the total number of centers increased by 35%, from 124 to 167. Conclusion: Oral morphine use has increased over time in Kerala but remains substantially lower than estimated need. There is significant geographic variation of use. Efforts are needed to improve palliative care in Kerala and to reduce regional disparities in access to opioids.

  14. Introducing the concept of a new pre-referral treatment for severely ill febrile children at community level: a sociological approach in Guinea-Bissau.

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    Vermeersch, Audrey; Libaud-Moal, Anaëlle; Rodrigues, Amabelia; White, Nicholas J; Olliaro, Piero; Gomes, Melba; Ashley, Elizabeth A; Millet, Pascal

    2014-02-06

    Innovative strategies are needed to tackle childhood mortality in the rural tropics. Artesunate suppositories were developed to bring emergency treatment closer to severely ill children with malaria in rural areas where injectable treatment is not possible for several hours. Adding an antibacterial rectal drug would extend this strategy to treat non-malarial febrile illness as well. The objective of these studies was to assess acceptability of such a new pre-referral strategy by healthcare providers and likely uptake by the population. Two qualitative studies were conducted between May and July 2009. Study 1 investigated the acceptability of introducing a combined antimalarial-antibacterial suppository by interviewing 27 representatives of the three administrative levels (central government, regional, local) of the health sector; Study 2 investigated treatment-seeking behaviour and acceptability of this intervention at community level by interviewing 74 mothers in 2 villages. Up to 92% of health representatives were in favour of introducing a new pre-referral strategy to tackle both malaria and non-malaria related severe illnesses in Guinea-Bissau, provided it was endorsed by international health authorities. The main obstacles to implementation were the very limited human and financial resources. In the two villages surveyed, 44% of the mothers associated severe illness with fever only, or fever plus one additional symptom. Mothers' judgement of severity and ensuing decisions were not specific for serious illness, indicating that initial training to recognize signs of severe disease and treatment availability for non-severe, fever-associated symptoms will be required to prevent overuse of a new intervention designed as a pre-referral treatment for severely ill children. Level C health centres were the first resort in both villages (50% and 87% of respondents respectively). This information is encouraging for the implementation of a pre-referral treatment.

  15. Hydrogen-rich saline attenuates anxiety-like behaviors in morphine-withdrawn mice.

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    Wen, Di; Zhao, Peng; Hui, Rongji; Wang, Jian; Shen, Qianchao; Gong, Miao; Guo, Hongyan; Cong, Bin; Ma, Chunling

    2017-05-15

    Hydrogen therapy is a new medical approach for a wide range of diseases. The effects of hydrogen on central nervous system-related diseases have recently become increasingly appreciated, but little is known about whether hydrogen affects the morphine withdrawal process. This study aims to investigate the potential effects of hydrogen-rich saline (HRS) administration on naloxone-precipitated withdrawal symptoms and morphine withdrawal-induced anxiety-like behaviors. Mice received gradually increasing doses (25-100 mg/kg, i.p.) of morphine over 3 days. In the naloxone-precipitated withdrawal procedure, the mice were treated with three HRS (20 μg/kg, i.p.) injections, and naloxone (1 mg/kg, i.p.) was given 30 min after HRS administration. Body weight, jumping behavior and wet-dog shakes were immediately assessed. In the spontaneous withdrawal procedure, the mice were treated with HRS (20 μg/kg, i.p.) every 8-h. Mice underwent naloxone-precipitated or spontaneous withdrawal were tested for anxiety-like behaviors in the elevated plus-maze (EPM) and light/dark box (L/D box) paradigm, respectively. In addition, the levels of plasma corticosterone were measured. We found that HRS administration significantly reduced body weight loss, jumping behavior and wet-dog shakes in mice underwent naloxone-precipitated withdrawal, and attenuated anxiety-like behaviors in the EPM and L/D box tests after naloxone-precipitated withdrawal or a 2-day spontaneous withdrawal period. Hypo-activity or motor impairment after HRS administration was not observed in the locomotion tests. Furthermore, HRS administration significantly decreased the levels of corticosterone in morphine-withdrawn mice. These are the first findings to indicate that hydrogen might ameliorate withdrawal symptoms and exert an anxiolytic-like effect in morphine-withdrawal mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Overexpression of Thioredoxin-1 Blocks Morphine-Induced Conditioned Place Preference Through Regulating the Interaction of γ-Aminobutyric Acid and Dopamine Systems.

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    Li, Xiang; Huang, Mengbing; Yang, Lihua; Guo, Ningning; Yang, Xiaoyan; Zhang, Zhimin; Bai, Ming; Ge, Lu; Zhou, Xiaoshuang; Li, Ye; Bai, Jie

    2018-01-01

    Morphine is one kind of opioid, which is currently the most effective widely utilized pain relieving pharmaceutical. Long-term administration of morphine leads to dependence and addiction. Thioredoxin-1 (Trx-1) is an important redox regulating protein and works as a neurotrophic cofactor. Our previous study showed that geranylgeranylaceton, an inducer of Trx-1 protected mice from rewarding effects induced by morphine. However, whether overexpression of Trx-1 can block morphine-induced conditioned place preference (CPP) in mice is still unknown. In this study, we first examined whether overexpression of Trx-1 affects the CPP after morphine training and further examined the dopamine (DA) and γ-aminobutyric acid (GABA) systems involved in rewarding effects. Our results showed that morphine-induced CPP was blocked in Trx-1 overexpression transgenic (TG) mice. Trx-1 expression was induced by morphine in the ventral tegmental area (VTA) and nucleus accumbens (NAc) in wild-type (WT) mice, which was not induced in Trx-1 TG mice. The DA level and expressions of tyrosine hydroxylase (TH) and D1 were induced by morphine in WT mice, which were not induced in Trx-1 TG mice. The GABA level and expression of GABA B R were decreased by morphine, which were restored in Trx-1 TG mice. Therefore, Trx-1 may play a role in blocking CPP induced by morphine through regulating the expressions of D1, TH, and GABA B R in the VTA and NAc.

  17. Overexpression of Thioredoxin-1 Blocks Morphine-Induced Conditioned Place Preference Through Regulating the Interaction of γ-Aminobutyric Acid and Dopamine Systems

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    Xiang Li

    2018-05-01

    Full Text Available Morphine is one kind of opioid, which is currently the most effective widely utilized pain relieving pharmaceutical. Long-term administration of morphine leads to dependence and addiction. Thioredoxin-1 (Trx-1 is an important redox regulating protein and works as a neurotrophic cofactor. Our previous study showed that geranylgeranylaceton, an inducer of Trx-1 protected mice from rewarding effects induced by morphine. However, whether overexpression of Trx-1 can block morphine-induced conditioned place preference (CPP in mice is still unknown. In this study, we first examined whether overexpression of Trx-1 affects the CPP after morphine training and further examined the dopamine (DA and γ-aminobutyric acid (GABA systems involved in rewarding effects. Our results showed that morphine-induced CPP was blocked in Trx-1 overexpression transgenic (TG mice. Trx-1 expression was induced by morphine in the ventral tegmental area (VTA and nucleus accumbens (NAc in wild-type (WT mice, which was not induced in Trx-1 TG mice. The DA level and expressions of tyrosine hydroxylase (TH and D1 were induced by morphine in WT mice, which were not induced in Trx-1 TG mice. The GABA level and expression of GABABR were decreased by morphine, which were restored in Trx-1 TG mice. Therefore, Trx-1 may play a role in blocking CPP induced by morphine through regulating the expressions of D1, TH, and GABABR in the VTA and NAc.

  18. Effect of Potassium Channel Modulators on Morphine Withdrawal in Mice

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    Vikas Seth

    2010-01-01

    Full Text Available The present study was conducted to investigate the effect of potassium channel openers and blockers on morphine withdrawal syndrome. Mice were rendered dependent on morphine by subcutaneous injection of morphine; four hours later, withdrawal was induced by using an opioid antagonist, naloxone. Mice were observed for 30 minutes for the withdrawal signs ie, the characteristic jumping, hyperactivity, urination and diarrhea. ATP-dependent potassium (K + ATP channel modulators were injected intraperitoneally (i.p. 30 minutes before the naloxone. It was found that a K + ATP channel opener, minoxidil (12.5–50 mg/kg i.p., suppressed the morphine withdrawal significantly. On the other hand, the K + ATP channel blocker glibenclamide (12.5–50 mg/kg i.p. caused a significant facilitation of the withdrawal. Glibenclamide was also found to abolish the minoxidil's inhibitory effect on morphine withdrawal. The study concludes that K + ATP channels play an important role in the genesis of morphine withdrawal and K + ATP channel openers could be useful in the management of opioid withdrawal. As morphine opens K + ATP channels in neurons, the channel openers possibly act by mimicking the effects of morphine on neuronal K + currents.

  19. Amperometric morphine sensing using a molecularly imprinted polymer-modified electrode

    International Nuclear Information System (INIS)

    Yeh, W.-M.; Ho, K.-C.

    2005-01-01

    This study incorporates morphine into a molecularly imprinted polymer (MIP) for the amperometric detection of morphine. The polymer, poly(3,4-ethylenedioxythiophene), PEDOT, is an electroactive film that catalyzes morphine oxidation and lowers the oxidization potential on an indium tin oxide (ITO) electrode. The MIP-PEDOT modified electrode is prepared by electropolymerizing PEDOT onto an ITO electrode in a 0.1 M LiClO 4 solution with template addition (morphine). After template molecule extraction, the oxidizing current of the MIP-PEDOT modified electrode is measured in a 0.1 M KCl solution (pH = 5.3) at 0.75 V (versus Ag/AgCl/sat'd KCl) with the morphine concentration varying in the 0.1-5 mM range. A linear range, displaying the relationship between steady-state currents and morphine concentrations, from 0.1 to 1 mM, is obtained. The proposed amperometric sensor could be used for morphine detection with a sensitivity of 91.86 μA/cm 2 per mM. A detection limit of 0.2 mM at a signal-to-noise ratio of 3 is achieved. Moreover, the proposed method can discriminate between morphine and its analogs, such as codeine

  20. Does adding ketamine to morphine patient-controlled analgesia safely improve post-thoracotomy pain?

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    Mathews, Timothy J; Churchhouse, Antonia M D; Housden, Tessa; Dunning, Joel

    2012-02-01

    A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'is the addition of ketamine to morphine patient-controlled analgesia (PCA) following thoracic surgery superior to morphine alone'. Altogether 201 papers were found using the reported search, of which nine represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. This consisted of one systematic review of PCA morphine with ketamine (PCA-MK) trials, one meta-analysis of PCA-MK trials, four randomized controlled trials of PCA-MK, one meta-analysis of trials using a variety of peri-operative ketamine regimes and two cohort studies of PCA-MK. Main outcomes measured included pain score rated on visual analogue scale, morphine consumption and incidence of psychotomimetic side effects/hallucination. Two papers reported the measurements of respiratory function. This evidence shows that adding ketamine to morphine PCA is safe, with a reported incidence of hallucination requiring intervention of 2.9%, and a meta-analysis finding an incidence of all central nervous system side effects of 18% compared with 15% with morphine alone, P = 0.31, RR 1.27 with 95% CI (0.8-2.01). All randomized controlled trials of its use following thoracic surgery found no hallucination or psychological side effect. All five studies in thoracic surgery (n = 243) found reduced morphine requirements with PCA-MK. Pain scores were significantly lower in PCA-MK patients in thoracic surgery papers, with one paper additionally reporting increased patient satisfaction. However, no significant improvement was found in a meta-analysis of five papers studying PCA-MK in a variety of surgical settings. Both papers reporting respiratory outcomes found improved oxygen saturations and PaCO(2) levels in PCA-MK patients following thoracic surgery

  1. Effects of environmental enrichment on behavioral deficits and alterations in hippocampal BDNF induced by prenatal exposure to morphine in juvenile rats.

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    Ahmadalipour, A; Sadeghzadeh, J; Vafaei, A A; Bandegi, A R; Mohammadkhani, R; Rashidy-Pour, A

    2015-10-01

    Prenatal morphine exposure throughout pregnancy can induce a series of neurobehavioral and neurochemical disturbances by affecting central nervous system development. This study was designed to investigate the effects of an enriched environment on behavioral deficits and changes in hippocampal brain-derived neurotrophic factor (BDNF) levels induced by prenatal morphine in rats. On pregnancy days 11-18, female Wistar rats were randomly injected twice daily with saline or morphine. Offspring were weaned on postnatal day (PND) 21. They were subjected to a standard rearing environment or an enriched environment on PNDs 22-50. On PNDs 51-57, the behavioral responses including anxiety and depression-like behaviors, and passive avoidance memory as well as hippocampal BDNF levels were investigated. The light/dark (L/D) box and elevated plus maze (EPM) were used for the study of anxiety, forced swimming test (FST) was used to assess depression-like behavior and passive avoidance task was used to evaluate learning and memory. Prenatal morphine exposure caused a reduction in time spent in the EPM open arms and a reduction in time spent in the lit side of the L/D box. It also decreased step-through latency and increased time spent in the dark side of passive avoidance task. Prenatal morphine exposure also reduced immobility time and increased swimming time in FST. Postnatal rearing in an enriched environment counteracted with behavioral deficits in the EPM and passive avoidance task, but not in the L/D box. This suggests that exposure to an enriched environment during adolescence period alters anxiety profile in a task-specific manner. Prenatal morphine exposure reduced hippocampal BDNF levels, but enriched environment significantly increased BDNF levels in both saline- and morphine-exposed groups. Our results demonstrate that exposure to an enriched environment alleviates behavioral deficits induced by prenatal morphine exposure and up-regulates the decreased levels of BDNF

  2. Comparison of morphine and carprofen administered alone or in combination for analgesia in dogs undergoing ovariohysterectomy

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    T.B. Dzikiti

    2006-06-01

    Full Text Available In this study the analgesic efficacy of the pure agonistic opioid morphine and the cyclo-oxygenase type-2-selective carprofen were compared since there is no previous specific comparative study for these two common analgesics. Forty-five bitches undergoing elective ovariohysterectomy were randomly assigned to one of three groups; receiving morphine 0.4 mg/kg bodyweight pre-operatively and 0.2 mg/kg every 4-6 hours thereafter (Morphine group, receiving a once-off carprofen 4 mg/kg injection (Carprofen group or receiving both morphine and carprofen (MorphCarp group. The dogs were premedicated with acepromazine 0.01 mg/kg and induced with either thiopentone 5-10 mg/kg or propofol 4-6 mg/kg. General anaesthesia was maintained with halothane in oxygen. The degree of pain was assessed over a 24-hour period under blinded conditions using a pain scale modified from the University of Melbourne pain scale and the Glasgow composite pain tool. Physiological parameters such as respiratory rate, pulse rate and body temperature were also assessed over the same time period. There was no significant difference in pain-scores and thus analgesia offered by the three analgesia protocols at any assessment point across the three groups, but there were differences within groups across time points. Baseline total pain-scores were lower than scores at all post-operative points within all three groups. Both morphine and carprofen provided good analgesia without any obvious adverse effects. This study indicates that at the dosages indicated above, carprofen administered on its own produces analgesia equal to that produced by morphine and that the two drugs administered together do not produce better analgesia than either drug administered on its own.

  3. Effects of acute and long-term typical or atypical neuroleptics on morphine-induced behavioural effects in mice.

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    Hollais, André W; Patti, Camilla L; Zanin, Karina A; Fukushiro, Daniela F; Berro, Laís F; Carvalho, Rita C; Kameda, Sonia R; Frussa-Filho, Roberto

    2014-03-01

    1. It has been suggested that the high prevalence of drug abuse in schizophrenics is related to chronic treatment with typical neuroleptics and dopaminergic supersensitivity that develops as a consequence. Within this context, atypical neuroleptics do not seem to induce this phenomenon. In the present study, we investigated the effects of acute administration or withdrawal from long-term administration of haloperidol and/or ziprasidone on morphine-induced open-field behaviour in mice. 2. In the first experiment, mice were given a single injection of haloperidol (1 mg/kg, i.p.) or several doses of ziprasidone (2, 4 or 6 mg/kg, i.p.) and motor activity was quantified by the open-field test. The aim of the second experiment was to verify the effects of an acute injection of haloperidol (1 mg/kg) or ziprasidone (6 mg/kg) on 20 mg/kg morphine-induced behaviours in the open-field test. In the third experiment, mice were treated with 1 mg/kg haloperidol and/or 2, 4 or 6 mg/kg ziprasidone for 20 days. Seventy-two hours after the last injection, mice were injected with 20 mg/kg, i.p., morphine and then subjected to the open-field test. Acute haloperidol or ziprasidone decreased spontaneous general activity and abolished morphine-induced locomotor stimulation. 3. Withdrawal from haloperidol or ziprasidone did not modify morphine-elicited behaviours in the open-field test. The results suggest that withdrawal from neuroleptic treatments does not contribute to the acute effect of morphine in schizophrenic patients. © 2014 Wiley Publishing Asia Pty Ltd.

  4. Oral Morphine Consumption Reduces Lens Development in Rat Embryos

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    Hossein Bahadoran

    2012-07-01

    Full Text Available Objective: Consumption of morphine, during pregnancy, in addition to inducing defects in the mother’s nervous system function, caused defects or delays in the formation and evolution of embryonic visual system. In the present study, changes in lens development was assessed in embryos exposed in utero to morphine. Material and Methods: Female Wistar rats (250-300 g were mated with male rats and pregnancy was determined by sperm observation in vaginal smear. This day was considered as embryonic day zero (E0. The females were then divided randomly into the experimental and the control groups. The control group received tap water and the experimental group received morphine (0.05 mg/ml in their water. On embryonic day 13 ( E13, blood samples were collected from the retro-orbital sinus of all animals for plasma corticosterone detection. On embryonic day 17(E17, the animals were killed by an overdose of chloroform and the embryos were taken out surgically. The embryos were fixed in 10% formalin for 30 days. At this time, the head of the embryos were removed for tissue processing and Hematoxylin- Eosin (H&E staining. The samples were evaluated using light microscope and MOTIC software. Results: Our data indicated that plasma corticosterone level was dramatically increased and the lens was thinner in the experimental group. (Although the proliferation of lens cells increased in the experiment group but that lens had delay in removing the proliferated and elongation cells with abnormal density in the lateral part of the lens in compare with control group. I have no idea what the authors are stating here. Moreover, the opening of the eyelids was delayed in the off springs of the mothers who received morphine. Conclusions: This study showed that morphine consumption during pregnancy leads to defects in fetal visual system development, particularly in the lens, and eyelids.

  5. The effect of pregnancy and estradiol-17 beta treatment on the biliary transport maximum of dibromosulfophthalein, and the glucuronide conjugates of 5-phenyl-5-p-hydroxyphenyl[14C]hydantoin and [14C]morphine in the isolated perfused rat liver

    International Nuclear Information System (INIS)

    Auansakul, A.C.; Vore, M.

    1982-01-01

    The biliary transport maximum (Tm) of three organic axions was determined in the isolated perfused livers of untreated female (control), estradiol-17 beta (E2)-treated female (1 mg/kg/day, s.c. for 14 days), and pregnant (19-21 days of gestation) rats. Dibromosulfophthalein (DBSP), 5-phenyl-5-p-hydroxyphenyl[ 14 C]hydantoin (HPPH) and [ 14 C]morphine were infused continuously into the perfusate for a total dose of 41.2, 18, or 40.5 mumol, respectively. The concentration of [ 14 C]HPPH and [ 14 C]morphine declined in the perfusate, whereas the concentrations of [ 14 C]HPPH glucuronide and [ 14 C]morphine glucuronide increased during the 90-min experiment, indicating that the rate of formation of the glucuronide exceeded its rate of excretion in bile. E2 treatment decreased the Tm (nmol/min/g liver) for [ 14 C]HPPH glucuronide and [ 14 C]morphine glucuronide but not for DBSP, whereas pregnancy decreased the Tm for all three organic anions. Pregnancy, and to a lesser extent E2 treatment, increased liver weight. When expressed per whole liver, the Tm was not altered by pregnancy for any of three organic anions. E2 treatment increased the Tm for DBSP, had no effect on the Tm for HPPH glucuronide and decreased the Tm for [ 14 C]morphine glucuronide. These data suggest the presence of multiple carriers for organic anions which are differentially affected by estrogen treatment and pregnancy

  6. The effect of a single dose of morphine on muscle fatigue indices in male rats

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    Sedigheh Amiresmaili

    2016-09-01

    Full Text Available Background and Aim: Endogenous opioids and addictive opiate drugs change many body functions. . Previous studies have referred to the effects of morphine on smooth and pulmonary muscles ., but the  effects of opioids on skeletal muscles is not known well. Thus, the current study aimed at assessing the effect of a single dose of morphine on muscle fatigue in male rats. Materials and Methods: In this experimental study, 40 male Wistar rats weighing 220-270 g were randomly divided into four equal groups: control (the mice were kept in their cages and received food and water, morphine receiving group, fatigue group (the mice in this group were kept running on  a treadmill . for120 minutes at a rate of 20 meters per minute, and morphine plus fatigue group. At the end of the experiments, blood samples were obtained from the corner of their eyes and were sent to the laboratory for measurement of muscle fatigue indexes including lactate dehydrogenase (LDH and creatine phosphokinase (CPK. Results: Administration of morphine to the fatigue group decreased running time compared with the control group (P=0.009. Furthermore, administration of morphine to the fatigue group significantly increased serum levels of LDH (P=0.009 and CPK (P=0.008. Conclusion: The present study showed that administration of a single dose of morphine in rats increases muscle fatigue biomarkers (LDH, CPK.

  7. The effect of morphine on biliary dynamics

    International Nuclear Information System (INIS)

    Pedersen, S.A.; Oester-Joergensen, E.; Kraglund, K.

    1987-01-01

    The effect of morphine on biliary dynamics was studied by cholescintigraphy with 99m Tc-HIDA. Among 30 normals without morphine injection 3 did not demonstrate intestinal radioactivity after 1 h, whereas all visualized the gallbladder. Eight normals with morphine injection did not demonstrate intestinal radioactivity after 2 h, but all had gallbladder visualization very early. Variables of the time-activity curves from liver areas did not point to impaired uptake or excretion. Morphine-induced increase in resistance to passage from the common duct to the intestines in normals is of a magnitude that forces the total amount of bile to accumulate in the gallbladder. Results from 11 patients after cholecystectomy indicate that the increase in pressure is less than the maximal secretory pressure of the liver. The resorptive capacity and the compliance of the gallbladder enable these events to take place without signs of secondary liver impairment

  8. Neonatal morphine enhances nociception and decreases analgesia in young rats.

    Science.gov (United States)

    Zhang, Guo Hua; Sweitzer, Sarah M

    2008-03-14

    The recognition of the impact of neonatal pain experience on subsequent sensory processing has led to the increased advocacy for the use of opioids for pain relief in infants. However, following long-term opioid exposure in intensive care units more than 48% of infants exhibited behaviors indicative of opioid abstinence syndrome, a developmentally equivalent set of behaviors to opioid withdrawal as seen in adults. Little is known about the long-term influence of repeated neonatal morphine exposure on nociception and analgesia. To investigate this, we examined mechanical and thermal nociception on postnatal days 11, 13, 15, 19, 24, 29, 39 and 48 following subcutaneous administration of morphine (3 mg/kg) once daily on postnatal days 1-9. The cumulative morphine dose-response was assessed on postnatal days 20 and 49, and stress-induced analgesia was assessed on postnatal days 29 and 49. Both basal mechanical and thermal nociception in neonatal, morphine-exposed rats were significantly lower than those in saline-exposed, handled-control rats and naive rats until P29. A rightward-shift of cumulative dose-response curves for morphine analgesia upon chronic neonatal morphine was observed both on P20 and P49. The swim stress-induced analgesia was significantly decreased in neonatal morphine-exposed rats on P29, but not on P49. These data indicate that morphine exposure equivalent to the third trimester of gestation produced prolonged pain hypersensitivity, decreased morphine antinociception, and decreased stress-induced analgesia. The present study illustrates the need to examine the long-term influence of prenatal morphine exposure on pain and analgesia in the human pediatric population.

  9. Mitochondrial events responsible for morphine's cardioprotection against ischemia/reperfusion injury

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    He, Haiyan [Department of Physiology & Pathophysiology, Tianjin Medical University, Tianjin 300070 (China); Department of Pharmacology, Tianjin Medical University, Tianjin 300070 (China); Huh, Jin [Department of Anesthesia and Pain Medicine, Medical College, Kangwon National University, Chuncheon City (Korea, Republic of); Wang, Huihua [Department of Anesthesiology, The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang Province (China); Kang, Yi; Lou, Jianshi [Department of Pharmacology, Tianjin Medical University, Tianjin 300070 (China); Xu, Zhelong, E-mail: zxu@tmu.edu.cn [Department of Physiology & Pathophysiology, Tianjin Medical University, Tianjin 300070 (China)

    2016-01-01

    Morphine may induce cardioprotection by targeting mitochondria, but little is known about the exact mitochondrial events that mediate morphine's protection. We aimed to address the role of the mitochondrial Src tyrosine kinase in morphine's protection. Isolated rat hearts were subjected to 30 min ischemia and 2 h of reperfusion. Morphine was given before the onset of ischemia. Infarct size and troponin I release were measured to evaluate cardiac injury. Oxidative stress was evaluated by measuring mitochondrial protein carbonylation and mitochondrial ROS generation. HL-1 cells were subjected to simulated ischemia/reperfusion and LDH release and mitochondrial membrane potential (ΔΨm) were measured. Morphine reduced infarct size as well as cardiac troponin I release which were aborted by the selective Src tyrosine kinase inhibitors PP2 and Src-I1. Morphine also attenuated LDH release and prevented a loss of ΔΨm at reperfusion in a Src tyrosine kinase dependent manner in HL-1 cells. However, morphine failed to reduce LDH release in HL-1 cells transfected with Src siRNA. Morphine increased mitochondrial Src phosphorylation at reperfusion and this was abrogated by PP2. Morphine attenuated mitochondrial protein carbonylation and mitochondrial superoxide generation at reperfusion through Src tyrosine kinase. The inhibitory effect of morphine on the mitochondrial complex I activity was reversed by PP2. These data suggest that morphine induces cardioprotection by preventing mitochondrial oxidative stress through mitochondrial Src tyrosine kinase. Inhibition of mitochondrial complex I at reperfusion by Src tyrosine kinase may account for the prevention of mitochondrial oxidative stress by morphine. - Highlights: • Morphine induced mito-Src phosphorylation and reduced infarct size in rat hearts. • Morphine failed to reduce I/R-induced LDH release in Src-silencing HL-1 cells. • Morphine prevented mitochondria damage caused by I/R through Src. • Morphine

  10. Effects of sleep deprivation on retrieval and reconsolidation of morphine reward memory in rats.

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    Shi, Hai-Shui; Luo, Yi-Xiao; Xue, Yan-Xue; Wu, Ping; Zhu, Wei-Li; Ding, Zeng-Bo; Lu, Lin

    2011-04-01

    Relapse induced by exposure to cues associated with drugs of abuse is a major challenge to the treatment of drug addiction. Drug seeking can be inhibited by manipulation of the reconsolidation of drug-related memory. Sleep has been proposed to be involved in various memory processes. However, the role of sleep in drug reward memory is not clear. The present study used conditioned place preference to examine the effects of total sleep deprivation on retrieval and reconsolidation of morphine reward memory in rats. Six-hour total sleep deprivation had no effect on the retrieval of morphine reward memory. However, sleep deprivation from 0-6 h, but not 6-12 h, after re-exposure disrupted the reconsolidation of morphine reward memory. This impairment was not attributable to the formation of an aversive associative memory between the drug-paired context and sleep deprivation. Our findings suggest that sleep plays a critical role in morphine reward memory reconsolidation, and sleep deprivation may be a potential non-pharmacotherapy for the management of relapse associated with drug-related memory. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Characterization of a Single Chain Fv Antibody that Reacts with Free Morphine

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    Kazuhisa Sugimura

    2013-02-01

    Full Text Available An immune phage library derived from mice, hyperimmunized with morphine-conjugated BSA, was used to isolate a single-chain Fv (scFv clone, M86, with binding activity to morphine-conjugated thyroglobulin (morphine-C-Tg but not to codeine-, cocaine-, or ketamine-conjugated Tg. Surface plasmon resonance analysis using a morphine-C-Tg-coupled CM5 sensor chip showed that the Kd value was 1.26 × 10−8 M. To analyze its binding activity to free morphine and related compounds, we performed a competitive ELISA with M86 and morphine-C-Tg in the absence or presence of varying doses of free morphine and related compounds. IC50 values for opium, morphine, codeine, and heroin were 257 ng/mL, 36.4, 7.3, and 7.4 nM, respectively. Ketamine and cocaine exhibited no competitive binding activity to M86. Thus, we established a phage library-derived scFv, M86, which recognized not only free morphine and codeine as opium components but also heroin. This characteristic of M86 may be useful for developing therapeutic reagents for opiate addiction and as a free morphine-specific antibody probe.

  12. The μ opioid agonist morphine modulates potentiation of capsaicin-evoked TRPV1 responses through a cyclic AMP-dependent protein kinase A pathway

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    Roberts-Thomson Sarah J

    2006-07-01

    Full Text Available Abstract Background The vanilloid receptor 1 (TRPV1 is critical in the development of inflammatory hyperalgesia. Several receptors including G-protein coupled prostaglandin receptors have been reported to functionally interact with the TRPV1 through a cAMP-dependent protein kinase A (PKA pathway to potentiate TRPV1-mediated capsaicin responses. Such regulation may have significance in inflammatory pain. However, few functional receptor interactions that inhibit PKA-mediated potentiation of TRPV1 responses have been described. Results In the present studies we investigated the hypothesis that the μ opioid receptor (MOP agonist morphine can modulate forskolin-potentiated capsaicin responses through a cAMP-dependent PKA pathway. HEK293 cells were stably transfected with TRPV1 and MOP, and calcium (Ca2+ responses to injection of the TRPV1 agonist capsaicin were monitored in Fluo-3-loaded cells. Pre-treatment with morphine did not inhibit unpotentiated capsaicin-induced Ca2+ responses but significantly altered capsaicin responses potentiated by forskolin. TRPV1-mediated Ca2+ responses potentiated by the direct PKA activator 8-Br-cAMP and the PKC activator Phorbol-12-myristate-13-acetatewere not modulated by morphine. Immunohistochemical studies confirmed that the TRPV1 and MOP are co-expressed on cultured Dorsal Root Ganglion neurones, pointing towards the existence of a functional relationship between the G-protein coupled MOP and nociceptive TRPV1. Conclusion The results presented here indicate that the opioid receptor agonist morphine acts via inhibition of adenylate cyclase to inhibit PKA-potentiated TRPV1 responses. Targeting of peripheral opioid receptors may therefore have therapeutic potential as an intervention to prevent potentiation of TRPV1 responses through the PKA pathway in inflammation.

  13. Impacts of morphine addiction on spermatogenesis in rats

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    Nasrin Takzare

    2016-05-01

    Full Text Available Background: There are numerous investigations on wide range of issues that disrupt regulatory spermatogenesis, individuals who are exposed to drug abuse faced infertility and immature spermatogenesis. Objective: The aim of this study was to evaluate the addiction effects of morphine and its derivatives on rats spermatogenesis. Materials and Methods: 40 male Wistar rats were randomly divided into 5 equal groups, which were exposed either with intravenous morphine, naloxone, naloxone and morphine, sham (with normal saline injection and a control group without infusion. Spermatogenesis was assessed after three months via histological sections with hematoxylin and eosin staining, using a light microscope based on measurement of spermatogonia, spermatocyte, spermatid, and spermatozoa. Results: Those rats that received opioids had changes in spermatogenesis function. The population of spermatogenesis cycle cells at spermatogonia, spermatocyte, spermatid, and spermatozoa stages was significantly decreased in those rats that received opioid in comparison to the control group (p<0.05. Histological studies revealed that changes in different groups of opioid application might affect sperm formation. Sperm count in morphine group was (0±0 and in naloxone group, naloxone+morphine, sham and control were 235±3.77, 220±3.81, 247.12±6.10 and 250±6.54, respectively (p<0.001. Conclusion: Morphine could affect all spermatogenesis stages

  14. Dextromethorphan attenuated the higher vulnerability to inflammatory thermal hyperalgesia caused by prenatal morphine exposure in rat offspring

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    Chen Chien-Fang

    2011-08-01

    Full Text Available Abstract Background Co-administration of dextromethorphan (DM with morphine during pregnancy and throughout lactation has been found to reduce morphine physical dependence and tolerance in rat offspring. No evidence was presented, however, for the effect of DM co-administered with morphine during pregnancy on inflammatory hyperalgesia in morphine-exposed offspring. Therefore, we attempt to investigate the possible effect of prenatal morphine exposure on the vulnerability to hyperalgesia and the possible therapeutic effect of DM in the present study. Methods Fifty μl of carrageenan (20 mg/ml was injected subcutaneously into the plantar surface of the right hind paw in p18 rats to induce hyperalgesia. Mean paw withdrawal latency was measured in the plantar test to index the severity of hyperalgesia. Using Western blotting and RT-PCR, the quantitative analyses of NMDA receptor NR1 and NR2B subunits were performed in spinal cords from different groups of animals. Results In the carrageenan-induced hyperalgesia model, rat offspring passively exposed to morphine developed a severe hyperalgesia on postnatal day 18 (p18, which also had a more rapid time course than those in the controls. Co-administration of DM with morphine in the dams prevented this adverse effect of morphine in the offspring rats. Western blot and RT-PCR analysis showed that the levels of protein and mRNA of NMDA receptor NR1 and NR2B subunits were significantly higher in the lumbar spinal cords of rats (p14 exposed to prenatal morphine; the co-administration of DM could reverse the effect of morphine on NR1 and attenuate the effect on NR2B. Conclusions Thus, DM may have a great potential in the prevention of higher vulnerability to inflammatory thermal hyperalgesia in the offspring of morphine-addicted mothers.

  15. Predicting the effectiveness of virtual reality relaxation on pain and anxiety when added to PCA morphine in patients having burns dressings changes.

    Science.gov (United States)

    Konstantatos, A H; Angliss, M; Costello, V; Cleland, H; Stafrace, S

    2009-06-01

    Pain arising in burns sufferers is often severe and protracted. The prospect of a dressing change can heighten existing pain by impacting both physically and psychologically. In this trial we examined whether pre-procedural virtual reality guided relaxation added to patient controlled analgesia with morphine reduced pain severity during awake dressings changes in burns patients. We conducted a prospective randomized clinical trial in all patients with burns necessitating admission to a tertiary burns referral centre. Eligible patients requiring awake dressings changes were randomly allocated to single use virtual reality relaxation plus intravenous morphine patient controlled analgesia (PCA) infusion or to intravenous morphine patient controlled analgesia infusion alone. Patients rated their worst pain intensity during the dressing change using a visual analogue scale. The primary outcome measure was presence of 30% or greater difference in pain intensity ratings between the groups in estimation of worst pain during the dressing change. Of 88 eligible and consenting patients having awake dressings changes, 43 were assigned to virtual reality relaxation plus intravenous morphine PCA infusion and 43 to morphine PCA infusion alone. The group receiving virtual reality relaxation plus morphine PCA infusion reported significantly higher pain intensities during the dressing change (mean=7.3) compared with patients receiving morphine PCA alone (mean=5.3) (p=0.003) (95% CI 0.6-2.8). The addition of virtual reality guided relaxation to morphine PCA infusion in burns patients resulted in a significant increase in pain experienced during awake dressings changes. In the absence of a validated predictor for responsiveness to virtual reality relaxation such a therapy cannot be recommended for general use in burns patients having awake dressings changes.

  16. A double blind, within subject comparison of spontaneous opioid withdrawal from buprenorphine versus morphine.

    Science.gov (United States)

    Tompkins, D Andrew; Smith, Michael T; Mintzer, Miriam Z; Campbell, Claudia M; Strain, Eric C

    2014-02-01

    Preliminary evidence suggests that there is minimal withdrawal after the cessation of chronically administered buprenorphine and that opioid withdrawal symptoms are delayed compared with those of other opioids. The present study compared the time course and magnitude of buprenorphine withdrawal with a prototypical μ-opioid agonist, morphine. Healthy, out-of-treatment opioid-dependent residential volunteers (N = 7) were stabilized on either buprenorphine (32 mg/day i.m.) or morphine (120 mg/day i.m.) administered in four divided doses for 9 days. They then underwent an 18-day period of spontaneous withdrawal, during which four double-blind i.m. placebo injections were administered daily. Stabilization and spontaneous withdrawal were assessed for the second opioid using the same time course. Opioid withdrawal measures were collected eight times daily. Morphine withdrawal symptoms were significantly (P withdrawal as measured by mean peak ratings of Clinical Opiate Withdrawal Scale (COWS), Subjective Opiate Withdrawal Scale (SOWS), all subscales of the Profile of Mood States (POMS), sick and pain (0-100) Visual Analog Scales, systolic and diastolic blood pressure, heart rate, respiratory rate, and pupil dilation. Peak ratings on COWS and SOWS occurred on day 2 of morphine withdrawal and were significantly greater than on day 2 of buprenorphine withdrawal. Subjective reports of morphine withdrawal resolved on average by day 7. There was minimal evidence of buprenorphine withdrawal on any measure. In conclusion, spontaneous withdrawal from high-dose buprenorphine appears subjectively and objectively milder compared with that of morphine for at least 18 days after drug cessation.

  17. Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia.

    Science.gov (United States)

    Gong, Kerui; Jasmin, Luc

    2017-02-01

    It is not uncommon for patients chronically treated with opioids to exhibit opioid-induced hyperalgesia, and this has been widely reported clinically and experimentally. The molecular substrate for this hyperalgesia is multifaceted, and associated with a complex neural reorganization even in the periphery. For instance, we have recently shown that chronic morphine-induced heat hyperalgesia is associated with an increased expression of GluN2B containing N-methyl-D-aspartate receptors, as well as of the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1, in small-diameter primary sensory neurons only. Cold allodynia is also a common complaint of patients chronically treated with opioids, yet its molecular mechanisms remain to be understood. Here we present evidence that the cold sensor TRPM8 channel is involved in opioid-induced hyperalgesia. After 7 days of morphine administration, we observed an upregulation of TRPM8 channels using patch clamp recording on sensory neurons and Western blot analysis on dorsal root ganglia. The selective TRPM8 antagonist RQ-00203078 blocked cold hyperalgesia in morphine-treated rats. Also, TRPM8 knockout mice failed to develop cold hyperalgesia after chronic administration of morphine. Our results show that chronic morphine upregulates TRPM8 channels, which is in contrast with the previous finding that acute morphine triggers TRPM8 internalization. Patients receiving chronic opioid are sensitive to cold. We show in mice and rats that sustained morphine administration induces cold hyperalgesia and an upregulation of TRPM8. Knockout or selectively blocking TRPM8 reduces morphine-induced cold hyperalgesia suggesting TRPM8 is regulated by opioids. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

  18. Evaluation the effects of adding ketamine to morphine in intravenous patient-controlled analgesia after orthopedic surgery

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    Godrat Akhavanakbari

    2014-01-01

    Full Text Available Background: Intravenous patient-controlled analgesia (PCA with morphine is commonly used for post-operative pain after major surgery. Ketamine has analgesic property at lower doses, and in combination with opioids it could have synergistic effect. The aim of this study is to determine effects of the addition of ketamine to morphine for PCA after orthopedic surgery. Materials and Methods: In this double-blind randomized clinical trial, 60 patients were randomly allocated to receive PCA consisting: Group 1 (morphine 0.2 mg/ml, Group 2 (morphine 0.2 mg/ml + ketamine 1 mg/ml, and Group 3 (morphine 0.1 mg/ml + ketamine 2 mg/ml. In this, anesthesiologists managed study, patients had orthopedic surgery. Assessments were made at 24 h and 48 h post-operatively. Visual analog scale (VAS was used for recording pain score. PCA morphine use was recorded at 24 h and 48 h. VAS scores over 48 h were analyzed with analysis of variance for repeated measures. Significance level was taken as 0.05. Results: There is no significant difference between demographic information of the three groups ( P > 0.05. Control of pain in Group 2 and Group 3 was better than in Group 1 (only morphine ( P = 0.001 but there was no significant difference between Group 2 and Group 3 ( P > 0.05. Rate of narcotic consumption in groups 2 and 3 was significantly lower than Group 1 ( P < 0.05. Conclusion: After orthopedic surgery, the addition of ketamine to morphine for intravenous PCA was superior to Intravenous PCA opioid alone. The combination induces a significant reduction in pain score and cumulative morphine consumption.

  19. Picrotoxin-induced seizures modified by morphine and opiate antagonists.

    Science.gov (United States)

    Thomas, J; Nores, W L; Kenigs, V; Olson, G A; Olson, R D

    1993-07-01

    The effects of naloxone, Tyr-MIF-1, and MIF-1 on morphine-mediated changes in susceptibility to picrotoxin-induced seizures were studied. Rats were pretreated with naloxone, MIF-1, Tyr-MIF-1, or saline. At 15-min intervals, they received a second pretreatment of morphine or saline and then were tested for seizures following a convulsant dose of picrotoxin. Several parameters of specific categories of seizures were scored. Morphine increased the number of focal seizure episodes, duration of postseizure akinesis, and incidence of generalized clonic seizures. Naloxone tended to block the morphine-mediated changes in susceptibility. Tyr-MIF-1 had effects similar to naloxone on duration of postseizure immobility but tended to potentiate the effects of morphine on focal seizure episodes. The effects of morphine and the opiate antagonists on focal seizure episodes and postseizure duration suggest the general involvement of several types of opiate receptors in these picrotoxin-induced behaviors. However, the observation of antagonistic effects for Tyr-MIF-1 on immobility but agonistic effects for focal seizures suggests that the type of effect exerted by opiate agents may depend upon other neuronal variables.

  20. Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury

    Science.gov (United States)

    Ellis, Amanda; Grace, Peter M.; Wieseler, Julie; Favret, Jacob; Springer, Kendra; Skarda, Bryce; Hutchinson, Mark R.; Falci, Scott; Rice, Kenner C.; Maier, Steven F.; Watkins, Linda R.

    2016-01-01

    Central neuropathic pain (CNP) is a pervasive, debilitating problem that impacts thousands of people living with central nervous system disorders, including spinal cord injury (SCI). Current therapies for treating this type of pain are ineffective and often have dose-limiting side effects. Although opioids are one of the most commonly used CNP treatments, recent animal literature has indicated that administering opioids shortly after a traumatic injury can actually have deleterious effects on long-term health and recovery. In order to study the deleterious effects of administering morphine shortly after trauma, we employed our low thoracic (T13) dorsal root avulsion model (Spinal Neuropathic Avulsion Pain, SNAP). Administering a weeklong course of 10 mg/kg/day morphine beginning 24 hr after SNAP resulted in amplified mechanical allodynia. Co-administering the non-opioid toll-like receptor 4 (TLR4) antagonist (+)-naltrexone throughout the morphine regimen prevented morphine-induced amplification of SNAP. Exploration of changes induced by early post-trauma morphine revealed that this elevated gene expression of TLR4, TNF, IL-1β, and NLRP3, as well as IL-1β protein at the site of spinal cord injury. These data suggest that a short course of morphine administered early after spinal trauma can exacerbate CNP in the long term. TLR4 initiates this phenomenon and, as such, may be potential therapeutic targets for preventing the deleterious effects of administering opioids after traumatic injury. PMID:27519154

  1. [Effects of odor cue on morphine-induced dependence and craving in mice].

    Science.gov (United States)

    Liu, Xiao-Fen; Yang, Guang; Yang, Rui; Jia, Qiang; Guan, Su-Dong

    2012-04-01

    The olfactory system may play a pivotal role in drug addiction. To clarify the issues, we investigated the morphine dependence and psychological craving in morphine addicted mice using the conditioned place preference (CPP) paradigm by taking an only odor cue as the conditioned stimulus (CS). The results showed that by pairing morphine with odor, the CPP could be induced in mice. When the morphine addicted mice were exposed to a novel environment during morphine withdrawal, they spent significantly longer time in the chamber with morphine-paired odor than in the control chamber. The effects of odor cue on the morphine CPP were blocked by the administration of dopamine D1 or D2 antagonists. The studies indicated that olfactory system plays an important role in drug addiction.

  2. Biological profile and bioavailability of imidazoline compounds on morphine tolerance modulation.

    Science.gov (United States)

    Caprioli, Giovanni; Mammoli, Valerio; Ricciutelli, Massimo; Sagratini, Gianni; Ubaldi, Massimo; Domi, Esi; Mennuni, Laura; Sabatini, Chiara; Galimberti, Chiara; Ferrari, Flora; Milia, Chiara; Comi, Eleonora; Lanza, Marco; Giannella, Mario; Pigini, Maria; Del Bello, Fabio

    2015-12-15

    Tolerance to opioid administration represents a serious medical alert in different chronic conditions. This study compares the effects of the imidazoline compounds 1, 2, and 3 on morphine tolerance in an animal model of inflammatory pain in the rat. 1, 2, and 3 have been selected in that, although bearing a common scaffold, preferentially bind to α2-adrenoceptors, imidazoline I2 receptors, or both systems, respectively. Such compounds have been tested in vivo by measuring the paw withdrawal threshold to mechanical pressure after complete Freund's adjuvant injection. To determine the ligand levels in rat plasma, an HPLC-mass spectrometry method has been developed. All the compounds significantly reduced the induction of morphine tolerance, showing different potency and duration of action. Indeed, the selective imidazoline I2 receptor interaction (2) restored the analgesic response by maintaining the same time-dependent profile observed after a single morphine administration. Differently, the selective α2C-adrenoceptor activation (1) or the combination between α2C-adrenoceptor activation and imidazoline I2 receptor engagement (3) promoted a change in the temporal profile of morphine analgesia by maintaining a mild but long lasting analgesic effect. Interestingly, the kinetics of compounds in rat plasma supported the pharmacodynamic data. Therefore, this study highlights that both peculiar biological profile and bioavailability of such ligands complement each other to modulate the reduction of morphine tolerance. Based on these observations, 1-3 can be considered useful leads in the design of new drugs able to turn off the undesired tolerance induced by opioids. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice.

    Science.gov (United States)

    Fitting, Sylvia; Stevens, David L; Khan, Fayez A; Scoggins, Krista L; Enga, Rachel M; Beardsley, Patrick M; Knapp, Pamela E; Dewey, William L; Hauser, Kurt F

    2016-01-01

    Despite considerable evidence that chronic opiate use selectively affects the pathophysiologic consequences of human immunodeficiency virus type 1 (HIV-1) infection in the nervous system, few studies have examined whether neuro-acquired immune deficiency syndrome (neuroAIDS) might intrinsically alter the pharmacologic responses to chronic opiate exposure. This is an important matter because HIV-1 and opiate abuse are interrelated epidemics, and HIV-1 patients are often prescribed opiates as a treatment of HIV-1-related neuropathic pain. Tolerance and physical dependence are inevitable consequences of frequent and repeated administration of morphine. In the present study, mice expressing HIV-1 Tat in a doxycycline (DOX)-inducible manner [Tat(+)], their Tat(-) controls, and control C57BL/6 mice were chronically exposed to placebo or 75-mg morphine pellets to explore the effects of Tat induction on morphine tolerance and dependence. Antinociceptive tolerance and locomotor activity tolerance were assessed using tail-flick and locomotor activity assays, respectively, and physical dependence was measured with the platform-jumping assay and recording of other withdrawal signs. We found that Tat(+) mice treated with DOX [Tat(+)/DOX] developed an increased tolerance in the tail-flick assay compared with control Tat(-)/DOX and/or C57/DOX mice. Equivalent tolerance was developed in all mice when assessed by locomotor activity. Further, Tat(+)/DOX mice expressed reduced levels of physical dependence to chronic morphine exposure after a 1-mg/kg naloxone challenge compared with control Tat(-)/DOX and/or C57/DOX mice. Assuming the results seen in Tat transgenic mice can be generalized to neuroAIDS, our findings suggest that HIV-1-infected individuals may display heightened analgesic tolerance to similar doses of opiates compared with uninfected individuals and show fewer symptoms of physical dependence. Copyright © 2015 by The American Society for Pharmacology and Experimental

  4. The involvement of CRF1 receptor within the basolateral amygdala and dentate gyrus in the naloxone-induced conditioned place aversion in morphine-dependent mice.

    Science.gov (United States)

    Valero, E; Gómez-Milanés, I; Almela, P; Ribeiro Do Couto, B; Laorden, M L; Milanés, M V; Núñez, C

    2018-06-08

    Drug withdrawal-associated aversive memories trigger relapse to drug-seeking behavior. Corticotrophin-releasing factor (CRF) is an important mediator of the reinforcing properties of drugs of abuse. However, the involvement of CRF1 receptor (CRF1R) in aversive memory induced by opiate withdrawal has yet to be elucidated. We used the conditioned-place aversion (CPA) paradigm to evaluate the role of CRF1R on opiate withdrawal memory acquisition, along with plasticity-related processes that occur after CPA within the basolateral amygdala (BLA) and dentate gyrus (DG). Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone-associated compartment. The CPA scores as well as the number of TH-positive neurons (in the NTS-A2 noradrenergic cell group), and the expression of the transcription factors Arc and pCREB (in the BLA and DG) were measured with and without CRF1R blockade. Mice subjected to conditioned naloxone-induced morphine withdrawal robustly expressed CPA. Pre-treatment with the selective CRF1R antagonist CP-154,526 before naloxone conditioning session impaired morphine withdrawal-induced aversive memory acquisition. CP-154,526 also antagonized the enhanced number of TH-positive neurons in the NTS-A2 that was seen after CPA. Increased Arc expression and Arc-pCREB co-localization were seen in the BLA after CPA, which was not modified by CP-154,526. In the DG, CPA was accompanied by a decrease of Arc expression and no changes in Arc-pCREB co-localization, whereas pre-treatment with CP-154,526 induced an increase in both parameters. These results indicate that CRF-CRF1R pathway could be a critical factor governing opiate withdrawal memory storage and retrieval and might suggest a role for TH-NA pathway in the effects of withdrawal on memory. Our results might indicate that the blockade of CRF1R could represent a promising pharmacological treatment strategy approach for the attenuation of the relapse

  5. Global Changes in the Rat Heart Proteome Induced by Prolonged Morphine Treatment and Withdrawal

    Czech Academy of Sciences Publication Activity Database

    Drastichová, Z.; Škrabalová, J.; Jedelský, P.; Neckář, Jan; Kolář, František; Novotný, J.

    2012-01-01

    Roč. 7, č. 10 (2012), e47167 E-ISSN 1932-6203 R&D Projects: GA AV ČR(CZ) IAA501110901 Institutional support: RVO:67985823 Keywords : morphine * rat * heart * proteome Subject RIV: ED - Physiology Impact factor: 3.730, year: 2012

  6. Morphine and Codeine in Biological Fluids: Approaches to Source Differentiation.

    Science.gov (United States)

    ElSohly, M A; Jones, A B

    1989-06-01

    Heroin, morphine, and codeine are among the most abused opiate analgesics today. Analysis of individuals' urines for morphine and codeine is sued as an indication of prior ingestion of these dugs. Poppy seeds and products containing poppy seeds are found to have small amounts of morphine and codeine (usually less than 200 µg morphine/g seeds and much less codeine), which is enough to produce a positive urine test for opiates. This manuscript reviews current data on the analysis of various poppy seed products and urine specimens from individuals ingesting these products. A brief review of the metabolism and elimination of these drugs is presented, with general guidelines for differentiation of poppy seed use versus condone, morphine, or heroin abuse. Copyright © 1989 Central Police University.

  7. Differential analgesic effects of low-dose epidural morphine and morphine-bupivacaine at rest and during mobilization after major abdominal surgery

    DEFF Research Database (Denmark)

    Dahl, J B; Rosenberg, J; Hansen, B L

    1992-01-01

    In a double-blind, randomized study, epidural infusions of low-dose morphine (0.2 mg/h) combined with low-dose bupivacaine (10 mg/h) were compared with epidural infusions of low-dose morphine (0.2 mg/h) alone for postoperative analgesia at rest and during mobilization and cough in 24 patients after...... elective major abdominal surgery. All patients in addition received systemic piroxicam (20 mg daily). No significant differences were observed between the groups at any assessment of pain at rest (P greater than 0.05), whereas pain in the morphine/bupivacaine group was significantly reduced during...... mobilization from the supine into the sitting position 12 and 30 h after surgical incision and during cough 8, 12, and 30 h after surgical incision (P less than 0.05). We conclude, that low-dose epidural bupivacaine potentiates postoperative low-dose epidural morphine analgesia during mobilization and cough...

  8. Modelling concentration-analgesia relationships for morphine to evaluate experimental pain models

    DEFF Research Database (Denmark)

    Sverrisdóttir, Eva; Foster, David John Richard; Upton, Richard Neil

    2015-01-01

    The aim of this study was to develop population pharmacokinetic-pharmacodynamic models for morphine in experimental pain induced by skin heat and muscle pressure, and to evaluate the experimental pain models with regard to assessment of morphine pharmacodynamics. In a randomized, double......-blind, placebo-controlled, crossover study, 39 healthy volunteers received an oral dose of 30 mg morphine hydrochloride or placebo. Non-linear mixed effects modelling was used to describe the plasma concentrations of morphine and metabolites, and the analgesic effect of morphine on experimental pain in skin...... and muscle. Baseline pain metrics varied between individuals and occasions, and were described with interindividual and interoccasion variability. Placebo-response did not change with time. For both pain metrics, morphine effect was proportional to baseline pain and was described with a linear model...

  9. The pharmacokinetics of morphine and lidocaine in nine severe trauma patients.

    Science.gov (United States)

    Berkenstadt, H; Mayan, H; Segal, E; Rotenberg, M; Almog, S; Perel, A; Ezra, D

    1999-12-01

    To study the pharmacokinetic parameters of morphine and lidocaine after a single intravenous (i.v.) bolus in severe trauma patients. Clinical case study. Department of Anesthesiology and Intensive Care of a university hospital. Nine patients, ages 24 to 91 years (mean 54.4 yrs), admitted to the hospital with severe trauma (Injury Severity Score > 20) were included in the study. After initial evaluation and stabilization, a single i.v. dose of morphine 0.025 mg/kg and lidocaine 1.5 mg/kg was given separately, and blood samples were drawn for each drug serum concentration. Morphine pharmacokinetics was studied in eight patients, lidocaine pharmacokinetics in seven patients, and both drugs were studied in six patients. Morphine clearance 2.5 to 10 ml/kg/min (6 +/- 2.6, mean +/- SD) and volume of distribution 0.28 to 3.30 L/kg (1.4 +/- 1.0) were found to be lower than values described previously for healthy volunteers (33.5 +/- 9 ml/kg/min and 5.16 +/- 1.40 L/kg, respectively), and are similar to those described in trauma patients (5 +/- 2.9 ml/kg/min and 0.9 +/- 0.2 L/kg, respectively). In contrast, lidocaine clearance 4.5 to 9.4 ml/kg/min (6.7 +/- 1.7) and volume of distribution 0.39 to 1.20 L/kg (0.72 +/- 0.28) were similar to the value described in healthy volunteers (10 ml/kg/min and 1.32 L/kg, respectively). Changes in pharmacokinetics of drugs eliminated by the liver may occur in patients with severe trauma. The preserved lidocaine clearance indicates an almost normal hepatic blood flow and suggests that other mechanisms may be involved in the lower morphine clearance. The findings may have applications for the treatment of severe trauma patients and suggest that drug monitoring might be needed in some instances so as to avoid toxicity.

  10. Protective role of Delphinium denudatum (Jadwar) against morphine induced tolerance and dependence in mice.

    Science.gov (United States)

    Zafar, S; Ahmad, M A; Siddiqui, T A

    2001-11-01

    Chronic treatment with Delphinium denudatum (Dd) (Jadwar) (family: Ranunculaceae, 200-1600 mg/kg) suppressed morphine withdrawal jumps in a dose-dependent manner, a sign of the development of dependence to opiate as assessed by naloxone (2 mg/kg) precipitation withdrawal on day 10 of testing in mice. Repeated administration of Dd (200-1600 mg/kg) for 9 days attenuated the development of tolerance to the analgesic effect of morphine (10 mg/kg), also produces significant change in tail-flick latency from the saline pretreated group in a dose-dependent manner.

  11. Reanalysis of morphine consumption from two randomized controlled trials of gabapentin using longitudinal statistical methods

    Directory of Open Access Journals (Sweden)

    Zhang S

    2015-02-01

    Full Text Available Shiyuan Zhang,1 James Paul,2 Manyat Nantha-Aree,2 Norman Buckley,2 Uswa Shahzad,2 Ji Cheng,2 Justin DeBeer,5 Mitchell Winemaker,5 David Wismer,5 Dinshaw Punthakee,5 Victoria Avram,5 Lehana Thabane1–4 1Department of Clinical Epidemiology and Biostatistics, McMaster University, 2Department of Anesthesia, McMaster University, 3Biostatistics Unit/Centre for Evaluation of Medicines, St Joseph’s Healthcare-Hamilton, 4Population Health Research Institute, Hamilton Health Science/McMaster University, 5Department of Surgery, Division of Orthopaedics, McMaster University, Hamilton, ON, Canada Background: Postoperative pain management in total joint replacement surgery remains ineffective in up to 50% of patients and has an overwhelming impact in terms of patient well-being and health care burden. We present here an empirical analysis of two randomized controlled trials assessing whether addition of gabapentin to a multimodal perioperative analgesia regimen can reduce morphine consumption or improve analgesia for patients following total joint arthroplasty (the MOBILE trials. Methods: Morphine consumption, measured for four time periods in patients undergoing total hip or total knee arthroplasty, was analyzed using a linear mixed-effects model to provide a longitudinal estimate of the treatment effect. Repeated-measures analysis of variance and generalized estimating equations were used in a sensitivity analysis to compare the robustness of the methods. Results: There was no statistically significant difference in morphine consumption between the treatment group and a control group (mean effect size estimate 1.0, 95% confidence interval −4.7, 6.7, P=0.73. The results remained robust across different longitudinal methods. Conclusion: The results of the current reanalysis of morphine consumption align with those of the MOBILE trials. Gabapentin did not significantly reduce morphine consumption in patients undergoing major replacement surgeries. The

  12. Specific behavioral and cellular adaptations induced by chronic morphine are reduced by dietary omega-3 polyunsaturated fatty acids.

    Directory of Open Access Journals (Sweden)

    Joshua Hakimian

    Full Text Available Opiates, one of the oldest known drugs, are the benchmark for treating pain. Regular opioid exposure also induces euphoria making these compounds addictive and often misused, as shown by the current epidemic of opioid abuse and overdose mortalities. In addition to the effect of opioids on their cognate receptors and signaling cascades, these compounds also induce multiple adaptations at cellular and behavioral levels. As omega-3 polyunsaturated fatty acids (n-3 PUFAs play a ubiquitous role in behavioral and cellular processes, we proposed that supplemental n-3 PUFAs, enriched in docosahexanoic acid (DHA, could offset these adaptations following chronic opioid exposure. We used an 8 week regimen of n-3 PUFA supplementation followed by 8 days of morphine in the presence of this diet. We first assessed the effect of morphine in different behavioral measures and found that morphine increased anxiety and reduced wheel-running behavior. These effects were reduced by dietary n-3 PUFAs without affecting morphine-induced analgesia or hyperlocomotion, known effects of this opiate acting at mu opioid receptors. At the cellular level we found that morphine reduced striatal DHA content and that this was reversed by supplemental n-3 PUFAs. Chronic morphine also increased glutamatergic plasticity and the proportion of Grin2B-NMDARs in striatal projection neurons. This effect was similarly reversed by supplemental n-3 PUFAs. Gene analysis showed that supplemental PUFAs offset the effect of morphine on genes found in neurons of the dopamine receptor 2 (D2-enriched indirect pathway but not of genes found in dopamine receptor 1(D1-enriched direct-pathway neurons. Analysis of the D2 striatal connectome by a retrogradely transported pseudorabies virus showed that n-3 PUFA supplementation reversed the effect of chronic morphine on the innervation of D2 neurons by the dorsomedial prefontal and piriform cortices. Together these changes outline specific behavioral and

  13. Comparison of Intravenous Morphine with Sublingual Buprenorphine in Management of Postoperative Pain after Closed Reduction Orthopedic Surgery

    OpenAIRE

    Ghasem Soltani; Mahmood Khorsand; ALireza Sepehri Shamloo; Lida Jarahi; Nahid Zirak

    2015-01-01

    Background: Postoperative pain is a common side effect following surgery that can significantly reduce surgical quality and patient’s satisfaction. Treatment options are morphine and buprenorphine. We aimed to compare the efficacy of a single dose of intravenous morphine with sublingual buprenorphine in postoperative pain control following closed reduction surgery. Methods: This triple blind clinical trial was conducted on 90 patients referred for closed reduction orthopedic surgery. They wer...

  14. Comparative pharmacokinetics of two modified-release oral morphine formulations (Reliadol® and Kapanol®) and an immediate-release morphine tablet (Morfin 'DAK') in healthy volunteers

    DEFF Research Database (Denmark)

    Bochner, F.; Somogyi, A.A.; Danz, C.

    1999-01-01

    , its metabolites morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), after ingestion of Reliadol® (2 x 30 mg capsules) compared with Kapanolo (3 x 20 mg) [Glaxo Wellcome Australia Ltd] and an immediate-release morphine tablet (Morfin 'DAK', 30 mg; Nycomed Denmark A/S). Design and Setting...

  15. Comparison of the effects of magnesium and ketamine on postoperative pain and morphine consumption. A double-blind randomized controlled clinical study.

    Science.gov (United States)

    Arıkan, Müge; Aslan, Bilge; Arıkan, Osman; Horasanlı, Eyüp; But, Abdulkadir

    2016-01-01

    To compare the effects of magnesium sulfate and ketamine on postoperative pain and total morphine consumption in a placebo-controlled design. One hundred and twenty women scheduled for total abdominal hysterectomy were included in this prospective, randomized, double-blind study. Postoperatively, when the Numeric Pain Rating Scale (NPRS) was four or more, IV-PCA morphine was applied to all patients. The patients were randomized into three groups: Group K ketamine, Group M magnesium, and Group C saline received as infusion. Total morphine consumption for 48h, pain scores, adverse effects, and patients' satisfaction were evaluated. Total morphine consumption was significantly lower in Group K (32.6±9.2 mg) than in Group M (58.9±6.5 mg) and in Group C (65.7±8.2 mg). The satisfaction level of patients in Group K was higher than the other two groups (petamine to IV-PCA morphine reduces the total consumption of morphine without psychotic effects; however, magnesium did not influence morphine consumption.

  16. Comparison of efficacy of intra-articular morphine and steroid in patients with knee osteoarthritis

    Directory of Open Access Journals (Sweden)

    Serbülent Gökhan Beyaz

    2012-01-01

    Full Text Available Introduction: Primary therapeutic aim in treatment of osteoarthritis of the knee is to relieve the pain of osteoarthritis. The aim of this study was to compare the efficacy of intra-articular triamcinolone with intra-articular morphine in pain relief due to osteoarthritis of the knee in the elderly population. Materials and Methods: Patients between 50 and 80 years of age were randomized into three groups. Group M received morphine plus bupivacaine intra-articularly, Group T received triamcinolone plus bupivacaine intra-articularly, and Group C received saline plus bupivacaine intra-articularly. Patients were evaluated before injection and in 2nd, 4th, 6th, and 12th weeks after injection. First-line supplementary analgesic was oral paracetamol 1500 mg/day. If analgesia was insufficient with paracetamol, oral dexketoprofen trometamol 50 mg/day was recommended to patients. Results: After the intra-articular injection, there was statistically significant decrease in visual analog scale (VAS scores in Groups M and T, when compared to Group C. The decrease of VAS scores seen at the first 2 weeks continued steadily up to the end of 12th week. There was a significant decrease in Groups M and T in the WOMAC scores, when compared to Group C. There was no significant difference in the WOMAC scores between morphine and steroid groups. Significantly less supplementary analgesics was used in the morphine and steroid groups. Conclusion: Intra-articular morphine was as effective as intra-articular triamcinolone for analgesia in patients with osteoarthritis knee. Intra-articular morphine is possibly a better option than intra-articular steroid as it has lesser side effects.

  17. Synergistic Effects of Citalopram and Morphine in the Renal Colic Pain Relief; a Randomized Clinical Trial

    Directory of Open Access Journals (Sweden)

    Mehrdad Esmailian

    2014-03-01

    , respectively. Log rank test showed a significant difference in the treatment success between the two groups (p=0.001. Conclusion: It seems that the combination of citalopram and morphine sulfate causes increased efficacy and higher success rate in pain control of patients presented to the emergency department with a complaint of renal colic.

  18. Morphine sparing effect of low dose ketamine during patient ...

    African Journals Online (AJOL)

    Adele

    2003-09-12

    Sep 12, 2003 ... KEY WORDS: Ketamine, morphine sparing effect, patient controlled intravenous analgesia. ... Measurements: Morphine consumption, visual analogue pain score (VAPS), pulse ..... Brain Research, 1990; 518: 218-222. 7.

  19. Attenuation of morphine tolerance and dependence by thymoquinone in mice

    Directory of Open Access Journals (Sweden)

    Hossein Hosseinzadeh

    2016-01-01

    Full Text Available Objectives: Dependence and tolerance are major restricting factors in the clinical use of opioid analgesics. In the present study, the effects of thymoquinone, the major constituent of Nigella sativa seeds, on morphine dependence and tolerance were investigated in mice. Materials and Methods: Male adult NMRI mice were made tolerant and dependent by repeated injections of morphine (50, 50, and 75 mg/kg, i.p. on 9 a.m., 1 p.m., and 5 p.m., respectively during a 3-day administration schedule. The hot-plate test was used to assess tolerance to the analgesic effects of morphine. Naloxone (2 mg/kg, i.p. was injected to precipitate withdrawal syndrome in order to assess the morphine dependence. To evaluate the effects of thymoquinone on tolerance and dependence to morphine, different single or repeated doses of thymoquinone were administered in mice. Rotarod was used to assess the motor coordination. Results: Administration of single or repeated doses of thymoquinone (20 and 40 mg/kg, i.p. significantly decreased the number of jumps in morphine dependent animals. Repeated administration of thymoquinone (20 and 40 mg/kg, for 3 days and also single injection of thymoquinone (40 mg/kg, on the fourth day attenuated tolerance to the analgesic effect of morphine. None of the thymoquinone doses (10, 20, and 40 mg/kg produced any antinociceptive effects on their own. Motor coordination of animals was impaired by the high dose of thymoquinone (40 mg/kg. Conclusion: Based on these results, it can be concluded that thymoquinone prevents the development of tolerance and dependence to morphine.

  20. Characterization of a Single Chain Fv Antibody that Reacts with Free Morphine

    OpenAIRE

    Matsukizono, Miho; Kamegawa, Mariko; Tanaka, Koichi; Kohra, Shinya; Arizono, Koji; Hamazoe, Yuta; Sugimura, Kazuhisa

    2013-01-01

    An immune phage library derived from mice, hyperimmunized with morphine-conjugated BSA, was used to isolate a single-chain Fv (scFv) clone, M86, with binding activity to morphine-conjugated thyroglobulin (morphine-C-Tg) but not to codeine-, cocaine-, or ketamine-conjugated Tg. Surface plasmon resonance analysis using a morphine-C-Tg-coupled CM5 sensor chip showed that the Kd value was 1.26 × 10−8 M. To analyze its binding activity to free morphine and related compounds, we performed a competi...

  1. A Methanol Extract of Brugmansia arborea Affects the Reinforcing and Motor Effects of Morphine and Cocaine in Mice

    Directory of Open Access Journals (Sweden)

    Antonio Bracci

    2013-01-01

    Full Text Available Previous reports have shown that several of the effects of morphine, including the development of tolerance and physical withdrawal symptoms, are reduced by extracts of Brugmansia arborea (L. Lagerheim (Solanaceae (B. arborea. In the present study we evaluate the action of the methanol extract of B. arborea (7.5–60 mg/kg on the motor and reinforcing effects of morphine (20 and 40 mg/kg and cocaine (25 mg/kg using the conditioned place preference (CPP procedure. At the doses employed, B. arborea did not affect motor activity or induce any effect on CPP. The extract partially counteracted morphine-induced motor activity and completely blocked the CPP induced by 20 mg/kg morphine. On the other hand, B. arborea blocked cocaine-induced hyperactivity but did not block cocaine-induced CPP. Reinstatement of extinguished preference with a priming dose of morphine or cocaine was also inhibited by B. arborea. The complex mechanism of action of B. arborea, which affects the dopaminergic and the cholinergic systems, seems to provide a neurobiological substrate for the effects observed. Considered as a whole, these results point to B. arborea as a useful tool for the treatment of morphine or cocaine abuse.

  2. A Randomized Controlled Trial on the Effect of Tapentadol and Morphine on Conditioned Pain Modulation in Healthy Volunteers.

    Directory of Open Access Journals (Sweden)

    Chris Martini

    Full Text Available Modulatory descending pathways, originating at supraspinal sites that converge at dorsal horn neurons, influence pain perception in humans. Defects in descending pain control are linked to chronic pain states and its restoration may be a valuable analgesic tool. Conditioned pain modulation (CPM is a surrogate marker of descending inhibition that reduces the perception of pain from a primary test stimulus during application of a conditioning stimulus. Here the effects of the analgesics tapentadol, a combined mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and morphine, a strong mu-opioid receptor agonist, were tested on CPM in a randomized, double-blind, placebo-controlled crossover trial in 12 healthy pain-free volunteers, to understand possible differences in mechanism of action between these opioids.On three occasions CPM responses were obtained 60-90 and 120-150 min following intake of tapentadol (100 mg immediate release tablet, morphine (40 mg immediate release tablet or placebo. At both time points, CPM was detectable after treatment with placebo and tapentadol (peak pain ratings reduced by 20-30% after application of the conditioning stimulus but not after morphine. Compared to placebo morphine displayed significantly less CPM: mean treatment difference 18.2% (95% CI 3.4 to 32.9% at 60-90 min after drug intake and 19.5% (95% CI 5.7 to 33.2% at 120-150 min after drug intake (p = 0.001. No difference in CPM between placebo and tapentadol was detected: mean treatment difference 1.5% (95% CI -11.6 to 14.6% at 60-90 min after drug intake and 1.5% (95% CI -16.0 to 18.9% at 120-150 min after drug intake (p = 0.60.Our data show that in volunteers morphine affects CPM, while tapentadol was without effect despite identical experimental conditions. These data confirm that tapentadol's main mechanism of action is distinct from that of morphine and likely related to the effect of adrenergic stimulation on descending controls

  3. Peripheral antinociceptive effects of morphine after burn injury

    DEFF Research Database (Denmark)

    Møiniche, S; Dahl, J B; Kehlet, H

    1993-01-01

    In a double-blind study, 2 mg of morphine in saline, or saline only, was given subcutaneously into a second-degree bilateral leg-burn injury in 12 volunteers. Heat-pain thresholds and pressure-pain thresholds were significantly increased by local morphine administration. These results confirm...

  4. Laboratory Report on Performance Evaluation of Key Constituents during Pre-Treatment of High Level Waste Direct Feed

    Energy Technology Data Exchange (ETDEWEB)

    Huber, Heinz J.

    2013-06-24

    The analytical capabilities of the 222-S Laboratory are tested against the requirements for an optional start up scenario of the Waste Treatment and Immobilization Plant on the Hanford Site. In this case, washed and in-tank leached sludge would be sent directly to the High Level Melter, bypassing Pretreatment. The sludge samples would need to be analyzed for certain key constituents in terms identifying melter-related issues and adjustment needs. The analyses on original tank waste as well as on washed and leached material were performed using five sludge samples from tanks 241-AY-102, 241-AZ-102, 241-AN-106, 241-AW-105, and 241-SY-102. Additionally, solid phase characterization was applied to determine the changes in mineralogy throughout the pre-treatment steps.

  5. Laboratory Report on Performance Evaluation of Key Constituents during Pre-Treatment of High Level Waste Direct Feed

    International Nuclear Information System (INIS)

    Huber, Heinz J.

    2013-01-01

    The analytical capabilities of the 222-S Laboratory are tested against the requirements for an optional start up scenario of the Waste Treatment and Immobilization Plant on the Hanford Site. In this case, washed and in-tank leached sludge would be sent directly to the High Level Melter, bypassing Pretreatment. The sludge samples would need to be analyzed for certain key constituents in terms identifying melter-related issues and adjustment needs. The analyses on original tank waste as well as on washed and leached material were performed using five sludge samples from tanks 241-AY-102, 241-AZ-102, 241-AN-106, 241-AW-105, and 241-SY-102. Additionally, solid phase characterization was applied to determine the changes in mineralogy throughout the pre-treatment steps

  6. Midazolam Plus Haloperidol as Adjuvant Analgesics to Morphine in Opium Dependent Patients: A Randomized Clinical Trial.

    Science.gov (United States)

    Afzalimoghaddam, Mohammad; Edalatifard, Maryam; Nejati, Amir; Momeni, Mehdi; Isavi, Nader; Karimialavijeh, Ehsan

    2016-01-01

    Tolerance to opioids among opium-dependent patients creates obstacles for proper pain management of these patients in the emergency department (ED). The aim of the present study was to investigate the efficacy of intramuscular (IM) haloperidol plus midazolam on morphine analgesia among opium-dependent patients. Opium-dependent adults who were admitted to the ED for new-onset severe pain in the limbs or abdomen (within 24 hours of admission and a pain score of over six, using a numerical rating scale [NRS]) were recruited. Participants were randomly assigned into two groups. Group A received morphine 0.05 mg/kg intravenously (IV) and a mixture of midazolam 2.5 mg and haloperidol 2.5 mg (diluted in 5 cc of distilled water, IM); group B received morphine 0.05 mg/kg IV and distilled water 5 cc, IM. Measured outcomes were related to: 1) pain intensity; 2) total doses of morphine; 3) changes in hemodynamic status and level of consciousness of patients. NRS scores (zero to 10) before and one, three and six hours following intervention, as well as total doses of morphine, were recorded. We recruited 68 males (78.16%) and 19 females (21.83%). The mean age was 38.28±6.59 years. The pain score in group A declined more rapidly over six hours than that in group B. Moreover, as compared to group B, the amount of morphine use decreased significantly in group A. Based on the present data, adding haloperidol plus midazolam to morphine for pain management improved pain scores and lowered morphine consumption among opium-dependent patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Narp regulates long-term aversive effects of morphine withdrawal

    Science.gov (United States)

    Reti, Irving M.; Crombag, Hans S.; Takamiya, Kogo; Sutton, Jeffrey M.; Guo, Ning; Dinenna, Megan L.; Huganir, Richard L.; Holland, Peter C.; Baraban, Jay M.

    2008-01-01

    Although long-lasting effects of drug withdrawal are thought to play a key role in motivating continued drug use, the mechanisms mediating this type of drug-induced plasticity are unclear. As Narp is an immediate early gene product that is secreted at synaptic sites and binds to AMPA receptors, it has been implicated in mediating enduring forms of synaptic plasticity. In previous studies, we found that Narp is selectively induced by morphine withdrawal in the extended amygdala, a group of limbic nuclei that mediate aversive behavioral responses. Accordingly, in this study, we evaluated whether long-term aversive effects of morphine withdrawal are altered in Narp KO mice. We found that acute physical signs of morphine withdrawal are unaffected by Narp deletion. However, Narp KO mice acquire and sustain more aversive responses to the environment conditioned with morphine withdrawal than WT controls. Paradoxically, Narp KO mice undergo accelerated extinction of this heightened aversive response. Taken together, these studies suggest that Narp modulates both acquisition and extinction of aversive responses to morphine withdrawal and, therefore, may regulate plasticity processes underlying drug addiction. PMID:18729628

  8. Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice.

    Science.gov (United States)

    Kim, Woojin; Kim, Min Joon; Go, Donghyun; Min, Byung-Il; Na, Heung Sik; Kim, Sun Kwang

    2016-01-22

    Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechanical allodynia, acetone and von Frey filament tests were used, respectively. Significant allodynia signs were observed three days after an oxaliplatin injection (6 mg/kg, i.p.). BVA (0.25, 1, and 2.5 mg/kg, s.c., ST36) or morphine (0.5, 2, and 5 mg/kg, i.p.) alone showed dose-dependent anti-allodynic effects. The combination of BVA and morphine at intermediate doses showed a greater and longer effect than either BVA or morphine alone at the highest dose. Intrathecal pretreatment with the opioidergic (naloxone, 20 μg) or 5-HT3 (MDL-72222, 15 μg) receptor antagonist, but not with α2 adrenergic (idazoxan, 10 μg) receptor antagonist, blocked this additive effect. Therefore, we suggest that the combination effect of BVA and morphine is mediated by spinal opioidergic and 5-HT3 receptors and this combination has a robust and enduring analgesic action against oxaliplatin-induced neuropathic pain.

  9. Epidural morphine for postoperative pain relief in children

    DEFF Research Database (Denmark)

    Henneberg, S W; Hole, P; Haas, Inge Madsen De

    1993-01-01

    the investigation. We observed a change in the sleeping pattern with an increased number of sleep-induced myoclonia during the administration of epidural morphine. In conclusion, the use of epidural morphine in children for postoperative pain relief is very efficient. The minimal effective dose has not been...

  10. Effect of irradiation on analgesia induced by morphine and endorphin

    International Nuclear Information System (INIS)

    Kim, Jin Kyu; Lee, Byoung Hun; Hyun, Soung Hee; Chung, Ki Myung

    2003-01-01

    Morphine and endorphin administered intracerebroventricularly (i.c.v.) produce analgesia by activating different descending pain inhibitory systems. Gamma irradiation attenuates the acute analgesic action of i.c.v. injected morphine in mice. This study was done to investigate the effect of-irradiation on the analgesia produced by i.c.v. injected morphine and endorphin in male ICR mice. In one group, mice were exposed to whole-body irradiation at a dose of 5 Gy from a 60 Co source and the analgesic effects were tested 5, 30, 60, 90 and 180 min after irradiation using the acetic acid-induced writhing test. The analgesic effect was produced time-dependently and reached its maximum at 90 min after irradiation. Thus, time was fixed in the following studies. In another group, mice were irradiated with 5 Gy and tested 90 minutes later for analgesia produced by i.c.v. administration of morphine or endorphin. Irradiation significantly potentiated the analgesia produced by endorphin. However, the antinociception produced by morphine was not affected by irradiation. These results support the hypothesis that morphine and endorphin administered supraspinally produce antinocieception by different neuronal mechanisms

  11. Effect of irradiation on analgesia induced by morphine and endorphin

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin Kyu; Lee, Byoung Hun; Hyun, Soung Hee; Chung, Ki Myung [KAERI, Daejeon (Korea, Republic of)

    2003-07-01

    Morphine and endorphin administered intracerebroventricularly (i.c.v.) produce analgesia by activating different descending pain inhibitory systems. Gamma irradiation attenuates the acute analgesic action of i.c.v. injected morphine in mice. This study was done to investigate the effect of-irradiation on the analgesia produced by i.c.v. injected morphine and endorphin in male ICR mice. In one group, mice were exposed to whole-body irradiation at a dose of 5 Gy from a {sup 60}Co source and the analgesic effects were tested 5, 30, 60, 90 and 180 min after irradiation using the acetic acid-induced writhing test. The analgesic effect was produced time-dependently and reached its maximum at 90 min after irradiation. Thus, time was fixed in the following studies. In another group, mice were irradiated with 5 Gy and tested 90 minutes later for analgesia produced by i.c.v. administration of morphine or endorphin. Irradiation significantly potentiated the analgesia produced by endorphin. However, the antinociception produced by morphine was not affected by irradiation. These results support the hypothesis that morphine and endorphin administered supraspinally produce antinocieception by different neuronal mechanisms.

  12. Neonatal Morphine Exposure in Very Preterm Infants – Cerebral Development and Outcomes

    Science.gov (United States)

    Steinhorn, Rachel; McPherson, Chris; Anderson, Peter J; Neil, Jeffrey; Doyle, Lex W; Inder, Terrie

    2015-01-01

    Objective To investigate the association of morphine exposure in very preterm infants with cerebral volumes and neurodevelopmental outcome from birth through middle childhood. Study design Observational study of very preterm infants in the Victorian Infant Brain Study cohort. 230 infants born neonatal intensive care unit (NICU) of the Royal Women’s Hospital. 57 (25%) infants received morphine analgesia during their NICU stay at the attending physician’s discretion. Primary outcomes were regional brain volumes at term and 7 years; neurobehavioral performance at term; and cognitive, motor, emotional, behavioral, communication, and executive function scores at age 2 and 7 years. Linear regressions were used to compare outcomes between participants who did and did not receive morphine. Results At term, preterm infants who received morphine had similar rates of grey matter injury to no-morphine infants, but a trend towards smaller cortical volumes in the orbitofrontal (pleft=0.002, pright=0.01) and subgenual (pleft=0.01) regions. At seven years, cortical volumes did not differ between groups. At 2 years, morphine-exposed children were more likely to show behavioral dysregulation (p=0.007) than no-morphine children, but at seven years no detrimental impacts of morphine on neurobehavioral outcome were observed. Conclusions Low-dose morphine analgesia received during neonatal intensive care was associated with early alterations in cerebral structure and short-term neurobehavioral problems that did not persist into childhood. PMID:25919729

  13. Morphine reduces the threshold of helium preconditioning against myocardial infarction: the role of opioid receptors in rabbits

    Science.gov (United States)

    Pagel, Paul S.; Krolikowski, John G.; Amour, Julien; Warltier, David C.; Weihrauch, Dorothee

    2015-01-01

    Objectives Brief, repetitive administration of helium before prolonged coronary artery occlusion and reperfusion protects myocardium against infarction. Opioid receptors mediate the cardioprotective effects of ischemic pre- and postconditioning, but whether these receptors also play a role in helium preconditioning is unknown. We tested the hypotheses that opioid receptors mediate helium preconditioning and that morphine (a μ1-opioid receptor agonist with δ1-opioid agonist properties) lowers the threshold of cardioprotection produced by helium in vivo. Design Randomized, prospective study. Setting University research laboratory. Participants Male New Zealand white rabbits. Interventions Rabbits (n=56) were instrumented for measurement of systemic hemodynamics and subjected to a 30 min left anterior descending coronary artery (LAD) occlusion and 3 h reperfusion. In separate experimental groups, rabbits (n=6 or 7 per group) received 0.9% saline (control), one or three cycles of 70% helium-30% oxygen administered for 5 min interspersed with 5 min of an air-oxygen mixture, morphine (0.1 mg/kg, i.v.), or the nonselective opioid antagonist naloxone (6 mg/kg, i.v.) before LAD occlusion. Other groups of rabbits received three cycles of helium or one cycle of helium plus morphine (0.1 mg/kg) in the absence or presence of naloxone (6 mg/kg) before ischemia and reperfusion. Statistical analysis of data was performed with analysis of variance for repeated measures followed by Bonferroni’s modification of Student’s t test. Measurements and Main Results Myocardial infarct size was determined using triphenyltetrazolium chloride staining and presented as a percentage of the left ventricular area at risk. Helium reduced myocardial infarct size in an exposure-related manner [36±6 (P>0.05) and 25±4% (P<0.05 versus control) for one and three cycles of helium, respectively; data are mean±SD] compared with control (44±7%). Morphine and naloxone alone did not affect infarct

  14. Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation.

    Science.gov (United States)

    Chen, Ming; Zhao, Yanfang; Yang, Hualan; Luan, Wenjie; Song, Jiaojiao; Cui, Dongyang; Dong, Yi; Lai, Bin; Ma, Lan; Zheng, Ping

    2015-07-24

    One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.

  15. Does exercise deprivation increase the tendency towards morphine dependence in rats?

    Science.gov (United States)

    Nakhaee, Mohammad Reza; Sheibani, Vahid; Ghahraman Tabrizi, Kourosh; Marefati, Hamid; Bahreinifar, Sareh; Nakhaee, Nouzar

    2010-01-01

    Exercise deprivation has been concluded to have some negative effectson psychological well-being. This study was conducted to find outwhether exercise deprivation may lead to morphine dependence in rats. Forty male Wistar rats weighing 162 ± 9 g were housed in clear plasticcages in groups of two under standard laboratory conditions. The studyhad two phases. In phase I, the animals were randomly divided intoexercised (E) and unexercised (UE) groups (n = 20 each) and treadmillrunning was performed based on a standard protocol for three weeks. Atthe end of the training period, plasma β-endorphin levels weredetermined in four rats from each group. In phase II, the animals wereprovided with two bottles, one containing tap water and the other 25mg/l morphine sulfate in tap water for a total of 12 weeks. At the end ofthis phase naloxone was injected intraperitoneally to precipitatemorphine withdrawal. THERE WAS NO SIGNIFICANT DIFFERENCE BETWEEN UE AND E GROUPS INMORPHINE CONSUMPTION (MG/KG/WK) [ F(1,14) = 0.2, P = 0.690; time:F(11,154) =18.72, P exercise does not increasethe tendency of morphine dependence in rats.

  16. Endogenous morphine-6-glucuronide (M6G) is present in the plasma of patients: validation of a specific anti-M6G antibody for clinical and basic research.

    Science.gov (United States)

    Laux-Biehlmann, Alexis; Chung, Hélène; Mouheiche, Jinane; Vérièpe, Julie; Delalande, François; Lamshöft, Marc; Welters, Ingeborg D; Soldevila, Stéphanie; Bazin, Hervé; Lamarque, Laurent; Van Dorsselaer, Alain; Poisbeau, Pierrick; Schneider, Francis; Goumon, Yannick; Garnero, Patrick

    2014-01-01

    Endogenous morphine and its derivatives (morphine-6-glucuronide [M6G]; morphine-3-glucuronide [M3G]) are formed by mammalian cells from dopamine. Changes in the concentrations of endogenous morphine have been demonstrated in several pathologies (sepsis, Parkinson's disease, etc.), and they might be relevant as pathological markers. While endogenous morphine levels are detectable using enzyme-linked immunosorbant assay (ELISA), mass spectrometry (MS) analysis was, so far, the only approach to detect and quantify M6G. This study describes the preparation of a specific anti-M6G rabbit polyclonal antibody and its validation. The specificity of this antibody was assessed against 30 morphine-related compounds. Then, a M6G-specific ELISA-assay was tested to quantify M6G in the plasma of healthy donors, morphine-treated, and critically ill patients. The antibody raised against M6G displays a strong affinity for M6G, codeine-6-glucuronide, and morphine-3-6-glucuronide, whereas only weak cross-reactivities were observed for the other compounds. Both M6G-ELISA and LC-MS/MS approaches revealed the absence of M6G in the plasma of healthy donors (controls, n = 8). In all positive donors treated with morphine-patch (n = 5), M6G was detected using both M6G-ELISA and LC-MS/MS analysis. Finally, in a study on critically ill patients with circulating endogenous morphine (n = 26), LC-MS/MS analysis revealed that 73% of the positive-patients (19 of 26), corresponding to high M6G-levels in M6G-ELISA, contained M6G. In conclusion, we show that endogenous M6G can be found at higher levels than morphine in the blood of morphine-naive patients. With respect to the interest of measuring endogenous M6G in pathologies, we provide evidences that our ELISA procedure represents a powerful tool as it can easily and specifically detect endogenous M6G levels. © 2013 International Union of Biochemistry and Molecular Biology.

  17. Inhibitory effects of ginseng total saponin on up-regulation of cAMP pathway induced by repeated administration of morphine.

    Science.gov (United States)

    Seo, Jeong-Ju; Lee, Jae-Woong; Lee, Wan-Kyu; Hong, Jin-Tae; Lee, Chong-Kil; Lee, Myung-Koo; Oh, Ki-Wan

    2008-02-01

    We have reported that ginseng total saponin (GTS) inhibited the development of physical and psychological dependence on morphine. However, the possible molecular mechanisms of GTS are unclear. Therefore, this study was undertaken to understand the possible molecular mechanism of GTS on the inhibitory effects of morphine-induced dependence. It has been reported that the up-regulated cAMP pathway in the LC of the mouse brain after repeated administration of morphine contributes to the feature of withdrawals. GTS inhibited up-regulation of cAMP pathway in the LC after repeated administration of morphine in this experiment. GTS inhibited cAMP levels and protein expression of protein kinase A (PKA). In addition, GTS inhibited the increase of cAMP response element binding protein (CREB) phosphorylation. Therefore, we conclude that the inhibitory effects of GTS on morphine-induced dependence might be mediated by the inhibition of cAMP pathway.

  18. Transdermal Nitroglycerin as an Adjuvant to Patient-Controlled Morphine Analgesia after Total Knee Arthroplasty

    Directory of Open Access Journals (Sweden)

    Sharon Orbach-Zinger

    2009-01-01

    Full Text Available BACKGROUND: Nitroglycerin (NTG has been shown to be a useful adjunct for pain treatment without increasing adverse side effects. The effects of NTG on postoperative morphine consumption after knee replacement were evaluated.

  19. Comparative efficacy assessment of Tramadol versus Morphine for post operative pain relief following abdominal surgery, Shariati Hospital (1999

    Directory of Open Access Journals (Sweden)

    Soroosh AR

    2002-11-01

    Full Text Available Introduction: The objective of the present study is to compare the respiratory function and pain relief of two parenteral analgesics tramadol and morphine under clinical conditions. Materials and Methods: The trial was conducted as an open label-randomized, single center study. The study was performed during 3 months in 1999. In total, 64 patients were enrolled in Shariatie University Hospital, while the other 32 patients were treated with morphine. Results: There were 12 male and 20 female in either groups. The mean age was 48±15 in tramadol versus 43±16 morphine group. Concerning the amount of the medication given to the patients. It would be observed that tramadol patients received 194±72 mg and morphine patients 17±7 mg out of drugs. At study admission vital signs were recorded. The pulse rate, blood pressure and respiratory rate are presented revealing no obvious differences between the treatment groups. There was a broad range regarding the underlying type of operation, however, a laparatomy or a cholecystectomy was performed in 24 (75.0% Vs. 26 (81.3% patients, respectively. All 64 patients were receiving anaesthetics as stipulated in the protocol. Of them being diazepam, sufentanil, succinylcholine chloride and thiopental as the most frequent reported, 4 Vs. 3 patient were given additional fentanylin a mean dosage of 220 mg Vs. 83 mcg. The oxygen saturation was the main safety parameter of the present study. No obvious differences between the two treatment groups can be detected (P<0.472. Primary efficacy end point was the pain assessment. The pain intensity at each scheduled time point was recorded. At study inclusion no differences between the treatment groups uncured, but during the 24 hour observation period the tramadol patients were in advantage (P<0.001. Conclusion: This study shows that long-term efficacy of tramadol is better than morphine.

  20. Myoelectric activity of the small intestine during morphine dependence and withdrawal in rats

    International Nuclear Information System (INIS)

    Kuperman, D.A.; Sninsky, C.A.; Lynch, D.F.

    1987-01-01

    The authors investigated (1) the effect of morphine dependence on the migrating myoelectric complex (MMC) of the small intestine, (2) whether bacterial overgrowth developed in morphine-dependent rats, and (3) the effect of naloxone and methylbromide naltrexone, a peripheral opioid antagonist, on the MMC in morphine-naive and morphine-dependent rats. They also evaluated intestinal motility during naloxone-induced withdrawal in animals pretreated with clonidine. Intestinal myoelectric activity was monitored by four indwelling electrodes in unanesthetized, fasted rats. D-[ 14 C]xylose breath tests were performed before and after morphine-pellet implantation to evaluate the presence of bacterial overgrowth of the small intestine. Naloxone had no effect on myoelectric activity of the small intestine in morphine-naive rats. Cycling activity fronts were present in morphine-dependent animals, but there was a significant prolongation of activity front periodicity and slowing of the propagation velocity. No significant increase in 14 CO 2 excretion was noted in the morphine-dependent rats. They conclude from their studies that (1) myoelectric activity of the small intestine develops incomplete tolerance to morphine; (2) bacterial overgrowth is not a feature of morphine dependence in the rat; (3) alterations of intestinal myoelectric activity are a component of the opiate withdrawal syndrome, and they appear at least partially mediated by a peripheral mechanism that can be suppressed by an α 2 -adrenergic agonist

  1. Myoelectric activity of the small intestine during morphine dependence and withdrawal in rats

    Energy Technology Data Exchange (ETDEWEB)

    Kuperman, D.A.; Sninsky, C.A.; Lynch, D.F.

    1987-04-01

    The authors investigated (1) the effect of morphine dependence on the migrating myoelectric complex (MMC) of the small intestine, (2) whether bacterial overgrowth developed in morphine-dependent rats, and (3) the effect of naloxone and methylbromide naltrexone, a peripheral opioid antagonist, on the MMC in morphine-naive and morphine-dependent rats. They also evaluated intestinal motility during naloxone-induced withdrawal in animals pretreated with clonidine. Intestinal myoelectric activity was monitored by four indwelling electrodes in unanesthetized, fasted rats. D-(/sup 14/C)xylose breath tests were performed before and after morphine-pellet implantation to evaluate the presence of bacterial overgrowth of the small intestine. Naloxone had no effect on myoelectric activity of the small intestine in morphine-naive rats. Cycling activity fronts were present in morphine-dependent animals, but there was a significant prolongation of activity front periodicity and slowing of the propagation velocity. No significant increase in /sup 14/CO/sub 2/ excretion was noted in the morphine-dependent rats. They conclude from their studies that (1) myoelectric activity of the small intestine develops incomplete tolerance to morphine; (2) bacterial overgrowth is not a feature of morphine dependence in the rat; (3) alterations of intestinal myoelectric activity are a component of the opiate withdrawal syndrome, and they appear at least partially mediated by a peripheral mechanism that can be suppressed by an ..cap alpha../sub 2/-adrenergic agonist.

  2. Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers

    DEFF Research Database (Denmark)

    Villesen, Hanne H.; Kristensen, Kim; Hansen, Steen Honoré

    2007-01-01

    After oral administration, morphine-6-glucuronide (M6G) displays an atypical absorption profile with two peak plasma concentrations. A proposed explanation is that M6G is hydrolysed to morphine in the colon, which is then absorbed and subsequently undergoes metabolism in the liver to morphine-3-g......-glucuronide (M3G) and M6G. The aims of this study were to confirm and elucidate the biphasic absorption profile as well as clarify the conversion of M6G to morphine after a single oral administration of M6G in healthy volunteers....

  3. Electromechanical coupling in rat basilar artery in response to morphine.

    Science.gov (United States)

    Waters, A; Harder, D R

    1983-12-01

    Force development, intracellular membrane potential (Em), and voltage vs. current curves were measured in rat basilar artery to help elucidate the mechanism of action of morphine sulfate and a synthetic narcotic, meperidine hydrochloride, on this preparation. Morphine sulfate caused a dose-dependent contraction of these vessels, which was reversible with naloxone. Electrical studies show that morphine may act upon this vascular smooth muscle preparation by decreasing potassium conductance (gk). This hypothesis is supported by the findings that morphine sulfate depolarized these cells and increased the input resistance (rin) determined by the application of rectangular hyperpolarizing and depolarizing current pulses through the microelectrode during impalement and recording of the associated voltage changes (delta V). Meperidine hydrochloride had significantly less effect on this preparation than morphine sulfate. Further studies show that the vehicular medium used for the commercially available preparation of naloxone (viz. the methyl and propyl esters of p-hydroxybenzoic acid in a ratio of 9:1) is, in vitro, a vasodilator of cerebral vascular smooth muscle.

  4. Microinjection of Orexin-A into the Locus Coeruleus Area Induces Morphine Withdrawal Behaviors in Morphine Independent Rats

    Directory of Open Access Journals (Sweden)

    Hosin Azizi

    2012-02-01

    Full Text Available Introduction: Orexin neuropeptide has a role in opioid withdrawal behaviors. Orexin-expressing neurons that are present in the hypothalamic nuclei send dense projections to the Locus Coeruleus (LC. Withdrawal syndrome is temporally associated with hyperactivity of LC neurons. LC neurons do not show withdrawal-induced hyperactivity in brain slices from morphine-dependent rats. Thus, it has been suggested that the increase in LC neuronal activity seen in vivo is mediated by extrinsic factors. Therefore, this study was carried out to find whether LC microinjection of orexin-A can induce withdrawal behaviors. Method: Adult male Wistar rats were used in this study. Intra-LC microinjection of orexin-A or orexin-A vehicle was performed one week after LC cannulation. Thereafter, somatic signs of withdrawal were evaluated during a period of 25 min.Findings: Orexin-A induced several signs of morphine withdrawal. Conclusion: It may be concluded that orexin at LC acts as an extrinsic factor in the expression of morphine withdrawal syndrome.

  5. Simultaneous determination of morphine, codeine and 6-acetyl morphine in human urine and blood samples using direct aqueous derivatisation: validation and application to real cases.

    Science.gov (United States)

    Chericoni, S; Stefanelli, F; Iannella, V; Giusiani, M

    2014-02-15

    Opiates play a relevant role in forensic toxicology and their assay in urine or blood is usually performed for example in workplace drug-testing or toxicological investigation of drug impaired driving. The present work describes two new methods for detecting morphine, codeine and 6-monoacethyl morphine in human urine or blood using a single step derivatisation in aqueous phase. Propyl chloroformate is used as the dramatizing agent followed by liquid-liquid extraction and gas-chromatography-mass spectroscopy to detect the derivatives. The methods have been validated both for hydrolysed and unhydrolysed urine. For hydrolysed urine, the LOD and LOQ were 2.5ng/ml and 8.5ng/ml for codeine, and 5.2ng/ml and 15.1ng/ml for morphine, respectively. For unhydrolysed urine, the LOD and LOQ were 3.0ng/ml and 10.1ng/ml for codeine, 2.7ng/ml and 8.1ng/ml for morphine, 0.8ng/ml and 1.5ng/ml for 6-monoacetyl morphine, respectively. In blood, the LOD and LOQ were 0.44ng/ml and 1.46ng/ml for codeine, 0.29ng/ml and 0.98ng/ml for morphine, 0.15ng/ml and 0.51ng/ml for 6-monoacetyl morphine, respectively. The validated methods have been applied to 50 urine samples and 40 blood samples (both positive and negative) and they can be used in routine analyses. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Premedication with oral Dextromethorphan reduces intra-operative Morphine requirement

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    R Talakoub

    2005-09-01

    Full Text Available Background: Intra-operative pain has adverse effects on hemodynamic parameters. Due to complications of opioids for pain relief, using non-opioids medication is preferred. The purpose of this study was to investigate the effect of oral dextrometorphan premedication on intra-operative Morphine requirement. Methods: After approval of the Ethics committee and informed consent, 40 adult patients who stand in American Society of Anesthesiologists Physical Status I and II, under general anesthesia for elective laparatomy were selected and classified in two equal groups randomly. In group A, oral dextromethorphan (60mg was administered at 10 PM and 6 AM preoperatively. In group B, placebo (dextrose was administered. After induction of general anesthesia and before skin incision, intravenous morphine (0.01 mg/kg was administered. During surgery, when systolic blood pressure or heart rate was increased more than 20% of the preoperative baseline, 0.01 mg/kg morphine was administered. At the end of surgery, the totally prescribed morphine (mg/kg and maximal increase in systolic, diastolic, mean arterial blood pressure and heart rate relative to the baseline values were calculated and statistically compared with student’s t-test. Results: The mean dose of administered morphine during surgery was significantly less in group A than group B (P<0.0001. Also, Maximal increase in systolic, diastolic and mean arterial blood pressure was significantly less in group A (p<0.003, p<0.004, p<0.0001, respectively. There was no significant difference in maximal heart rate increase between two groups (p<0.114. Conclusion: Oral dextromethorphan premedication may decrease intra-operative morphine requirement and reduce maximal increase in systolic and mean arterial blood pressure during surgery. Key words: Dextromethorphan, Morphine, Intra-operative, Premedication Hemodynamic

  7. Digestible tryptophan levels for male broilers in pre-starter and starter diets

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    Bruno Samuel Borges

    2016-09-01

    Full Text Available The objective was to determine the digestible tryptophan requirements for male broilers in pre-starter and starter phases. Two experiments using 400 Cobb broilers were performed 200 males in the first experiment for the pre-starter phase (one to seven days old, and 200 males in the second experiment for the starter phase (eight to 21 days old. Chicks were housed in batter boxes made of galvanized steel as an experimental shed. The experiments were performed in a completely randomized design, with four treatments and five replicates, with ten birds each. In both experiments, the tryptophan requirement was determined using diets with different levels of digestible tryptophan. A tryptophan-deficient diet was formulated, as a basal diet, which was supplemented with increased levels of L-tryptophan in order to achieve the desirable digestible tryptophan levels. Treatments consisted of 0.209% (basal diet; 0.223%; 0.235% and 0.248% digestible tryptophan for the pre-starter phase (experiment 1 and 0.187% (basal diet; 0.200%, 0.211% and 0.223% digestible tryptophan for the starter phase (experiment 2. We evaluated feed intake, weight gain and feed conversion, as well as the metabolizability of feed nutrients. The performance and metabolic data were subjected to analysis of variance, and estimates of digestible tryptophan levels were made through polynomial regression models at 5% probability. There was no significant difference between the digestible tryptophan levels in the diet over performance and digestibility in both treatments. It is possible to conclude that the basal diet with 0.209% digestible tryptophan for the pre-starter phase and 0.187% for the starter phase, at a tryptophan: lysine ratio of 16%, as sufficient to meet the broilers requirements.

  8. Modulation of morphine antinociceptive tolerance and physical dependence by co-administration of simvastatin.

    Science.gov (United States)

    Mansouri, Mohammad Taghi; Khodayar, Mohammad Javad; Tabatabaee, Amirhossein; Ghorbanzadeh, Behnam; Naghizadeh, Bahareh

    2015-10-01

    Statins, 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, are widely used in the management of different diseases beyond their primary indication for lowering cholesterol. Previous studies have demonstrated the neuroprotective effects of simvastatin in different animal models. In the present study, we examined the effects of simvastatin (30, 60, 100 and 300mg/kg, p.o.) on the development and expression of morphine-induced tolerance and dependence in mice. For the induction of morphine tolerance and dependence, mice were twice daily treated with morphine (10mg/kg, s.c.) for 5 consecutive days. Tolerance was evaluated by the hot-plate test and physical dependence by naloxone challenge, on the sixth day. The results showed that oral administration of simvastatin produced antinociceptive activity in a dose-dependent way. Co-administration of simvastatin with morphine did not affect the acute morphine-induced analgesia (10mg/kg, s.c.). However, repeated co-administration of simvastatin with morphine significantly attenuated the development of tolerance to the analgesic effect of morphine and inhibited the naloxone (5mg/kg, s.c.)-precipitated withdrawal signs (jumping and body weight loss). Also, simvastatin at doses of 100 and 300mg/kg attenuated the expression of morphine-induced tolerance and dependence. These data indicated that, while simvastatin can alleviate both development and expression of morphine-induced tolerance, it cannot enhance morphine-induced antinociception. Taken together, simvastatin may be used as an adjutant therapeutic agent in combination with morphine and or other opioids in patients with severe chronic pain. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. The significance of the adenosinergic system in morphine dependence

    Directory of Open Access Journals (Sweden)

    Lupina Malgorzata

    2015-09-01

    Full Text Available Addiction is a chronic and recurrent disease. In its pathology, neuroadaptive changes within the dopaminergic pathways inside the mesolimbic system play a predominant role. Of note, the manner in which various neurotransmitters act on their receptors, may modulate the addictive process. Adenosine, an important neuromodulator in the central nervous system, is able to modify the opioid dependence, doing so mainly by its activity on the adenosine A1 and A2A receptors. In the present manuscript, the actual state of knowledge on the relationships between adenosinergic receptors and opioid dependence has been described. Various literature data on the involvement of adenosine ligands, mainly in the signs of morphine withdrawal, as well as morphine-induced sensitization, were also collected. Additionally, in this paper, some important interactions between adenosine and other neurotransmitters (e.g. dopamine, glutamate are described. It is put forward that these connections are the major mechanism of involvement of the adenosinergic system in morphine addiction. The repeatedly confirmed effectiveness of adenosine ligands in morphine dependence, as seen in various experimental protocols, suggests that adenosine ligands may be useful tools for developing new strategies for attenuating morphine dependence.

  10. Morphine-assisted cholescintigraphy in the diagnosis of acalculous cholecystitis

    International Nuclear Information System (INIS)

    Sajewicz, Z.; Paradowski, L.; Kowal, A.

    2001-01-01

    Detecting acalculous cholecystitis still causes difficulties. The aim of the study was to assess the usefulness of morphine-assisted cholescintigraphy in the diagnosis of acute and chronic acalculous cholecystitis. Sixteen patients with suspicion of acute or chronic acalculous cholecystitis were examined. in the above mentioned patients choscintigraphy was performed by the intravenous administration of 5 mCi 99mTc-HIDA. None of the patients displayed the gallbladder within 60 min. The intravenous administration of 0.04 mg/kg b.w. morphine did not result in filling a tracer into the gallbladder in 10 patients, which allowed to confirm that acute acalculous cholecystitis. In the remaining 6 patients the morphine induction caused influx of radiotracer into the gallbladder, which allowed to diagnose the chronic acalculous cholecystitis. Morphine-assisted cholescintigraphy turned out to be useful in detecting acute and chronic cholecystitis. (author)

  11. Modulation of ethanol-intake by morphine: Evidence for a central site of action

    Energy Technology Data Exchange (ETDEWEB)

    Wild, K.D.; Reid, L.D. (Rensselaer Polytechnic Institute, Troy, NY (USA))

    1990-01-01

    Previous studies have shown that subcutaneous administration of low doses of morphine increase, while subcutaneous naloxone decreases, ethanol-intake in rats. However, the site of action of morphine modulation of ethanol-intake remains unclear. In an attempt to elucidate this issue, seven graded doses of morphine were given intracerebroventricularly to rats 15 min prior to an opportunity to consume water and sweetened alcoholic beverage for 2 hr. Two lower doses of intracerebroventricular morphine reliably increased ethanol-intake, while higher doses decreased intake of water. Preference ratios were reliably increased by morphine doses of 1 {mu}g and higher. The present data provide support for a central site of morphine modulation of ethanol-intake.

  12. Silane pre-treatments on copper and aluminium

    International Nuclear Information System (INIS)

    Deflorian, F.; Rossi, S.; Fedrizzi, L.

    2006-01-01

    A large part of aluminium products are coated with an organic layer in order to improve the corrosion resistance. Copper surfaces are also sometimes protected with an organic coating to improve the durability or the aesthetic properties. Examples of industrial applications are household appliances and heat exchanger components. For these applications it is not rare to have the industrial need to treat at the same time components made of aluminium and copper. In order to extend the service life of the organic coated copper a specific surface pre-treatment is often required. Nevertheless, probably because of the limited market of this application, no specific pre-treatments for copper are industrially developed, with the exception of cleaning procedures, but simply extensions of existing pre-treatments optimised for other metals (aluminium, zinc) are used. The application of silane pre-treatments as adhesion promoters for organic coated metals is remarkably increasing in the last decade, because silanes offer very good performance together with high environmental compatibility. The idea is therefore to try to develop a specific silane based pre-treatment for copper. The starting point is the existing silane products for aluminium, optimising the composition and the application conditions (concentration, temperature, pH of the bath, etc.) in order to develop a high performance copper alloy pre-treatment increasing the protective properties and the adhesion of a successively applied organic coating. Moreover these pre-treatments could be used for aluminium alloys too and therefore could be suggested for multi-metals components. The deposits were analysed using FTIR spectroscopy and optical and electron microscopic observations. A careful electrochemical characterisation, mainly by electrochemical impedance spectroscopy measurements (EIS) was carried out to highlight the presence of silane and to evaluate the performance of the different deposits. In order to study an

  13. Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice

    Directory of Open Access Journals (Sweden)

    Woojin Kim

    2016-01-01

    Full Text Available Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechanical allodynia, acetone and von Frey filament tests were used, respectively. Significant allodynia signs were observed three days after an oxaliplatin injection (6 mg/kg, i.p.. BVA (0.25, 1, and 2.5 mg/kg, s.c., ST36 or morphine (0.5, 2, and 5 mg/kg, i.p. alone showed dose-dependent anti-allodynic effects. The combination of BVA and morphine at intermediate doses showed a greater and longer effect than either BVA or morphine alone at the highest dose. Intrathecal pretreatment with the opioidergic (naloxone, 20 μg or 5-HT3 (MDL-72222, 15 μg receptor antagonist, but not with α2-adrenergic (idazoxan, 10 μg receptor antagonist, blocked this additive effect. Therefore, we suggest that the combination effect of BVA and morphine is mediated by spinal opioidergic and 5-HT3 receptors and this combination has a robust and enduring analgesic action against oxaliplatin-induced neuropathic pain.

  14. [Advances in research on mechanisms of seed pre-treatments.

    Science.gov (United States)

    Liu, Xu; Liu, Juan; Liu, Qian; Gao, Ya Ni; Wang, Quan Zhen

    2016-11-18

    Seeds play a vital role in nature and agro-ecosystems. The success of seed germination and the establishment of a normal seedling determine the propagation and survival of a plant species, but seed vigor is often seriously damaged because of seed aging, dormancy and the deterioration of natural habitat. Thus, exploring methods for improving germination quality is of great significance to ecology and the economy. Based on the latest international reports, seed pre-treatments are the most practical and effective methods for improving plant performance, increasing yields and enhancing stress resistance. This review provided a summary of the current pre-sowing treatment technologies and the physiological and biochemical responses of plants to these methods by addressing gene expression, cytological effects, enzyme system activities, material and energy metabolism, antioxidation mechanisms and signal transduction pathways. We also interpreted the mechanisms of the seed pre-treatment methods from aspects of seed germination acceleration and stress resistance enhancement. The bottleneck in seed pre-treatments at the cytological and molecular levels and the problems involved in their application were also discussed. Thus far, most studies had largely focused on the partial reaction alterations of plant biochemistry and enzyme activities, and they had generally been characterized by a lack of systematic and holistic study for applications to crop production. Finally, we proposed an outlook for further study in an attempt to provide a prospective and scientific reference for plant germplasm conservation, high-efficiency organic agriculture development and ecological environment re-construction.

  15. Morphine Induces Splenocyte Trafficking into the CNS

    OpenAIRE

    Olin, Michael R; Oh, Seunguk; Roy, Sabita; Peterson, Phillip K; Molitor, Thomas

    2011-01-01

    Opioids significantly alter functional responses of lymphocytes following activation. Morphine, an opioid derivative, alters the Th1 to Th2 response and modulates functional responses such as cytolytic activity and proliferation. Although there has been extensive research involving morphine’s effects on lymphocytes, little is known about the effects morphine has on lymphocyte trafficking. The objective of the study was to use in vivo bioluminescent imaging to determine morphine’s effect on th...

  16. On the Measurement of Morphine Level and Determination of Consumption of Different Drugs in People’s Urine at Different Ages through High-Performance Liquid Chromatography

    Directory of Open Access Journals (Sweden)

    saeed shahabi

    2015-06-01

    Full Text Available Objective: Morphine is one of the important narcotics which constitutes one of the alkaloid and opium components. If this substance is prepared defectively, it will appear in a variety of colors. Therefore, it is not possible to identify this substance by its color. Method: In this study, drug addicts were invited to take urine tests. After morphine extraction from urine samples by chromium toxicity method, different standard concentrations were injected into HPLC device and the resultant diagrams were analyzed. Then, some changes were made into the methodology for the optimality of measurement process and morphine determination in human urine. Results: It was found that the amount of morphine available in the urine samples was measureable through high-performance liquid chromatography and the amount of impurities added to drugs could be determined. Conclusion: This method can be used for diagnosis.

  17. Pavement Pre- and Post-Treatment Performance Models Using LTPP Data

    OpenAIRE

    Lu, Pan; Tolliver, Denver

    2012-01-01

    This paper determines that pavement performance in International Roughness Index (IRI) is affected by exogenous interventions such as pavement age, precipitation level, freeze-thaw level, and lower level preservation maintenance strategies. An exponential function of pavement age was used to represent pavement IRI performance curves. Moreover, this paper demonstrates a method which calculates short-term post-pavement performance models from maintenance effect models and pre-treatment performa...

  18. Inhibitory effect of harmane on morphine-dependent Guinea pig ileum.

    Science.gov (United States)

    Aricioglu, Feyza; Utkan, Tijen

    2003-12-01

    Studies on the occurrence and properties of b-carbolines structurally related to harmala alkaloids have gained attention since it was hypothesized that some of these compounds play a role in processes of substance abuse and dependence. This study investigates the effects of harmane on naloxone-precipitated withdrawal syndrome in morphine-dependent guinea pig ileum. Segments of ilea from starved male guinea pigs were obtained and fixed at a resting tension of 1 g in an organ bath containing 10(-6) M morphine in Tyrode solution at 37 degrees C, which was bubbled with 95% O(2) and 5% CO(2). Tissues were incubated in 10(-6) M morphine containing Tyrode solution for 4 hours before harmane was added. Naloxone and harmane had no effect on naive ilea. Naloxone (10(-6) M) contracted morphine-dependent ilea. Harmane significantly inhibited the contractile response to naloxone in a dose-dependent manner (10(-7) M = 24%; 10(-6) M = 49.3%; 10(-5) = 70%). These results suggest that harmane may have beneficial effects on morphine withdrawal syndrome.

  19. Sympathetic activity induced by naloxone-precipitated morphine withdrawal is blocked in genetically engineered mice lacking functional CRF1 receptor

    International Nuclear Information System (INIS)

    García-Carmona, Juan-Antonio; Martínez-Laorden, Elena; Milanés, María-Victoria; Laorden, María-Luisa

    2015-01-01

    There is large body evidence indicating that stress can lead to cardiovascular disease. However, the exact brain areas and the mechanisms involved remain to be revealed. Here, we performed a series of experiments to characterize the role of CRF1 receptor (CRF1R) in the stress response induced by naloxone-precipitated morphine withdrawal. The experiments were performed in the hypothalamic paraventricular nucleus (PVN) ventrolateral medulla (VLM), brain regions involved in the regulation of cardiovascular activity, and in the right ventricle by using genetically engineered mice lacking functional CRF1R levels (KO). Mice were treated with increasing doses of morphine and withdrawal was precipitated by naloxone administration. Noradrenaline (NA) turnover, c-Fos, expression, PKA and TH phosphorylated at serine 40, was evaluated by high-performance liquid chromatography (HPLC), immunohistochemistry and immunoblotting. Morphine withdrawal induced an enhancement of NA turnover in PVN in parallel with an increase in TH neurons expressing c-Fos in VLM in wild-type mice. In addition we have demonstrated an increase in NA turnover, TH phosphorylated at serine 40 and PKA levels in heart. The main finding of the present study was that NA turnover, TH positive neurons that express c-Fos, TH phosphorylated at serine 40 and PKA expression observed during morphine withdrawal were significantly inhibited in CRF1R KO mice. Our results demonstrate that CRF/CRF1R activation may contribute to the adaptive changes induced by naloxone-precipitated withdrawal in the heart and in the brain areas which modulate the cardiac sympathetic function and suggest that CRF/CRF1R pathways could be contributing to cardiovascular disease associated to opioid addiction. - Highlights: • Naloxone-precipitated morphine withdrawal increases sympathetic activity in the PVN and heart. • Co-localization of TH phosphorylated at serine 40/c-Fos in the VLM after morphine withdrawal • Naloxone

  20. Sympathetic activity induced by naloxone-precipitated morphine withdrawal is blocked in genetically engineered mice lacking functional CRF1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    García-Carmona, Juan-Antonio; Martínez-Laorden, Elena; Milanés, María-Victoria; Laorden, María-Luisa

    2015-02-15

    There is large body evidence indicating that stress can lead to cardiovascular disease. However, the exact brain areas and the mechanisms involved remain to be revealed. Here, we performed a series of experiments to characterize the role of CRF1 receptor (CRF1R) in the stress response induced by naloxone-precipitated morphine withdrawal. The experiments were performed in the hypothalamic paraventricular nucleus (PVN) ventrolateral medulla (VLM), brain regions involved in the regulation of cardiovascular activity, and in the right ventricle by using genetically engineered mice lacking functional CRF1R levels (KO). Mice were treated with increasing doses of morphine and withdrawal was precipitated by naloxone administration. Noradrenaline (NA) turnover, c-Fos, expression, PKA and TH phosphorylated at serine 40, was evaluated by high-performance liquid chromatography (HPLC), immunohistochemistry and immunoblotting. Morphine withdrawal induced an enhancement of NA turnover in PVN in parallel with an increase in TH neurons expressing c-Fos in VLM in wild-type mice. In addition we have demonstrated an increase in NA turnover, TH phosphorylated at serine 40 and PKA levels in heart. The main finding of the present study was that NA turnover, TH positive neurons that express c-Fos, TH phosphorylated at serine 40 and PKA expression observed during morphine withdrawal were significantly inhibited in CRF1R KO mice. Our results demonstrate that CRF/CRF1R activation may contribute to the adaptive changes induced by naloxone-precipitated withdrawal in the heart and in the brain areas which modulate the cardiac sympathetic function and suggest that CRF/CRF1R pathways could be contributing to cardiovascular disease associated to opioid addiction. - Highlights: • Naloxone-precipitated morphine withdrawal increases sympathetic activity in the PVN and heart. • Co-localization of TH phosphorylated at serine 40/c-Fos in the VLM after morphine withdrawal • Naloxone

  1. Clinical manifestations of combined methamphetamine with morphine and their effects on brain dopamine and 5-hydroxytryptamine release in mice

    Directory of Open Access Journals (Sweden)

    Shing-Hwa Liu

    2015-01-01

    Full Text Available Background: Methamphetamine (MA is often mixed with morphine by polydrug addicts, and polydrug abuse has become a serious health problem worldwide. The purpose of this study was to investigate the major signs and symptoms of combined MA and morphine abuse in the Emergency Department (ED. In addition, we used a mouse model to study their effects on the release of dopamine (DA and 5-hydroxytryptamine (5-HT in the central nervous system. Materials and Methods: Seventy-two patients with combined MA and morphine abuse were collected during a 3-year period, and their medical records were reviewed. Mice were intraperitoneally administered MA (0.75 and 2.5 mg/kg/day and morphine (5 mg/kg/day either alone or in combination for 5 consecutive days. The mechanisms underlying the interaction between MA and morphine were explored by measuring the extracellular levels of DA and 5-HT in the shell of the nucleus accumbens using an in vivo microdialysis technique. Results: The most common manifestations of combined MA and morphine abuse included tachypnea, tachycardia, confusion, anxiety, delirium, insomnia, and diaphoresis in the ED. Of those, 25% of acute intoxication required hospitalization for intensive care. The group of mice treated with a combination of MA and morphine had higher concentrations of DA and 5-HT in the accumbens than with either drug alone. Conclusion: These findings suggest that MA pharmacologically interacts with morphine to induce characteristic signs and symptoms. Our preclinical results also implicate the involvement of increased DAergic and 5-HTergic neurotransmission among polydrug abusers with a combination of MA and morphine.

  2. Antinociceptive Effect of Morphine Microinjections into the Dorsal Hippocampus in the Formalin-Induced Orofacial Pain in Rats

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    Emad Khalilzadeh

    2010-09-01

    Full Text Available In the present study, the effects of intra-hippocampal microinjections of morphine (an opioid agonist and naloxone (an opioid antagonist were investigated in the formalin-induced orofacial pain in rats. Orofacial pain was induced by subcutaneous injection of formalin (1 %, 50 μl in the upper lip region and the time spent of face rubbing was measured in 3-min blocks for 45 min. Formalin induced a biphasic (first phase: 0-3 min; second phase: 15-33 min pain response. Intra-hippocampal microinjections of morphine at doses of 2 and 4 μg significantly (P < 0.05 attenuated the first phase, and at doses of 1, 2 and 4 μg, morphine significantly (P < 0.05 suppressed both phases of formalin-induced orofacial pain response. Intra-hippocampal microinjections of naloxone (1 and 4 μg non-significantly increased pain when used alone, and in pretreatment microinjection, naloxone (4 μg reversed morphine (2 μg-induced antinociception. These results indicate that at the level of hippocampus of the brain, morphine through a naloxone-reversible mechanism produced an antinociceptive effect confronting the pain induced by formalin in the orofacial region in rats.

  3. Brain cholinergic involvement during the rapid development of tolerance to morphine

    Science.gov (United States)

    Wahba, Z. Z.; Oriaku, E. T.; Soliman, S. F. A.

    1987-01-01

    The effect of repeated administration of morphine on the activities of the cholinergic enzymes, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), in specific brain regions were studied in rats treated with 10 mg/kg morphine for one or two days. Repeated administration of morphine was associated with a decline in the degree of analgesia produced and with a significant increase of AChE activity of the medulla oblongata. A single injection of morphine resulted in a significant decline in ChAT activity in the hypothalamus, cerebellum, and medulla oblongata regions. After two consecutive injections, no decline in ChAT was observed in these regions, while in the cerebral cortex the second administration elicited a significant decline. The results suggest that the development of tolerance to morphine may be mediated through changes in ChAT activity and lend support to the involvement of the central cholinergic system in narcotic tolerance.

  4. Pre-treatment social anxiety severity moderates the impact of mindfulness-based stress reduction and aerobic exercise.

    Science.gov (United States)

    Jazaieri, Hooria; Lee, Ihno A; Goldin, Philippe R; Gross, James J

    2016-06-01

    We examined whether social anxiety severity at pre-treatment would moderate the impact of mindfulness-based stress reduction (MBSR) or aerobic exercise (AE) for generalized social anxiety disorder. MBSR and AE produced equivalent reductions in weekly social anxiety symptoms. Improvements were moderated by pre-treatment social anxiety severity. Mindfulness-based stress reduction (MBSR) and aerobic exercise (AE) are effective in reducing symptoms of social anxiety. Pre-treatment social anxiety severity can be used to inform treatment recommendations. Both MBSR and AE produced equivalent reductions in weekly levels of social anxiety symptoms. MBSR appears to be most effective for patients with lower pre-treatment social anxiety symptom severity. AE appears to be most effective for patients with higher pre-treatment social anxiety symptom severity. © 2015 The British Psychological Society.

  5. Morphine Reduces Myocardial Infarct Size via Heat Shock Protein 90 in Rodents

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    Bryce A. Small

    2015-01-01

    Full Text Available Opioids reduce injury from myocardial ischemia-reperfusion in humans. In experimental models, this mechanism involves GSK3β inhibition. HSP90 regulates mitochondrial protein import, with GSK3β inhibition increasing HSP90 mitochondrial content. Therefore, we determined whether morphine-induced cardioprotection is mediated by HSP90 and if the protective effect is downstream of GSK3β inhibition. Male Sprague-Dawley rats, aged 8–10 weeks, were subjected to an in vivo myocardial ischemia-reperfusion injury protocol involving 30 minutes of ischemia followed by 2 hours of reperfusion. Hemodynamics were continually monitored and myocardial infarct size determined. Rats received morphine (0.3 mg/kg, the GSK3β inhibitor, SB216763 (0.6 mg/kg, or saline, 10 minutes prior to ischemia. Some rats received selective HSP90 inhibitors, radicicol (0.3 mg/kg, or deoxyspergualin (DSG, 0.6 mg/kg alone or 5 minutes prior to morphine or SB216763. Morphine reduced myocardial infarct size when compared to control (42 ± 2% versus 60 ± 1%. This protection was abolished by prior treatment of radicicol or DSG (59 ± 1%, 56 ± 2%. GSK3β inhibition also reduced myocardial infarct size (41 ± 2% with HSP90 inhibition by radicicol or DSG partially inhibiting SB216763-induced infarct size reduction (54 ± 3%, 47 ± 1%, resp.. These data suggest that opioid-induced cardioprotection is mediated by HSP90. Part of this protection afforded by HSP90 is downstream of GSK3β, potentially via the HSP-TOM mitochondrial import pathway.

  6. Effect of Nimodipine on Morphine-related Withdrawal Syndrome in Rat Model: An Observational Study

    Science.gov (United States)

    Mishra, Pravash Ranjan; Barik, Mayadhar; Ray, Subrata Basu

    2017-01-01

    Objective: To observe the effect of L-type calcium channel blocker like nimodipine on morphine's withdrawal when it was administered continuously along with morphine versus a single bolus dose of nimodipine, which was administered at the end of the experiment before the precipitation of withdrawal reaction in morphine-dependent rats. Materials and Methods: Four groups of adult male Wistar rats were rendered morphine dependent by subcutaneous injections of morphine at a dose of 10 mg/kg for 10 days. Nimodipine 10 mg/kg intraperitoneally (ip) administered to one group once daily before morphine administration in the entire experimental period, and another group received nimodipine only once at the end of the experiment as a single bolus dose 2 mg/kg before the administration of naloxone. Naloxone 3 mg/kg was administered ip to all the groups to precipitate withdrawal reactions. The withdrawal reactions were evaluated and scored as per the Gellert and Holtzman global withdrawal rating scale. Results: Nimodipine when administered as a single bolus dose before naloxone administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period. Conclusion: We discovered that nimodipine helps in attenuating the severity of morphine withdrawal having potential role encountered during pharmacotherapy with morphine management of opioid dependence, well memory, impairement, cell signaling and phosphorylation of neuron. PMID:28553371

  7. Seizures induced by carbachol, morphine, and leucine-enkephalin: a comparison.

    Science.gov (United States)

    Snead, O C

    1983-04-01

    The electrical, behavioral, and pharmacological properties of seizures induced by morphine, leucine-enkephalin, and the muscarinic cholinergic agonist carbachol were examined and compared. Low-dose carbachol given intracerebroventricularly (ICV) produced seizures similar electrically to those produced by ICV morphine and leucine-enkephalin, although there was some difference in site of subcortical origin of onset. Carbachol and morphine were similar in that they had the same anticonvulsant profile, produced similar behavioral changes, caused generalized absence seizures in low doses and generalized convulsive seizures in high doses, and were capable of chemical kindling. However, opiate-induced seizures were not overcome by cholinergic antagonists, nor were carbachol seizures blocked by opiate antagonists. These data suggest that there may be a common noncholinergic, nonopiatergic system involved in mediating carbachol- and morphine-induced seizures but not enkephalin seizures.

  8. Low doses of dextromethorphan attenuate morphine-induced rewarding via the sigma-1 receptor at ventral tegmental area in rats.

    Science.gov (United States)

    Chen, Shiou-Lan; Hsu, Kuei-Ying; Huang, Eagle Yi-Kung; Lu, Ru-Band; Tao, Pao-Luh

    2011-09-01

    Chronic use of morphine causes rewarding and behavioral sensitization, which may lead to the development of psychological craving. In our previous study, we found that a widely used antitussive dextromethorphan (known as a low affinity NMDA receptor antagonist), at doses of 10-20 mg/kg (i.p.), effectively decreased morphine rewarding in rats. In this study, we further investigated the effects and mechanisms of low doses of DM (μg/kg range) on morphine rewarding and behavioral sensitization. A conditioned place preference test was used to determine the rewarding and a locomotor activity test was used to determine the behavioral sensitization induced by the drug(s) in rats. When a low dose of DM (3 or 10 μg/kg, i.p.) was co-administered with morphine (5 mg/kg, s.c.), the rewarding effect, but not behavioral sensitization, induced by morphine was inhibited. The inhibiting effect of DM could be blocked by systemically administering a sigma-1 receptor antagonist, BD1047 (3 mg/kg, i.p.). When BD1047 (5 nmole/site) was locally given at the VTA, it also blocked the effects of a low dose of DM in inhibiting morphine rewarding. Our findings suggest that the activation of the sigma-1 receptor at the VTA may be involved in the mechanism of low doses of DM in inhibiting the morphine rewarding effect and the possibility of using extremely low doses of DM in treatment of opioid addiction in clinics. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  9. THE INFLUENCE OF PRE-HEAT TREATMENT ON WHITE CAST IRONS PLASTICITY

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    T. M. Myronova

    2013-11-01

    Full Text Available Purpose. The development of heat treatment modes of white cast irons for structure changes in their eutectic constituent, namely in disturbing the monolithic structure of ledeburite colonies cementite structure and eutectic net continuity. Also the mentioned heat treatment modes are targeted to the eutectic net shift for the most suitable position from the point of plastic deforming. Methodology. The hypoeutectic white cast irons with 2.92…3.35 % carbon content and additionally alloyed by 3.18 % vanadium have been used as the research materials. The mentioned alloys have been pre-heat treated and hot twist tested. Findings. The research results showed that the carbide net breaking by plastic deforming leads to cast irons mechanical properties increasing but has difficulties in implementation due to the white cast irons low plasticity. The influence of different pre-heat treatment modes on structure and plasticity of white hypoeutectic cast irons have been investigated. They include the isotherm soaking under the different temperatures as well as multiply soakings and thermo-cycling. The influence of eutectic level, as well as pre heat treatment modes on different composition white cast irons hot plasticity have been investigated. Originality. It was determined that the heat treatment, which leads to double α→γ recrystallization under 860 – 950 °С and reperlitization under 720-680 °С results in significant increase of plasticity, as well as in un-alloyed and alloyed by vanadium white cast irons. It takes place due to carbide matrix phase separation in ledeburite colonies by new phase boundaries forming especially due to carbide transformations under vanadium alloying. Practical value. The implementation of pre-heat treatment with phase recrystallization resulted in hypoeutectic white cast irons plasticity increasing. The obtained level of cast iron plasticity corresponds to the one of carbide class steels, which ensures the successful

  10. Blood-brain distribution of morphine-6-glucuronide in sheep

    DEFF Research Database (Denmark)

    Villesen, H H; Foster, D J R; Upton, R N

    2006-01-01

    At present there are few data regarding the rate and extent of brain-blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented...

  11. Human gliomas contain morphine

    DEFF Research Database (Denmark)

    Olsen, Peter; Rasmussen, Mads; Zhu, Wei

    2005-01-01

    BACKGROUND: Morphine has been found in cancer cell lines originating from human and animal cells. Thus, it became important to demonstrate whether or not actual tumours contain this opiate alkaloid. MATERIAL/METHODS: Human glioma tissues were biochemically treated to isolate and separate endogenous...

  12. Effect of morphine-induced antinociception is altered by AF64A-induced lesions on cholinergic neurons in rat nucleus raphe magnus.

    Science.gov (United States)

    Abe, Kenji; Ishida, Kota; Kato, Masatoshi; Shigenaga, Toshiro; Taguchi, Kyoji; Miyatake, Tadashi

    2002-11-01

    To examine the role of cholinergic neurons in the nucleus raphe magnus (NRM) in noxious heat stimulation and in the effects of morphine-induced antinociception by rats. After the cholinergic neuron selective toxin, AF64A, was microinjected into the NRM, we examined changes in the antinociceptive threshold and effects of morphine (5 mg/kg, ip) using the hot-plate (HP) and tail-flick (TF) tests. Systemic administration of morphine inhibited HP and TF responses in control rats. Microinjection of AF64A (2 nmol/site) into the NRM significantly decreased the threshold of HP response after 14 d, whereas the TF response was not affected. Morphine-induced antinociception was significantly attenuated in rats administered AF64A. Extracellular acetylcholine was attenuated after 14 d to below detectable levels in rats given AF64A. Naloxone (1 microg/site) microinjected into control rat NRM also antagonized the antinociceptive effect of systemic morphine. These findings suggest that cholinergic neuron activation in the NRM modulates the antinociceptive effect of morphine simultaneously with the opiate system.

  13. Improvement of buccal delivery of morphine using the prodrug approach

    DEFF Research Database (Denmark)

    Christrup, Lona Louring; Jørgensen, A.; Christensen, C.B.

    1997-01-01

    relationship to the lipophilicity of the compounds. In the in vitro studies the optimal permeation was achieved for the prodrug morphine-3-propionate having a log P value of approximately 0.7. In contrast to that optimal in vivo absorption was obtained for the prodrug morphine-3-acetate having a log P value...... Improved by using ester prodrugs with higher lipophilicity than morphine itself. However, the enzymatic stability of the prodrugs in saliva also play an important role for the overall improvement in absorption properties....

  14. Effects of carprofen and morphine on the minimum alveolar concentration of isoflurane in dogs.

    Science.gov (United States)

    Ko, Jeff C H; Weil, Ann B; Inoue, Tomohito

    2009-01-01

    The minimum alveolar concentration (MAC) of isoflurane in dogs was determined following carprofen (2.2 mg/kg per os) alone, morphine (1 mg/kg intravenously) alone, carprofen and morphine, and no drug control in eight healthy adult dogs. Isoflurane MAC following administration of morphine alone (0.81%+/-0.18%) or carprofen and morphine (0.68%+/-0.31%) was significantly less than the control MAC (1.24%+/-0.15%). Isoflurane MAC after carprofen alone (1.13%+/-0.13%) was not significantly different from the control value. Results indicated that administration of morphine alone or in combination with carprofen significantly reduced the MAC of isoflurane in dogs. The isoflurane MAC reduction was additive between the effects of carprofen and morphine.

  15. Continuous intravenous morphine infusion for postoperative analgesia following posterior spinal fusion for idiopathic scoliosis.

    Science.gov (United States)

    Poe-Kochert, Connie; Tripi, Paul A; Potzman, Jennifer; Son-Hing, Jochen P; Thompson, George H

    2010-04-01

    A retrospective study of postoperative pain management. Evaluate the efficacy and safety of continuous intravenous morphine infusion for postoperative pain management in patients with idiopathic scoliosis (IS) undergoing posterior spinal fusion (PSF) and segmental spinal instrumentation (SSI). Postoperative pain is a common problem following surgery for IS. There are no published reports regarding the use of a continuous intravenous morphine infusion for this patient population. We retrospectively reviewed data regarding 339 consecutive patients with IS who underwent PSF and SSI between 1992 and 2006. All patients received intrathecal morphine after the induction of general anesthesia. Following surgery, preordered morphine infusion (0.01 mg/kg/h) was started at first reported pain. The infusion rate was titrated based on vital signs, visual analog scale (VAS) pain scores (0-10), and clinical status. It was continued until patients were able to take oral analgesics. We reviewed intrathecal morphine dosage, VAS pain scores through the third postoperative day, interval to start of morphine infusion, total morphine requirements in the first 48 hours, and any adverse reactions (nausea/vomiting, pruritus, respiratory depression, and pediatric intensive care unit admission). Mean intrathecal morphine dose was 15.5 +/- 3.9 microg/kg and mean interval to start of the intravenous morphine infusion was 17.5 +/- 5 hours. Mean VAS pain scores were 3.1, 4.5, 4.5, and 4.6 at 12 hours, 1, 2, and 3 days after surgery, respectively.The total mean morphine dose in the first 48 hours postoperatively was 0.03 +/- 0.01 mg/kg/h. Total morphine received was 1.44 +/- 0.5 mg/kg. Nausea/vomiting and pruritus, related to the morphine infusion occurred in 45 patients (13.3%) and 14 patients (4.1%), respectively. No patients had respiratory depression or required Pediatric Intensive Care Unit admission. A low frequency of adverse events and a mean postoperative VAS pain score of 5 or less

  16. Comparison of pre- and post-levothyroxine high-sensitivity c-reactive protein and fetuin-a levels in subclinical hypothyroidism

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    Oktay Bilgir

    2015-02-01

    Full Text Available OBJECTIVE: The objective of this trial was to determine the levels of inflammatory markers, high-sensitivity C-reactive protein and fetuin-A pre- and post-levothyroxine treatment in cases of subclinical hypothyroidism. MATERIALS AND METHODS: A total of 32 patients with a diagnosis of subclinical hypothyroidism and a control group of 30 healthy individuals were tested for high-sensitivity C-reactive protein and fetuin-A, followed by the administration of 50 µg of levothyroxine in the patient group for 3 months. During the post-treatment stage, high-sensitivity C-reactive protein and fetuin-A levels in the patient group were re-assessed and compared with pre-treatment values. RESULTS: Pre-treatment levels of both high-sensitivity C-reactive protein and fetuin-A were observed to be higher in the patient group than in the control group. The decrease in high-sensitivity C-reactive protein levels during the post-treatment stage was not statistically significant. However, the decrease observed in post-treatment fetuin-A levels was found to be statistically significant. CONCLUSION: The decrease in fetuin-A levels in subclinical hypothyroidism cases indicates that levothyroxine treatment exerts anti-inflammatory and anti-apoptotic effects. Although the decrease in high-sensitivity C-reactive protein levels was statistically non-significant, it is predicted to reach significance with sustained treatment.

  17. Gambling Disorder: Exploring Pre-treatment and In-treatment Dropout Predictors. A UK Study.

    Science.gov (United States)

    Ronzitti, Silvia; Soldini, Emiliano; Smith, Neil; Clerici, Massimo; Bowden-Jones, Henrietta

    2017-12-01

    The aim of this study was to identify predictors of treatment dropout in a sample of gamblers attending a specialist clinic for gambling disorder. We analysed data on 846 treatment-seeking pathological gamblers. Firstly, we investigated differences in socio-demographic and clinical variables between treatment completers and pre-treatment dropouts, as well as between treatment completers and during-treatment dropouts. Subsequently, variables were entered into a multinomial logistic regression model to identify significant predictors of pre-treatment and in-treatment dropout. Overall, 44.8% of clients did not complete the treatment: 27.4% dropped out before starting it, while 17.4% dropped out during the treatment. Younger age and use of drugs were associated with pre-treatment dropout, while family history of gambling disorder, a lower PGSI score, and being a smoker were related with in-treatment dropout. Our findings suggest that pre-treatment dropouts differ from in-treatment dropouts, and, thus, further research will benefit from considering these groups separately. In addition, this newly gained knowledge will also be helpful in increasing treatment retention in specific subgroups of problem gamblers.

  18. Effects of morphine and naloxone on feline colonic transit

    International Nuclear Information System (INIS)

    Krevsky, B.; Libster, B.; Maurer, A.H.; Chase, B.J.; Fisher, R.S.

    1989-01-01

    The effects of endogenous and exogenous opioid substances on feline colonic transit were evaluated using colonic transit scintigraphy. Naloxone accelerated emptying of the cecum and ascending colon, and filling of the transverse colon. Endogenous opioid peptides thus appear to play a significant role in the regulation of colonic transit. At a moderate dose of morphine cecum and ascending colon transit was accelerated, while at a larger dose morphine had no effect. Since naloxone, a relatively nonspecific opioid antagonist, and morphine, a principally mu opioid receptor agonist, both accelerate proximal colonic transit, a decelerating role for at least one of the other opioid receptors is inferred

  19. Effects of morphine and naloxone on feline colonic transit

    Energy Technology Data Exchange (ETDEWEB)

    Krevsky, B.; Libster, B.; Maurer, A.H.; Chase, B.J.; Fisher, R.S.

    1989-01-01

    The effects of endogenous and exogenous opioid substances on feline colonic transit were evaluated using colonic transit scintigraphy. Naloxone accelerated emptying of the cecum and ascending colon, and filling of the transverse colon. Endogenous opioid peptides thus appear to play a significant role in the regulation of colonic transit. At a moderate dose of morphine cecum and ascending colon transit was accelerated, while at a larger dose morphine had no effect. Since naloxone, a relatively nonspecific opioid antagonist, and morphine, a principally mu opioid receptor agonist, both accelerate proximal colonic transit, a decelerating role for at least one of the other opioid receptors is inferred.

  20. Acetaminophen and non-steroidal anti-inflammatory drugs interact with morphine and tramadol analgesia for the treatment of neuropathic pain in rats.

    Science.gov (United States)

    Shinozaki, Tomonari; Yamada, Toshihiko; Nonaka, Takahiro; Yamamoto, Tatsuo

    2015-06-01

    Although non-steroidal anti-inflammatory drugs and acetaminophen have no proven efficacy against neuropathic pain, they are frequently prescribed for neuropathic pain patients. We examined whether the combination of opioids (tramadol and morphine) with indomethacin or acetaminophen produce favorable effects on neuropathic pain and compared the efficacy for neuropathic pain with that for inflammatory pain. The carrageenan model was used as the inflammatory pain model while the tibial neuroma transposition (TNT) model was used as the neuropathic pain model. The tibial nerve is transected in the TNT model, with the tibial nerve stump then transpositioned to the lateral aspect of the hindlimb. Neuropathic pain (mechanical allodynia and neuroma pain) is observed after TNT injury. Drugs were administered orally. In the carrageenan model, all drugs produced anti-allodynic effects and all drug combinations, but not tramadol + indomethacin combination, produced synergistic anti-allodynic effects. In the TNT model, tramadol and morphine, but not acetaminophen and indomethacin, produced anti-neuropathic pain effects. In the combination, with the exception of morphine + acetaminophen combination, both acetaminophen and indomethacin reduced the 50% effective dose (ED50) of tramadol and morphine as compared with the ED50s for the single drug study in the TNT model. The ED50s of tramadol and morphine in the carrageenan combination test were not statistically significantly different from the ED50s in the TNT model combination study. The combination of opioids with indomethacin or acetaminophen produced a synergistic analgesic effect both in inflammatory and neuropathic pain with some exceptions. The efficacy of these combinations for neuropathic pain was not different from that for inflammatory pain.

  1. Are pre-treatment psychological characteristics influenced by pre-surgical orthodontics?

    Science.gov (United States)

    Cunningham, S J; Gilthorpe, M S; Hunt, N P

    2001-12-01

    A number of investigations have looked at psychological changes occurring in association with orthognathic treatment. However, most of these studies have used a pre-surgery questionnaire as the baseline measurement. There is little data relating to the true baseline, i.e. that prior to any active treatment. Until this aspect is investigated, it is not possible to assume that pre-surgery is an acceptable baseline. This questionnaire based study aimed to assess changes in six psychological outcome measures between T1 (prior to any active treatment) and T2 (following pre-surgical orthodontics/prior to surgery). The outcome variables were: state anxiety, trait anxiety, depression, self-esteem, body image, and facial body image. Sixty-two patients (39 females and 23 males) completed both questionnaires. The results showed that intervention, in the form of orthodontic treatment, had a minimal effect on the chosen psychometric outcome variables. There was a significant reduction in satisfaction with body image amongst patients who initially reported mild to moderate dental/facial problems, whilst a moderate increase in satisfaction occurred in those patients reporting severe conditions initially. Also of note were significant increases in state anxiety amongst older patients whilst trait anxiety showed greater increases in females than males.

  2. Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles.

    Science.gov (United States)

    Peccate, Cécile; Mollard, Amédée; Le Hir, Maëva; Julien, Laura; McClorey, Graham; Jarmin, Susan; Le Heron, Anita; Dickson, George; Benkhelifa-Ziyyat, Sofia; Piétri-Rouxel, France; Wood, Matthew J; Voit, Thomas; Lorain, Stéphanie

    2016-08-15

    In preclinical models for Duchenne muscular dystrophy, dystrophin restoration during adeno-associated virus (AAV)-U7-mediated exon-skipping therapy was shown to decrease drastically after six months in treated muscles. This decline in efficacy is strongly correlated with the loss of the therapeutic AAV genomes, probably due to alterations of the dystrophic myofiber membranes. To improve the membrane integrity of the dystrophic myofibers at the time of AAV-U7 injection, mdx muscles were pre-treated with a single dose of the peptide-phosphorodiamidate morpholino (PPMO) antisense oligonucleotides that induced temporary dystrophin expression at the sarcolemma. The PPMO pre-treatment allowed efficient maintenance of AAV genomes in mdx muscles and enhanced the AAV-U7 therapy effect with a ten-fold increase of the protein level after 6 months. PPMO pre-treatment was also beneficial to AAV-mediated gene therapy with transfer of micro-dystrophin cDNA into muscles. Therefore, avoiding vector genome loss after AAV injection by PPMO pre-treatment would allow efficient long-term restoration of dystrophin and the use of lower and thus safer vector doses for Duchenne patients. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. Neuromodulatory effects of the dorsal hippocampal endocannabinoid system in dextromethorphan/morphine-induced amnesia.

    Science.gov (United States)

    Ghasemzadeh, Zahra; Rezayof, Ameneh

    2017-01-05

    Dextromethorphan which is an active ingredient in many cough medicines has been previously shown to potentiate amnesic effect of morphine in rats. However, the effect of dextromethorphan, that is also a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, in combination with morphine on hippocampus-based long term memory has not been well characterized. The aim of the present study was to assess the possible role of endocannabinoid system of the dorsal hippocampus in dextromethorphan /morphine-induced amnesia. Our results showed that intraperitoneal (i.p.) injection of morphine (5mg/kg) or dextromethorphan (5-15mg/kg) before testing the passive avoidance learning induced amnesia. Combination of ineffective doses of dextromethorphan (7.5mg/kg, i.p.) and morphine (2mg/kg, i.p.) also produced amnesia, suggesting the enhancing effects of the drugs. To assess the effect of the activation or inhibition of the dorsal hippocampal cannabinoid CB 1 receptors on this amnesia, ACPA or AM251 as selective receptor agonists or antagonists were respectively injected into the CA1 regions before systemic injection of dextromethorphan and morphine. Interestingly, intra-CA1 microinjection of ACPA (0.5-1ng/rat) improved the amnesic effect of dextromethorphan /morphine combination. The microinjection of AM251 into the CA1 region enhanced the response of the combination of dextromethorphan /morphine in inducing amnesia. Moreover, Intra-CA1 microinjection of AM251 inhibited the improving effect of ACPA on dextromethorphan /morphine-induced amnesia. It is important to note that intra-CA1 microinjection of the same doses of the agonist or antagonist by itself had no effects on memory formation. Thus, it can be concluded that the dorsal hippocampal endocannabinoid system, via CB 1 receptor-dependent mechanism, may be involved in morphine/dextromethorphan -induced amnesia. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Reflections on: "A general role for adaptations in G-Proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function".

    Science.gov (United States)

    Nestler, Eric J

    2016-08-15

    -dependent protein kinase, and certain phosphoproteins in the rat locus coeruleus, but not in several other brain regions studied, and that chronic morphine decreases levels of Giα and increases levels of adenylate cyclase in dorsal root ganglion/spinal cord (DRG-SC) co-cultures. These findings led us to survey the effects of chronic morphine on the G-protein/cyclic AMP system in a large number of brain regions to determine how widespread such regulation might be. We found that while most regions showed no regulation in response to chronic morphine, nucleus accumbens (NAc) and amygdala did show increases in adenylate cyclase and cyclic AMP-dependent protein kinase activity, and thalamus showed an increase in cyclic AMP-dependent protein kinase activity only. An increase in cyclic AMP-dependent protein kinase activity was also observed in DRG-SC co-cultures. Morphine regulation of G-proteins was variable, with decreased levels of Giα seen in the NAc, increased levels of Giα and Goα amygdala, and no change in thalamus or the other brain regions studied. Interestingly, chronic treatment of rats with cocaine, but not with several non-abused drugs, produced similar changes compared to morphine in G-proteins, adenylate cyclase, and cyclic AMP-dependent protein kinase in the NAc, but not in the other brain regions studied. These results indicate that regulation of the G-protein/cyclic AMP system represents a mechanism by which a number of opiate-sensitive neurons adapt to chronic morphine and thereby develop aspects of opiate tolerance and/or dependence. The findings that chronic morphine and cocaine produce similar adaptations in the NAc, a brain region important for the reinforcing actions of many types of abused substances, suggest further that common mechanisms may underlie psychological aspects of drug addiction mediated by this brain region. © 1991. This article is part of a Special Issue entitled SI:50th Anniversary Issue. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Morphine mouthwash for the management of oral mucositis in patients with head and neck cancer

    Directory of Open Access Journals (Sweden)

    Mostafa Sarvizadeh

    2015-01-01

    Conclusions: Topical morphine is more effective and more satisfactory to patients than the magic mouthwash in reducing severity of cancer treatment-induced oral mucositis. More studies with larger sample size and longer follow-up are required in this regard.

  6. Morphine Protects Spinal Cord Astrocytes from Glutamate-Induced Apoptosis via Reducing Endoplasmic Reticulum Stress

    Directory of Open Access Journals (Sweden)

    Chao Zhang

    2016-10-01

    Full Text Available Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS. Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated whether morphine, a common opioid ligand, could affect glutamate-induced apoptosis in astrocytes. Primary cultured astrocytes were incubated with glutamate in the presence/absence of morphine. It was found that morphine could reduce glutamate-induced apoptosis of astrocytes. Furthermore, glutamate activated Ca2+ release, thereby inducing endoplasmic reticulum (ER stress in astrocytes, while morphine attenuated this deleterious effect. Using siRNA to reduce the expression of κ-opioid receptor, morphine could not effectively inhibit glutamate-stimulated Ca2+ release in astrocytes, the protective effect of morphine on glutamate-injured astrocytes was also suppressed. These results suggested that morphine could protect astrocytes from glutamate-induced apoptosis via reducing Ca2+ overload and ER stress pathways. In conclusion, this study indicated that excitotoxicity participated in the glutamate mediated apoptosis in astrocytes, while morphine attenuated this deleterious effect via regulating Ca2+ release and ER stress.

  7. Analgesic effect of the electromagnetic resonant frequencies derived from the NMR spectrum of morphine.

    Science.gov (United States)

    Verginadis, Ioannis I; Simos, Yannis V; Velalopoulou, Anastasia P; Vadalouca, Athina N; Kalfakakou, Vicky P; Karkabounas, Spyridon Ch; Evangelou, Angelos M

    2012-12-01

    Exposure to various types of electromagnetic fields (EMFs) affects pain specificity (nociception) and pain inhibition (analgesia). Previous study of ours has shown that exposure to the resonant spectra derived from biologically active substances' NMR may induce to live targets the same effects as the substances themselves. The purpose of this study is to investigate the potential analgesic effect of the resonant EMFs derived from the NMR spectrum of morphine. Twenty five Wistar rats were divided into five groups: control group; intraperitoneal administration of morphine 10 mg/kg body wt; exposure of rats to resonant EMFs of morphine; exposure of rats to randomly selected non resonant EMFs; and intraperitoneal administration of naloxone and simultaneous exposure of rats to the resonant EMFs of morphine. Tail Flick and Hot Plate tests were performed for estimation of the latency time. Results showed that rats exposed to NMR spectrum of morphine induced a significant increase in latency time at time points (p spectrum of morphine. Our results indicate that exposure of rats to the resonant EMFs derived from the NMR spectrum of morphine may exert on animals similar analgesic effects to morphine itself.

  8. Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression

    Science.gov (United States)

    Song, Zhi-Jing; Miao, Shuai; Zhao, Ye; Wang, Xiu-Li; Liu, Yue-Peng

    2018-01-01

    Purpose Preventing opioid-induced hyperalgesia and tolerance continues to be a major clinical challenge, and the underlying mechanisms of hyperalgesia and tolerance remain elusive. Here, we investigated the role of sonic hedgehog (Shh) signaling in opioid-induced hyperalgesia and tolerance. Methods Shh signaling expression, behavioral changes, and neurochemical alterations induced by morphine were analyzed in male adult CD-1 mice with repeated administration of morphine. To investigate the contribution of Shh to morphine-induced hyperalgesia (MIH) and tolerance, Shh signaling inhibitor cyclopamine and Shh small interfering RNA (siRNA) were used. To explore the mechanisms of Shh signaling in MIH and tolerance, brain-derived neurotrophic factor (BDNF) inhibitor K252 and anti-BDNF antibody were used. Results Repeated administration of morphine produced obvious hyperalgesia and tolerance. The behavioral changes were correlated with the upregulation and activation of morphine treatment-induced Shh signaling. Pharmacologic and genetic inhibition of Shh signaling significantly delayed the generation of MIH and tolerance and associated neurochemical changes. Chronic morphine administration also induced upregulation of BDNF. Inhibiting BDNF effectively delayed the generation of MIH and tolerance. The upregulation of BDNF induced by morphine was significantly suppressed by inhibiting Shh signaling. In naïve mice, exogenous activation of Shh signaling caused a rapid increase of BDNF expression, as well as thermal hyperalgesia. Inhibiting BDNF significantly suppressed smoothened agonist-induced hyperalgesia. Conclusion These findings suggest that Shh signaling may be a critical mediator for MIH and tolerance by regulating BDNF expression. Inhibiting Shh signaling, especially during the early phase, may effectively delay or suppress MIH and tolerance. PMID:29662325

  9. Photoaffinity labeling of rat liver microsomal morphine UDP-glucuronosyltransferase by ( sup 3 H)flunitrazepam

    Energy Technology Data Exchange (ETDEWEB)

    Thomassin, J.; Tephly, T.R. (Univ. of Iowa, Iowa City (USA))

    1990-09-01

    Benzodiazepines have been shown to competitively inhibit morphine glucuronidation in rat and human hepatic microsomes. Flunitrazepam exerted a potent competitive inhibition of rat hepatic morphine UDP-glucuronosyltransferase (UDPGT) activity (Ki = 130 microM). It has no effect on the activity of p-nitrophenol, 17 beta-hydroxysteroid, 3 alpha-hydroxysteroid, or 4-hydroxybiphenyl UDPGTs. Because flunitrazepam is an effective photoaffinity label for benzodiazepine receptors, studied were performed in solubilized rat hepatic microsomes and with partially purified preparations of morphine UDPGT to determine the enhancement of flunitrazepam inhibition and binding to morphine UDPGT promoted by exposure to UV light. Under UV light, flunitrazepam inhibition was markedly enhanced. UV light exposure also led to a marked increase in binding of (3H)flunitrazepam to microsomal protein, which was protected substantially by preincubation with morphine. Testosterone, androsterone, and UDP-glucuronic acid did not protect against UV-enhanced flunitrazepam binding, and morphine did not reverse flunitrazepam binding once binding had occurred. As morphine UDPGT was purified, a good correlation was found between the increases in specific activity of morphine UDPGT and flunitrazepam binding to protein. Chromatofocusing chromatography showed that flunitrazepam bound only to fractions containing active morphine UDPGT, and no binding to 4-hydroxybiphenyl UDPGT was observed. Fluorography of a sodium dodecyl sulfate-polyacrylamide electrophoresis gel of solubilized hepatic microsomes that had been treated with (3H) flunitrazepam under UV light revealed a band with a monomeric molecular weight between 54,000 and 58,000. This monomeric molecular weight compares favorably with the reported monomeric molecular weight of homogeneous morphine UDPGT (56,000).

  10. Olea Europea-derived phenolic products attenuate antinociceptive morphine tolerance: an innovative strategic approach to treat cancer pain.

    Science.gov (United States)

    Muscoli, C; Lauro, F; Dagostino, C; D'Agostino, C; Ilari, S; Giancotti, L A; Gliozzi, M; Costa, N; Carresi, C; Musolino, V; Casale, F; Ventrice, D; Oliverio, M; Oliverio, E; Palma, E; Nisticò, S; Nistico', S; Procopio, A; Rizzo, M; Mollace, V

    2014-01-01

    Morphine and related opioid drugs are currently the major drugs for severe pain. Their clinical utility is limited in the management of severe cancer pain due to the rapid development of tolerance. Restoring opioid efficacy is therefore of great clinical importance. A great body of evidence suggests the key role of free radicals and posttranslational modulation in the development of tolerance to the analgesic activity of morphine. Epidemiological studies have shown a relationship between the Mediterranean diet and a reduced incidence of pathologies such as coronary heart disease and cancer. A central hallmark of this diet is the high consumption of virgin olive oil as the main source of fat which contains antioxidant components in the non-saponifiable fraction, including phenolic compounds absent in seed oils. Here, we show that in a rodent model of opiate tolerance, removal of the free radicals with phenolic compounds of olive oil such as hydroxytyrosol and oleuropein reinstates the analgesic action of morphine. Chronic injection of morphine in mice led to the development of tolerance and this was associated with increased nitrotyrosin and malondialdehyde (MDA) formation together with nitration and deactivation of MnSOD in the spinal cord. Removal of free radicals by hydroxytyrosol and oleuropein blocked morphine tolerance by inhibiting nitration and MDA formation and replacing the MnSOD activity. The phenolic fraction of virgin olive oil exerts antioxidant activities in vivo and free radicals generation occurring during chronic morphine administration play a crucial role in the development of opioid tolerance. Our data suggest novel therapeutic approach in the management of chronic cancer pain, in particular for those patients who require long-term opioid treatment for pain relief without development of tolerance.

  11. Intracerebroventricular morphine for refractory cancer pain: transitioning to the home setting.

    Science.gov (United States)

    Adolph, Michael D; Stretanski, Michael F; McGregor, John M; Rawn, Bonnie L; Ross, Patrick M; Benedetti, Costantino

    2010-08-01

    Refractory cancer pain may be effectively controlled by titrating intracerebroventricular (ICV) preservative-free opioid. In this case report, a continuous infusion of ICV morphine permitted our patient with lung cancer and painful spinal metastases to be discharged to home hospice with family. The approach exploits the high potency of morphine injected into cerebrospinal fluid (CSF). Sterile, injectable, preservative-free morphine is directly infused into CSF through a subcutaneous Ommaya reservoir placed under the scalp by a neurosurgeon, with an attached catheter passed through a burr hole in the skull with its tip in a cerebral ventricle. Although investigators have described home care of patients receiving intraspinal analgesics, no report describes the process of transitioning the patient receiving continuous ICV morphine infusion to the home setting.

  12. Quasi-morphine abstinence behaviour GABA-ergic mechanisms and their localization

    NARCIS (Netherlands)

    J.W. van der Laan

    1981-01-01

    textabstractDi-n-propylacetate (DPA), generally known to be an anti-epileptic drug, induces a behavioural syndrome in rats resembling morphine abstinence behaviour, which is called, therefore, quasi-morphine abstinence beh~viour. An increase in GABA-ergic activity is probably responsible for this

  13. Influence of fentanyl and morphine on intestinal circulation

    International Nuclear Information System (INIS)

    Tverskoy, M.; Gelman, S.; Fowler, K.C.; Bradley, E.L.

    1985-01-01

    The influence of fentanyl and morphine on the intestinal circulation was evaluated in an isolated loop preparation in 37 dogs anesthetized with pentobarbital intravenously. Selected intestinal segments were pumped with aortic blood at a constant pressure of 100 mm Hg. A mixture of 86 Rb and 9-micron spheres labeled with 141 Ce was injected into the arterial cannula supplying the intestinal loop, while mesenteric venous blood was collected for activity counting. A strong correlation was found between the clearances of rubidium and microspheres (r = 0.97, P less than 0.0001), suggesting that the shunting of 9-micron spheres through the intestines reflects the shunting of blood through nonnutritive vessels. Intravenous fentanyl decreased oxygen uptake (O 2 up), and vascular resistance (VR), and increased blood flow (BF), rubidium and microsphere clearances (Cl-Rb, Cl-Sph, respectively), and permeability--surface area product (PS) in a dose-related fashion. Intravenous morphine in a dose of 1 mg X kg-1 increased Cl-Rb (nutritive BF) without changes in total (nutritive and nonnutritive) BF. This increase in nutritive BF is probably related to morphine-induced histamine release. Morphine in a dose of 5 mg X kg-1 was accompanied by vasoconstriction that was completely abolished by alpha-adrenoceptor blockade. The data suggest that morphine-induced intestinal vasoconstriction is mediated via a release of epinephrine, apparently from the adrenal medulla. It is concluded that changes in the intestinal circulation during anesthesia with narcotics might play a certain role in the cardiovascular homeostasis during anesthesia and surgery. An increase in oxygen content in portal venous blood, resulting from a decrease in intestinal oxygen uptake, should facilitate hepatic oxygenation

  14. Influence of fentanyl and morphine on intestinal circulation

    Energy Technology Data Exchange (ETDEWEB)

    Tverskoy, M.; Gelman, S.; Fowler, K.C.; Bradley, E.L.

    1985-06-01

    The influence of fentanyl and morphine on the intestinal circulation was evaluated in an isolated loop preparation in 37 dogs anesthetized with pentobarbital intravenously. Selected intestinal segments were pumped with aortic blood at a constant pressure of 100 mm Hg. A mixture of /sup 86/Rb and 9-micron spheres labeled with /sup 141/Ce was injected into the arterial cannula supplying the intestinal loop, while mesenteric venous blood was collected for activity counting. A strong correlation was found between the clearances of rubidium and microspheres (r = 0.97, P less than 0.0001), suggesting that the shunting of 9-micron spheres through the intestines reflects the shunting of blood through nonnutritive vessels. Intravenous fentanyl decreased oxygen uptake (O/sub 2/up), and vascular resistance (VR), and increased blood flow (BF), rubidium and microsphere clearances (Cl-Rb, Cl-Sph, respectively), and permeability--surface area product (PS) in a dose-related fashion. Intravenous morphine in a dose of 1 mg X kg-1 increased Cl-Rb (nutritive BF) without changes in total (nutritive and nonnutritive) BF. This increase in nutritive BF is probably related to morphine-induced histamine release. Morphine in a dose of 5 mg X kg-1 was accompanied by vasoconstriction that was completely abolished by alpha-adrenoceptor blockade. The data suggest that morphine-induced intestinal vasoconstriction is mediated via a release of epinephrine, apparently from the adrenal medulla. It is concluded that changes in the intestinal circulation during anesthesia with narcotics might play a certain role in the cardiovascular homeostasis during anesthesia and surgery. An increase in oxygen content in portal venous blood, resulting from a decrease in intestinal oxygen uptake, should facilitate hepatic oxygenation.

  15. Systemic morphine blocks the seizures induced by intracerebroventricular (i.c.v.) injections of opiates and opioid peptides.

    Science.gov (United States)

    Urca, G; Frenk, H

    1982-08-19

    Intracerebroventricular (i.c.v.) injections of the endorphins and of morphine in rats produce highly characteristic, naloxone sensitive, electrographic seizures. In contrast, systemic injections of morphine have been shown to exert a marked anticonvulsant effect. The present study demonstrates that systemic morphine pretreatment can prevent the occurrence of electrographic seizures injected by i.c.v. morphine, Leu-enkephalin and beta-endorphin and that the anti-epileptic effect of morphine can be reversed by naloxone. Male albino rats, previously prepared for chronic i.c.v. injections and EEG recordings, were pretreated with 0--100 mg/kg of intraperitoneal (i.p.) morphine. Thirty five minutes later morphine (520 nmol), Leu-enkephalin (80 nmol) or beta-endorphin (5 nmol) were injected i.c.v. Pretreatment with i.p. morphine blocked the occurrence of seizures induced by morphine and both endogenous opioids. Lower doses of systemic morphine (50 mg/kg) were necessary to block i.c.v. morphine seizures than the dose (100 mg/kg) necessary to block seizures induced by i.c.v. Leu-enkephalin and beta-endorphin. Naloxone (1 mg/kg) administered 25 min following 50 mg/kg of i.p. morphine and preceding the injections of i.c.v. morphine reversed the antiepileptic effect of systemic morphine. These results demonstrate the possible existence of two opiate sensitive systems, one with excitatory-epileptogenic effects and the other possessing inhibitory-antiepileptic properties. The possible relationship between these findings and the known heterogeneity of opiate receptors and opiate actions is discussed.

  16. Role of nitric oxide in additive anticonvulsant effects of agmatine and morphine.

    Science.gov (United States)

    Payandemehr, Borna; Rahimian, Reza; Bahremand, Arash; Ebrahimi, Ali; Saadat, Seyedehpariya; Moghaddas, Peiman; Fadakar, Kaveh; Derakhshanian, Hoda; Dehpour, Ahmad Reza

    2013-06-13

    The anticonvulsant effects of agmatine, an endogenous polyamine and a metabolite of l-arginine, have been shown in various experimental seizure models. Agmatine also potentiates the anti-seizure activity of morphine. The present study aimed to investigate a possible involvement of nitric oxide (NO) pathway in the protection by agmatine and morphine co-administration against pentylenetetrazole (PTZ) -induced seizure in male mice. To this end, the thresholds for the clonic seizures induced by the intravenous administration of PTZ, a GABA antagonist, were assessed. Intraperitoneal administration of morphine at lower dose (1mg/kg) increased the seizure threshold. Also intraperitoneal administration of agmatine (5 and 10mg/kg) increased the seizure threshold significantly. Combination of subeffective doses of morphine and agmatine led to potent anticonvulsant effects. Non-effective doses of morphine (0.1 and 0.5mg/kg) were able to induce anticonvulsant effects in mice pretreated with agmatine (3mg/kg). Concomitant administration of either the non-selective nitric oxide synthase (NOS) inhibitor L-NAME (1, 5mg/kg, i.p.) or the selective NOS inhibitor 7-NI (15, 30mg/kg, i.p.), with an ineffective combination of morphine (0.1mg/kg) plus agmatine (1mg/kg) produced significant anticonvulsant impacts. Moreover, the NO precursor, l-arginine (30, 60mg/kg, i.p.), inhibited the anticonvulsant action of agmatine (3mg/kg) plus morphine (0.5mg/kg) co-administration. Our results indicate that pretreatment of animals with agmatine enhances the anticonvulsant effects of morphine via a mechanism which may involve the NO pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Anti-allodynic Effect of Nefopam and Morphine in a Rat Model of Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Taraneh Moini Zanjani

    2013-05-01

    Full Text Available Please cite this article as: Moini Zanjani T, Saghaei E, Ameli H, Sabetkasaei M. Anti-allodynic Effect of Nefopam and Morphine in a Rat Model of Neuropathic Pain. Novel Biomed 2013;1:16-22.Background: Neuropathic pain is a chronic pain due to a disorder in the peripheral or central nervous system with different pathophysiological mechanisms. Current treatments are not effective. Here we compared the analgesic effect of nefopam, and morphine in chronic constriction injury (CCI model of neuropathic pain.Methods: Male wistar rat (150-200g, n=8 were divided into 3 different groups: 1- Saline-treated CCI group, 2- Saline-treated sham group, and 3- Drug-treated CCI groups. In CCI model of neuropathic pain, the left sciatic nerve was exposed and 4 loose chromic gut ligatures were placed around the nerve proximal to the trifurcation. Ketamine 60mg/kg and xylazine 10 mg/kg were used for anesthesia. Nefopam (10, 20, 30mg/kg, and morphine (1, 3, 5mg/kg were injected 30 minutes before surgery and continued daily to day 14 post-ligation. Von Frey filaments for mechanical allodynia and acetone test for cold allodynia were respectively used as pain behavioral tests. Experiments were performed on day 0 (before surgery and days 1, 3, 5,7,10 and 14 post injury. Behavioral studies were performed in a quiet room between 9:00 to 11:00 AM. All experiments followed the IASP guidelines on ethical standards for investigation of experimental pain in animals.Results: Nefopam (20 and 30mg/kg blocked mechanical and cold allodynia during the experimental period, but the analgesic effects of morphine (5mg/kg lasted for 7 days.Conclusions: It seems that nefopam could effectively reduce pain behavior compared to morphine with reduced adverse effects.

  18. Effects of morphine on the expression of cytokines and inflammatory mediators in a rabbit model of endotoxin-induced experimental uveitis

    Directory of Open Access Journals (Sweden)

    Kethye P. Ortencio

    2015-12-01

    Full Text Available ABSTRACT Purpose: To evaluate the effects of 1% morphine instillation on clinical parameters, aqueous humor turbidity, and expression levels of tumor necrosis factor alpha (TNF-α, interleukin-1 beta (IL-1beta, prostaglandin E2 (PGE2, and myeloperoxidase (MPO in rabbits with endotoxin-induced experimental uveitis. Methods: Twenty four New Zealand white rabbits were divided into four groups (n=6 each: control (CG, morphine (MG, naloxone (NG, and morphine-naloxone (MNG groups. Under dissociative anesthesia, 0.1 mL of solution containing 0.2 µg of lipopolysaccharide (LPS endotoxin from the Salmonella typhimurium cell wall was injected in the vitreous chamber. Clinical evaluations (conjunctical hyperemia, chemosis blepharospasm, and ocular discharge and laser flaremetry were performed before (baseline, and 10 and 20 hours after induction of uveitis. Rabbits were subsequently euthanized and eyes were enucleated to quantify expression levels of TNF-α, IL-1 beta, PGE2, and MPO. Results: No significant differences in clinical parameters and flare values were observed between the study groups. TNF-α and IL-1 beta levels increased significantly in the CG, MG, NG, and MNG groups compared to baseline (P0.05. Conclusions: Morphine has no effect on clinical parameters, flare, or expression levels of inflammatory mediators in a rabbit model of uveitis induced by intravitreal injection of LPS.

  19. A Bacoside containing Bacopa monnieri extract reduces both morphine hyperactivity plus the elevated striatal dopamine and serotonin turnover.

    Science.gov (United States)

    Rauf, Khalid; Subhan, Fazal; Sewell, Robert D E

    2012-05-01

    Bacopa monnieri (BM) has been used in Ayurvedic medicine as a nootropic, anxiolytic, antiepileptic and antidepressant. An n-butanol extract of the plant (nBt-ext BM) was analysed and found to contain Bacoside A (Bacoside A3, Bacopaside II and Bacopasaponin C). The effects of the BM extract were then studied on morphine-induced hyperactivity as well as dopamine and serotonin turnover in the striatum since these parameters have a role in opioid sensitivity and dependence. Mice were pretreated with saline or nBt-ext BM (5, 10 and 15 mg/kg, orally), 60 min before morphine administration and locomotor activity was subsequently recorded. Immediately after testing, striatal tissues were analysed for dopamine (DA), serotonin (5HT) and their metabolites using HPLC coupled with electrochemical detection. The results indicated that nBt-ext BM significantly (p < 0.001) decreased locomotor activity in both the saline and morphine treated groups. Additionally, nBt-ext BM significantly lowered morphine-induced dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-H1AA) upsurges in the striatum but failed to affect DA, 5-HT and their metabolites in the saline treated group. These findings suggest that nBt-ext BM has an antidopaminergic/serotonergic effect and may have potential beneficial effects in the treatment of morphine dependence. Copyright © 2011 John Wiley & Sons, Ltd.

  20. Examining the effect of the CaMKII inhibitor administration in the locus coeruleus on the naloxone-precipitated morphine withdrawal signs in rats.

    Science.gov (United States)

    Navidhamidi, M; Semnanian, S; Javan, M; Goudarzvand, M; Rohampour, K; Azizi, H

    2012-01-15

    Drug addiction is an occurrence with physiological, psychological, and social outcomes. Repeated drug exposure causes neuronal adaptations and dependency. It has been shown that CaMKIIα enzyme contributes to morphine dependency. The locus coeruleus nucleus has been implied in the morphine withdrawal syndrome. This research focuses on the behavioral and molecular adaptations that occur in the locus coeruleus neurons in response to the chronic morphine exposure. Adult male Wistar rats were injected by morphine sulfate (10 mg/kg/s.c.) at an interval of 12 h for a period of nine subsequent days. On the tenth day, naloxone (1 mg/kg/i.p.) was injected 2 h after the morphine administration. Somatic withdrawal signs were investigated for 30 min. We concluded that the inhibition of CaMKIIα by administration of KN-93, the specific inhibitor of this enzyme, significantly attenuated some of the withdrawal signs. In molecular method, the expression of CaMKIIα protein has been enhanced in locus coeruleus of the morphine dependent rats. These findings indicate that CaMKIIα may be involved in the modulation of the naloxone-induced withdrawal syndrome, and treatment with KN-93 may have some effects on this system. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration?

    DEFF Research Database (Denmark)

    Sjøgren, P; Thunedborg, L P; Christrup, Lona Louring

    1998-01-01

    Recently, clinical reports have suggested a relationship between the occurrence of hyperalgesia, allodynia and/or myoclonus and treatment with high doses of morphine in humans. Although few clinical descriptions of these phenomena are available, experimental work supports the notion that high dos...

  2. Relative contributions of norepinephrine and serotonin transporters to antinociceptive synergy between monoamine reuptake inhibitors and morphine in the rat formalin model.

    Directory of Open Access Journals (Sweden)

    Fei Shen

    Full Text Available Multimodal analgesia is designed to optimize pain relief by coadministering drugs with distinct mechanisms of action or by combining multiple pharmacologies within a single molecule. In clinical settings, combinations of monoamine reuptake inhibitors and opioid receptor agonists have been explored and one currently available analgesic, tapentadol, functions as both a µ-opioid receptor agonist and a norepinephrine transporter inhibitor. However, it is unclear whether the combination of selective norepinephrine reuptake inhibition and µ-receptor agonism achieves an optimal antinociceptive synergy. In this study, we assessed the pharmacodynamic interactions between morphine and monoamine reuptake inhibitors that possess different affinities and selectivities for norepinephrine and serotonin transporters. Using the rat formalin model, in conjunction with measurements of ex vivo transporter occupancy, we show that neither the norepinephrine-selective inhibitor, esreboxetine, nor the serotonin-selective reuptake inhibitor, fluoxetine, produce antinociceptive synergy with morphine. Atomoxetine, a monoamine reuptake inhibitor that achieves higher levels of norepinephrine than serotonin transporter occupancy, exhibited robust antinociceptive synergy with morphine. Similarly, a fixed-dose combination of esreboxetine and fluoxetine which achieves comparable levels of transporter occupancy potentiated the antinociceptive response to morphine. By contrast, duloxetine, a monoamine reuptake inhibitor that achieves higher serotonin than norepinephrine transporter occupancy, failed to potentiate the antinociceptive response to morphine. However, when duloxetine was coadministered with the 5-HT3 receptor antagonist, ondansetron, potentiation of the antinociceptive response to morphine was revealed. These results support the notion that inhibition of both serotonin and norepinephrine transporters is required for monoamine reuptake inhibitor and opioid

  3. Morphine biosynthesis in opium poppy involves two cell types: sieve elements and laticifers.

    Science.gov (United States)

    Onoyovwe, Akpevwe; Hagel, Jillian M; Chen, Xue; Khan, Morgan F; Schriemer, David C; Facchini, Peter J

    2013-10-01

    Immunofluorescence labeling and shotgun proteomics were used to establish the cell type-specific localization of morphine biosynthesis in opium poppy (Papaver somniferum). Polyclonal antibodies for each of six enzymes involved in converting (R)-reticuline to morphine detected corresponding antigens in sieve elements of the phloem, as described previously for all upstream enzymes transforming (S)-norcoclaurine to (S)-reticuline. Validated shotgun proteomics performed on whole-stem and latex total protein extracts generated 2031 and 830 distinct protein families, respectively. Proteins corresponding to nine morphine biosynthetic enzymes were represented in the whole stem, whereas only four of the final five pathway enzymes were detected in the latex. Salutaridine synthase was detected in the whole stem, but not in the latex subproteome. The final three enzymes converting thebaine to morphine were among the most abundant active latex proteins despite a limited occurrence in laticifers suggested by immunofluorescence labeling. Multiple charge isoforms of two key O-demethylases in the latex were revealed by two-dimensional immunoblot analysis. Salutaridine biosynthesis appears to occur only in sieve elements, whereas conversion of thebaine to morphine is predominant in adjacent laticifers, which contain morphine-rich latex. Complementary use of immunofluorescence labeling and shotgun proteomics has substantially resolved the cellular localization of morphine biosynthesis in opium poppy.

  4. Effect of pre-cooling and heat treatment on antioxidant enzymes ...

    African Journals Online (AJOL)

    Effect of pre-cooling and heat treatment on antioxidant enzymes profile of mango and banana. ... In banana, pre-cooling treatment (8 ºC) and heat treatment followed by cooling reduced CAT activity in peel and pulp, whereas POX activity increased. Pre-cooling and heat treatments altered normal homeostasis of these fruits, ...

  5. Effect of peripheral morphine in a human model of acute inflammatory pain

    DEFF Research Database (Denmark)

    Lillesø, J; Hammer, N A; Pedersen, J L

    2000-01-01

    Several studies have demonstrated the presence of opioid inducible receptors on peripheral nerves and peripheral antinociceptive effects of opioids. However, the effects of peripheral opioid administration in man are controversial. Our study used a randomized, double-blind, placebo-controlled, th......Several studies have demonstrated the presence of opioid inducible receptors on peripheral nerves and peripheral antinociceptive effects of opioids. However, the effects of peripheral opioid administration in man are controversial. Our study used a randomized, double-blind, placebo......-controlled, three-way crossover design in a human model of acute inflammatory pain (heat injury). We studied 18 healthy volunteers who each received morphine locally (2 mg), morphine systemically (2 mg), or placebo on three separate study days. The subjects received morphine infiltration subcutaneously (s.c.). 1 h......, but local morphine infiltration neither reduced pain during the burn, nor primary or secondary hyperalgesia to mechanical and heat stimuli after the burn. In conclusion, peripherally applied morphine had no acute antinociceptive effects in this human model of acute inflammatory pain....

  6. [Effect of Corydalis Rhizoma and L-tetrahydropalmatine on dopamine system of hippocampus and striatum in morphine-induced conditioned place preference rats].

    Science.gov (United States)

    Yu, Shou-Yang; Bai, Wei-Feng; Tu, Ping; Qiu, Cheng-Kai; Yang, Pei-Run; Luo, Su-Yuan

    2016-10-01

    To investigate the effects of Corydalis Rhizoma and L-tetrahydropalma-tine (L-THP) on the levels of dopamine neurotransmitter (DA), dopamine transporter (DAT) and the second dopamine receptor (D2R) in learning and memory-related brain areas, hippocampus and striatum, the DA, DAT and D2R were detected in conditioned place preference (CPP) rats suffered from morphine. And comparation the degree of similarity and consistency of the pharmacological effects was also studied. The rats were trained in black compartments and white ones (drug-paired compartment) with the increasing doses of morphine for 10 days (hypodermically injected from 10 mg•kg⁻¹ to 100 mg•kg⁻¹). Models of CPP were validated in those psychological dependence rats after 48 h training. The dopamine contents were detected as soon as the materials of hippocampus and striatum are harvested from rats of NS control group and model group. The DAT and D2R levels are measured by Western blot. The high, medium and low dose group of Corydalis Rhizoma are given Corydalis Rhizoma 2, 1, 0.5 g•kg⁻¹ water extraction liquid respectively (which contains L-THP were 0.274, 0.137 and 0.137 mg respectively), and the high, medium and low dose group of L-THP were given L-THP 3.76, 1.88, 0.94 mg•kg⁻¹ lavage treatment respectively, NS treatment group were lavaged normal saline for 6 days and they were killed after test of CPP, again tested DA levels and expression of DAT and D2R similar to the front of materials. The reduction effects of CPP were observed in the groups of both Corydalis Rhizoma (2, 1 g•kg⁻¹) and L-THP (3.76, 1.88 mg•kg⁻¹) subjected to medicine for 6 days (Peffect of L-THP. The similar effects were observed on the neurotransmitter dopamine, DAT and D2R in learning and memory-related brain areas, hippocampus and striatum of the morphine- dependent rats. Copyright© by the Chinese Pharmaceutical Association.

  7. Molecular interactions between selected sodium salts of bile acids and morphine hydrochloride.

    Science.gov (United States)

    Poša, Mihalj; Csanádi, János; Kövér, Katalin E; Guzsvány, Valéria; Batta, Gyula

    2012-06-01

    The objective of this study was to understand the prolonged analgesic action of morphine hydrochloride observed in the presence of sodium 12-oxochenodeoxycholanate. Based on literature, this phenomenon may be due to the formation of aggregates in the cell between the molecules of bile acids and morphine. In addition to the sodium 12-oxochenodeoxycholanate, the present investigation also included salts of cholic and 7-oxodeoxycholic acids. Saturation transfer difference NMR experiments showed that morphine binds to the bile acid molecule close to the aromatic protons H1 and H2 provided that the concentration of the bile acid salt approaches the critical micellar concentration (CMC). The spin-lattice relaxation times (T(1)) of the affected protons decrease significantly in the presence of micellar solutions of the bile acid salts, and the most pronounced change in T(1) was observed for sodium 7-oxodeoxycholate. Diffusion-ordered NMR experiments suggested that morphine hydrochloride can interact only with sodium 7-oxochenodeoxycholate. It can be supposed that the molecular ratio of sodium 7-oxodeoxycholate and morphine hydrochloride in the mixed micelle is 2:1. The CMC values of mixed micelles do not differ from the CMC values of the micelle constituents, which suggests that the binding of morphine hydrochloride does not perturb the hydrophobic domain of the bile acid molecule. In the presence of bile acids, the transfer rate constant (k(12)) of morphine hydrochloride from the buffered aqueous solution to chloroform (model of the cell membrane) shows a decrease. A significant decrease of the k(12) was also observed in the presence of micellar solutions. Kinetic measurements indicated that, in addition to micellar interaction between morphine hydrochloride and sodium salts of bile acids, a complex may also be formed in chloroform via hydrogen bonds formed between the drug and bile acid molecules. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. A Longitudinal Supra-Inguinal Fascia Iliaca Compartment Block Reduces Morphine Consumption After Total Hip Arthroplasty.

    Science.gov (United States)

    Desmet, Matthias; Vermeylen, Kris; Van Herreweghe, Imré; Carlier, Laurence; Soetens, Filiep; Lambrecht, Stijn; Croes, Kathleen; Pottel, Hans; Van de Velde, Marc

    The role of a fascia iliaca compartment block (FICB) for postoperative analgesia after total hip arthroplasty (THA) remains questionable. High-dose local anesthetics and a proximal injection site may be essential for successful analgesia. High-dose local anesthetics may pose a risk for local anesthetic systemic toxicity. We hypothesized that a high-dose longitudinal supra-inguinal FICB is safe and decreases postoperative morphine consumption after anterior approach THA. We conducted a prospective, double blind, randomized controlled trial. Patients scheduled for THA were randomized to group FICB (longitudinal supra-inguinal FICB with 40-mL ropivacaine 0.5%) or group C (control, no block). Standard hypothesis tests (t test or Mann-Whitney U test, χ test) were performed to analyze baseline characteristics and outcome parameters. The primary end point of the study was total morphine (mg) consumption at 24 hours postoperatively. Serial total and free ropivacaine serum levels were determined in 10 patients. After obtaining ethical committee approval and written informed consent, 88 patients were included. Mean (SD) morphine consumption at 24 hours postoperatively was reduced in group FICB compared to group C: 10.25 (1.64) mg versus 19.0 (2.4) mg (P = 0.004). Using a mean dose of 2.6-mg/kg ropivacaine (range, 2-3.4 mg/kg), none of the patients had total or free ropivacaine levels above the maximum tolerated serum concentration. We conclude that a high-dose longitudinal supra-inguinal FICB reduces postoperative morphine requirements after anterior approach THA.Clinical Trials Registry: EU Clinical Trials Register. www.clinicaltrialsregister.eu #2014-002122-12.

  9. Utilization of prodrugs to enhance the transdermal absorption of morphine

    DEFF Research Database (Denmark)

    Drustrup, J.; Fullerton, A.; Christrup, Lona Louring

    1991-01-01

    . The esters showed generally a higher water and lipid solubility than morphine and were also much more lipophilic than the parent drug in terms of octanol-buffer partition coefficients. Diffusion experiments in vitro using human skin samples showed that whereas morphine did not penetrate the skin to any...

  10. A test of the opponent-process theory of motivation using lesions that selectively block morphine reward.

    Science.gov (United States)

    Vargas-Perez, Hector; Ting-A-Kee, Ryan A; Heinmiller, Andrew; Sturgess, Jessica E; van der Kooy, Derek

    2007-06-01

    The opponent-process theory of motivation postulates that motivational stimuli activate a rewarding process that is followed by an opposed aversive process in a homeostatic control mechanism. Thus, an acute injection of morphine in nondependent animals should evoke an acute rewarding response, followed by a later aversive response. Indeed, the tegmental pedunculopontine nucleus (TPP) mediates the rewarding effects of opiates in previously morphine-naive animals, but not other unconditioned effects of opiates, or learning ability. The aversive opponent process for acute morphine reward was revealed using a place-conditioning paradigm. The conditioned place aversion induced by 16-h spontaneous morphine withdrawal from an acute morphine injection in nondependent rats was abolished by TPP lesions performed prior to drug experience. However, TPP-lesioned rats did show conditioned aversions for an environment paired with the acute administration of the opioid antagonist naloxone, which blocks endogenous opioids. The results show that blocking the rewarding effects of morphine with TPP lesions also blocked the opponent aversive effects of acute morphine withdrawal in nondependent animals. Thus, this spontaneous withdrawal aversion (the opponent process) is induced by the acute rewarding effects of morphine and not by other unconditioned effects of morphine, the pharmacological effects of morphine or endogenous opioids being displaced from opiate receptors.

  11. Effect of acetylcholine receptors on the pain-related electrical activities in the hippocampal CA3 region of morphine-addicted rats.

    Science.gov (United States)

    Li, Guan Zeng; Liu, Zhe Hui; Wei, XinYa; Zhao, Pan; Yang, Chun Xiao; Xu, Man Ying

    2015-07-01

    To determine the effect of acetylcholine (ACh), pilocarpine, and atropine on pain evoked responses of pain excited neurons (PEN) and pain inhibited neurons (PIN) in hippocampal CA3 region of morphine addicted rats. Female Wistar rats, weighing between 230-260 g were used in this study. Morphine addicted rats were generated by subcutaneous injection of increasing concentrations of morphine hydrochloride for six days. Trains of electrical impulses applied to the sciatic nerve were used as noxious stimulation and the evoked electrical activities of PEN or PIN in hippocampal CA3 area were recorded using extracellular electrophysiological recording techniques in hippocampal slices. The effect of acetylcholine receptor stimulation by ACh, the muscarinic agonist pilocarpine, and the muscarinic antagonist atropine on the pain evoked responses of pain related electrical activities was analyzed in hippocampal CA3 area of morphine addicted rats. Intra-CA3 microinjection of ACh (2 μg/1 μl) or pilocarpine (2 μg/1 μl) decreased the discharge frequency and prolonged the firing latency of PEN, but increased the discharge frequency and shortened the firing inhibitory duration (ID) of PIN. The intra-CA3 administration of atropine (0.5 μg/1 μl) produced opposite effect. The peak activity of cholinergic modulators was 2 to 4 min later in morphine addicted rats compared to peak activity previously observed in normal rats. ACh dependent modulation of noxious stimulation exists in hippocampal CA3 area of morphine addicted rats. Morphine treatment may shift the sensitivity of pain related neurons towards a delayed response to muscarinergic neurotransmission in hippocampal CA3 region.

  12. Effect of acetylcholine receptors on the pain-related electrical activities in the hippocampal CA3 region of morphine-addicted rats

    Directory of Open Access Journals (Sweden)

    Guan Zeng Li

    2015-07-01

    Full Text Available Objective(s:To determine the effect of acetylcholine (ACh, pilocarpine, and atropine on pain evoked responses of pain excited neurons (PEN and pain inhibited neurons (PIN in hippocampal CA3 region of morphine addicted rats. Materials and Methods:Female Wistar rats, weighing between 230-260 g were used in this study. Morphine addicted rats were generated by subcutaneous injection of increasing concentrations of morphine hydrochloride for six days. Trains of electrical impulses applied to the sciatic nerve were used as noxious stimulation and the evoked electrical activities of PEN or PIN in hippocampal CA3 area were recorded using extracellular electrophysiological recording techniques in hippocampal slices. The effect of acetylcholine receptor stimulation byACh, the muscarinic agonist pilocarpine, and the muscarinic antagonist atropine on the pain evoked responses of pain related electrical activities was analyzed in hippocampal CA3 area of morphine addicted rats. Results:Intra-CA3 microinjection of ACh (2 μg/1 μl or pilocarpine (2 μg/1 μl decreased the discharge frequency and prolonged the firing latency of PEN, but increased the discharge frequency and shortened the firing inhibitory duration (ID of PIN. The intra-CA3 administration of atropine (0.5 μg/1 μl produced opposite effect. The peak activity of cholinergic modulators was 2 to 4 min later in morphine addicted rats compared to peak activity previously observed in normal rats. Conclusion: ACh dependent modulation of noxious stimulation exists in hippocampal CA3 area of morphine addicted rats. Morphine treatment may shift the sensitivity of pain related neurons towards a delayed response to muscarinergic neurotransmission in hippocampal CA3 region.

  13. Safety of pain control with morphine: new (and old) aspects of ...

    African Journals Online (AJOL)

    Safety of pain control with morphine: new (and old) aspects of morphine ... In addition, nursing staff failed to recognise that snoring can indicate a dangerously ... monitor of respiratory depression; (iv) training in airway management should be ...

  14. Evidence of morphine like substance and μ-opioid receptor expression in Toxacara canis (Nematoda: Ascaridae).

    Science.gov (United States)

    Golabi, Mostafa; Naem, Soraya; Imani, Mehdi; Dalirezh, Nowruz

    2016-01-01

    Toxocara canis (Nematoda: Ascaridae) is an intestinal nematode parasite of dogs, which can also cause disease in humans. Transmission to humans usually occurs because of direct contact with T. canis eggs present in soil contaminated with the feces of infected dogs. This nematode has extraordinary abilities to survive for many years in different tissues of vertebrates, and develop to maturity in the intestinal tract of its definitive host. Survival of parasitic nematodes within a host requires immune evasion using complicated pathways. Morphine-like substance, as well as opioids, which are known as down regulating agents, can modulate both innate and acquired immune responses, and let the parasite survives in their hosts. In the present study, we aimed to find evidences of morphine-like substance and µ-opiate receptor expression in T. canis , using high performance liquid chromatography (HPLC) and reverse transcription polymerase chain reaction (RT-PCR). The results indicated that T. canis produced morphine-like substances at the level of 2.31± 0.26 ng g -1 wet weight, and expressed µ-opiate receptor as in expected size of 441 bp. According to our findings, it was concluded that T. canis , benefits using morphine-like substance to modulate host immunity.

  15. The Effect of Nitric Oxide Synthetase Inhibitor (L-NAME on Prevention of Morphine Dependence in Rats

    Directory of Open Access Journals (Sweden)

    A. Rafati

    2004-10-01

    Full Text Available Prevention of dependency to morphine or delaying to it and decreasing of tendency to morphine craving and also decreasing in morphine induced hyperalgesia(tolerance were the aims of this study. Nitric oxide is one of the neurotransmitters, which involves in the Dopamine reuptake in striatum. Dopamine is one of the most important neurotransmitters in reward system in central nervous system and it has a critical role in morphine addiction and dependency, tendency and tolerance to it, so in this study we survied the role of L- NAME as a nitric oxide synthetase (NOS inhibitor on the prevention of morphine addiction in rats. In this study we evaluated behavioral changes such as morphine craving by self - administration as a criterion for tendency, dependency by observation of withdrawal syndrom signs (e.g Jumping, wet dog shaking and also responses to nociceptive condenced bim of light by using tail flick analgesia metric device in sham (consuming tap water, control (consuming increasing doses of morphine sulfate solution from 0.1mg/ml up to 0.4mg/ml and test (treated with 45 mg/kg of L- NAME 30 minutes before consuming of morphine sulfate solution per day groups. The results showed that pretreatment with L- NAME in test group lead to a significant decline in tendency to morphine craving, withdrawal signs and also a significant reversal of morphine induced hyperalgesia. We concluded that L- NAME is a potent agent in the prevention of morphine addiction.

  16. Nurses' perceptions and experiences regarding Morphine usage in burn pain management.

    Science.gov (United States)

    Bayuo, J; Agbenorku, P

    2015-06-01

    Morphine, a classical example of opioid has been described as one of the analgesics of choice for burn pain management but there have been reports of under utilization of the medication and subsequent poor pain management. Nurses have a pivotal role in successful burn pain management and should therefore possess positive perception as well as strong knowledge base of pain care. In light of this realization, this study sought to investigate the perception and experiences of nurses working in the burns unit possess towards the medication. Purposive sampling approach was used to select twenty (20) nurses. Descriptive and themed content analysis approaches were used to analyze data. Mean years in general nursing practice and practice in the burns unit were obtained as 7.4 and 3.4 years respectively. Results indicate that nurses have a clear understanding of the intensity of burn pain but perception towards morphine was mixed and some respondents were unsure about some of the pertinent facts of morphine and thus, would prefer other medications such as paracetamol, diclofenac and pethidine. Addiction to the medication and morphine causing death were major themes identified. The resultant effect of these perception and experiences imply and confirm the under usage of morphine. It is therefore recommended that nurses within the burn unit be taken through training modules on the suitability of morphine in burn pain management. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

  17. Pharmacogenomics and Patient Treatment Parameters to Opioid Treatment in Chronic Pain: A Focus on Morphine, Oxycodone, Tramadol, and Fentanyl.

    Science.gov (United States)

    Lloyd, Renae A; Hotham, Elizabeth; Hall, Catherine; Williams, Marie; Suppiah, Vijayaprakash

    2017-12-01

    Opioids are one of the most commonly prescribed medicines for chronic pain. However, their use for chronic pain has been controversial. The objective of this literature review was to identify the role of genetic polymorphisms on patient treatment parameters (opioid dose requirements, response, and adverse effects) for opioids used in malignant and nonmalignant chronic pain. The opioids that this review focuses on are codeine, morphine, oxycodone, tramadol, and fentanyl. A literature search of databases Medline and Embase was carried out, and studies up to April 2016 were included in this review. Studies were included based on a combination of key words: chronic pain and related terms, pharmacogenetics and related terms, and opioids and related terms. Among the 1,408 individual papers retrieved from the search in Medline and Embase, 32 original articles were included in this review, with none related to codeine. The 32 papers reported various study designs, opioids, and polymorphisms being studied for associations with treatment outcomes. This literature review reveals that variants in ABCB1, OPRM1, and COMT have been replicated for opioid dosing and variants in ABCB1 have been replicated for both treatment response and adverse effects. Currently, there are few validated studies to form a strong evidence base to support pharmacogenomics testing when initiating opioid therapy. However, the field of pharmacogenomics in chronic pain is likely to expand over the coming years, with the increasing number of treatment options available and larger cohorts being assembled in order to identify true associations. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  18. Comparison of efficacy of dexketoprofen versus paracetamol on postoperative pain and morphine consumption in laminectomy patients.

    Science.gov (United States)

    Kesimci, Elvin; Gümüş, Tülin; Izdeş, Seval; Sen, Pelin; Kanbak, Orhan

    2011-10-01

    The aim of this prospective randomized, double-blind study was to evaluate the analgesic efficacy and opioid-sparing effects of preemptive single dose of dexketoprofen trometamol in comparison with that of paracetamol or placebo for elective lumbar disc surgery, over a 24-hour (h) investigation period. After institutional approval and informed consent had been obtained, 75 patients scheduled for single level lumbar disc surgery were randomly allocated into three equal groups. Patients received oral dexketoprofen 25 mg (Group D), 500 mg paracetamol (Group P) or placebo tablets (Group C) 30 minutes (min) before induction of standard anesthesia. Patient-controlled analgesia was supplied postoperatively using morphine. Hemodynamics, visual analogue scale (VAS), sedation score, morphine consumption, and side effects were recorded every 15 min in the first hour and at 2, 6 and 24 h after surgery. The mean pain scores were similar among groups (p>0.05). The cumulative (SD) 24-h morphine consumption was 28.1 mg, 40.6 mg, and 43.6 mg for Groups D, P and C, respectively. The amount of morphine use at 2, 6 and 24 h was significantly lower in Group D (p0.05). The study demonstrated that preemptive dexketoprofen trometamol 25 mg is associated with a decrease of up to 35% in morphine consumption compared with placebo over the first 24 h following lumbar disc surgery; however, paracetamol 500 mg did not show the expected opioid-sparing effect comparatively.

  19. Role of Estrogen on Prevention of Morphine Addiction in Ovarectomized Female Rats

    Directory of Open Access Journals (Sweden)

    A Rafati

    2008-04-01

    Full Text Available ABSTRACT: Introduction & Objective: Evidence indicates that the biological response and the causes of drug abuse may be different between women and men. These sex differences in drug abuse may be due to socio-cultural factors or biological (hormonal differences. Estrogen is one of the hormones which involves in dopamine release in striatum and nucleus accumbency and also is one of the most important neurotransmitters in central nervous system which has critical role in morphine addiction. So, in this study we survey the role of estrogen on dependency and tendency to morphine in rat as a factor of sex differences in addiction. Materials & Methods: This experimental study was carried out in Yazd University of Medical Sciences. Behavioral changes like morphine craving was evaluated by self-administration as a criterion for tendency and for assessment of dependency. we evaluated withdrawal syndrome sings (e.g. jumping, wet dog shaking, etc in control group (ovarectomized female rats receiving morphine sulfate solution and test group (ovarectomized female rats, pretreated with estradiol benzoate before receiving daily morphine sulfate solution. Data obtained were analyzed by SPSS software, using T-test analysis Results: Results showed that although pretreatment with estradiol in test group might lead to a significant decline in withdrawal syndrome sings in comparison with control group, differences in morphine craving as a criterion for tendency was not significant between the two groups. Conclusion: According to our findings, it seems that estrogen, through central mechanisms and its effect on brain dopaminergic system, reduces the physical dependency to morphine.

  20. Intra-articular morphine in horses

    DEFF Research Database (Denmark)

    Lindegaard, Casper

    separated by a three week washout period. Before each treatment, radiocarpal synovitis was induced by IA injection of lipopolysaccharide (LPS). For each of the two 168-hours study periods, local and systemic measures of pain and inflammation as well as blood and synovial fluid (SF) samples...... for pharmacological analysis were obtained repeatedly. Pain was evaluated by degree of lameness as well as using a visual analogue scale of pain intensity (VAS) and a composite measure pain scale (CMPS), developed for this purpose. Intra-articular injection of LPS elicited a marked synovitis resulting in lameness...... and pain. Intra-articularly administered morphine showed a significant analgesic effect as measured by reduced lameness scores, less administered rescue analgesia and lower pain scores. A significant anti-inflammatory effect was demonstrated by reduced joint swelling, reduced SF serum amyloid A (SAA...

  1. Analgesia induced by morphine microinjected into the nucleus raphe magnus: effects on tonic pain.

    Science.gov (United States)

    Dualé, Christian; Sierralta, Fernando; Dallel, Radhouane

    2007-07-01

    One of the possible sites of action of the analgesic effect of morphine is the Nucleus Raphe Magnus, as morphine injected into this structure induces analgesia in transient pain models. In order to test if morphine in the Nucleus Raphe Magnus is also analgesic in a tonic pain model, 5 microg of morphine or saline (control) were microinjected into the Nucleus Raphe Magnus of the rat. Analgesic effects were assessed following nociceptive stimulation using transient heating of the tail (phasic pain) and subcutaneous orofacial injection of 1.5 % formalin (tonic pain). While morphine was strongly analgesic for the tail-flick response (p <0.0001 compared to control), analgesia on the response to formalin was also observed for both early (p = 0.007) and late responses (p = 0.02). However, the response to formalin was not completely blunted. These results suggest that the Nucleus Raphe Magnus is not the exclusive site of action of morphine-induced analgesia in clinical conditions.

  2. Fungicidal Effects of Plasma and Radio-Wave Pre-treatments on Seeds of Grain Crops and Legumes

    Science.gov (United States)

    Filatova, Irina; Azharonok, Viktor; Shik, Alexander; Antoniuk, Alexandra; Terletskaya, Natalia

    An influence of RF plasma and RF electromagnetic field pre-treatments on level of fungal infection of some important agricultural plants has been studied. It is shown that pre-sowing plasma and radio-wave seeds treatments contribute to their germination enhancement and plant productivity improvement owing to stimulative and fungicidal effect of plasma and RF electromagnetic field irradiation.

  3. Carcinoembryonic antigen (CEA) level, CEA ratio, and treatment outcome of rectal cancer patients receiving pre-operative chemoradiation and surgery

    International Nuclear Information System (INIS)

    Yang, Kai-Lin; Chang, Shih-Ching; Chu, Lee-Shing; Wang, Ling-Wei; Yang, Shung-Haur; Liang, Wen-Yih; Kuo, Ying-Ju; Lin, Jen-Kou; Lin, Tzu-Chen; Chen, Wei-Shone; Jiang, Jeng-Kae; Wang, Huann-Sheng

    2013-01-01

    To investigate serum carcinoembryonic antigen (CEA) as a prognostic factor for rectal cancer patients receiving pre-operative chemoradiotherapy (CRT). Between 2000 and 2009, 138 patients with advanced rectal cancer receiving CRT before surgery at our hospital were retrospectively classified into 3 groups: pre-CRT CEA <6 ng/ml (group L; n = 87); pre-CRT CEA ≥ 6 ng/ml and post-CRT CEA <6 ng/ml (group H-L; n = 32); and both pre- and post-CRT CEA ≥ 6 ng/ml (group H-H; n = 19). CEA ratio (defined as post-CRT CEA divided by pre-CRT CEA), post-CRT CEA level and other factors were reviewed for prediction of pathologic complete response (pCR). Five-year disease-free survival (DFS) was better in groups L (69.0%) and H-L (74.5%) than in group H-H (44.9%) (p = 0.024). Pathologic complete response was observed in 19.5%, 21.9% and 5.3% of groups L, H-L and H-H respectively (p = 0.281). Multivariate analysis showed that ypN stage and pCR were independent prognostic factors for DFS and that post-CRT CEA level was independently predictive of pCR. As a whole, post-CRT CEA <2.61 ng/ml predicted pCR (sensitivity 76.0%; specificity 58.4%). For those with pre-CRT CEA ≥6 ng/ml, post-CRT CEA and CEA ratio both predicted pCR (sensitivity 87.5%, specificity 76.7%). In patients with pre-CRT serum CEA ≥6 ng/ml, those with “normalized” CEA levels after CRT may have similar DFS to those with “normal” (<6 ng/ml) pre-CRT values. Post-CRT CEA level is a predictor for pCR, especially in those with pre-CRT CEA ≥6 ng/ml

  4. Basal blood DHEA-S/cortisol levels predicts EMDR treatment response in adolescents with PTSD.

    Science.gov (United States)

    Usta, Mirac Baris; Gumus, Yusuf Yasin; Say, Gokce Nur; Bozkurt, Abdullah; Şahin, Berkan; Karabekiroğlu, Koray

    2018-04-01

    In literature, recent evidence has shown that the hypothalamic-pituitary-adrenal (HPA) axis can be dysregulated in patients with post-traumatic stress disorder (PTSD) and HPA axis hormones may predict the psychotherapy treatment response in patients with PTSD. In this study, it was aimed to investigate changing cortisol and DHEA-S levels post-eye movement desensitization and reprocessing (EMDR) therapy and the relationship between treatment response and basal cortisol, and DHEA-S levels before treatment. The study group comprised 40 adolescents (age, 12-18 years) with PTSD. The PTSD symptoms were assessed using the Child Depression Inventory (CDI) and Child Post-traumatic Stress Reaction Index (CPSRI) and the blood cortisol and DHEA-S were measured with the chemiluminescence method before and after treatment. A maximum of six sessions of EMDR therapy were conducted by an EMDR level-1 trained child psychiatry resident. Treatment response was measured by the pre- to post-treatment decrease in self-reported and clinical PTSD severity. Pre- and post-treatment DHEA-S and cortisol levels did not show any statistically significant difference. Pre-treatment CDI scores were negatively correlated with pre-treatment DHEA-S levels (r: -0.39). ROC analysis demonstrated that the DHEA-S/cortisol ratio predicts treatment response at a medium level (AUC: 0.703, p: .030, sensitivity: 0.65, specificity: 0.86). The results of this study suggested that the DHEA-S/cortisol ratio may predict treatment response in adolescents with PTSD receiving EMDR therapy. The biochemical parameter of HPA-axis activity appears to be an important predictor of positive clinical response in adolescent PTSD patients, and could be used in clinical practice to predict PTSD treatment in the future.

  5. Delay discounting of oral morphine and sweetened juice rewards in dependent and non-dependent rats.

    Science.gov (United States)

    Harvey-Lewis, Colin; Perdrizet, Johnna; Franklin, Keith B J

    2014-07-01

    Opioid-dependent humans are reported to show accelerated delay discounting of opioid rewards when compared to monetary rewards. It has been suggested that this may reflect a difference in discounting of consumable and non-consumable goods not specific to dependent individuals. Here, we evaluate the discounting of similar morphine and non-morphine oral rewards in dependent and non-dependent rats We first tested the analgesic and rewarding effects of our morphine solution. In a second experiment, we assigned rats randomly to either dependent or non-dependent groups that, 30 min after daily testing, received 30 mg/kg subcutaneous dose of morphine, or saline, respectively. Delay discounting of drug-free reward was examined prior to initiation of the dosing regimen. We tested discounting of the morphine reward in half the rats and retested the discounting of the drug-free reward in the other half. All tests were run 22.5 h after the daily maintenance dose. Rats preferred the morphine cocktail to the drug-free solution and consumed enough to induce significant analgesia. The control quinine solution did not produce these effects. Dependent rats discounted morphine rewards more rapidly than before dependence and when compared to discounting drug-free rewards. In non-dependent rats both reward types were discounted similarly. These results show that morphine dependence increases impulsiveness specifically towards a drug reward while morphine experience without dependence does not.

  6. Depression of home cage wheel running is an objective measure of spontaneous morphine withdrawal in rats with and without persistent pain

    Science.gov (United States)

    Kandasamy, Ram; Lee, Andrea T.; Morgan, Michael M.

    2017-01-01

    Opioid withdrawal in humans is often subtle and almost always spontaneous. In contrast, most preclinical studies precipitate withdrawal by administration of an opioid receptor antagonist such as naloxone. These animal studies rely on measurement of physiological symptoms (e.g., wet dog shakes) in the period immediately following naloxone administration. To more closely model the human condition, we tested the hypothesis that depression of home cage wheel running will provide an objective method to measure the magnitude and duration of spontaneous morphine withdrawal. Rats were allowed access to a running wheel in their home cage for 8 days prior to implantation of two 75 mg morphine or placebo pellets. The pellets were removed 3 or 5 days later to induce spontaneous withdrawal. In normal pain-free rats, removal of the morphine pellets depressed wheel running for 48 hours compared to rats that had placebo pellets removed. Morphine withdrawal-induced depression of wheel running was greatly enhanced in rats with persistent inflammatory pain induced by injection of Complete Freund’s Adjuvant (CFA) into the hindpaw. Removal of the morphine pellets following 3 days of treatment depressed wheel running in these rats for over 6 days. These data demonstrate that home cage wheel running provides an objective and more clinically relevant method to assess spontaneous morphine withdrawal compared to precipitated withdrawal in laboratory rats. Moreover, the enhanced withdrawal in rats with persistent inflammatory pain suggests that pain patients may be especially susceptible to opioid withdrawal. PMID:28366799

  7. Intravenous paracetamol versus dexketoprofen versus morphine in acute mechanical low back pain in the emergency department: a randomised double-blind controlled trial.

    Science.gov (United States)

    Eken, Cenker; Serinken, Mustafa; Elicabuk, Hayri; Uyanik, Emrah; Erdal, Muhammed

    2014-03-01

    The objective of this study was to determine the analgesic efficacy and safety of intravenous, single-dose paracetamol versus dexketoprofen versus morphine in patients presenting with mechanical low back pain (LBP) to the emergency department (ED). This randomised double-blind study compared the efficacy of intravenous 1 gm paracetamol, 50 mg dexketoprofen and 0.1 mg/kg morphine in patients with acute mechanical LBP. Visual analogue scale (VAS) was used for pain measurement at baseline, after 15 and after 30 min. A total of 874 patients were eligible for the study, and 137 of them were included in the final analysis: 46 patients from the paracetamol group, 46 patients in the dexketoprofen group and 45 patients in the morphine group. The mean age of study subjects was 31.5 ± 9.5 years, and 60.6% (n=83) of them were men. The median reduction in VAS score at the 30th minute for the paracetamol group was 65 mm (95% CI 58 to 72), 67 mm (95% CI 60 to 73) for the morphine group and 58 mm (95% CI 50 to 64) for the dexketoprophen group. Although morphine was not superior to paracetamol at 30 min (difference: 3.8 ± 4.9 (95% CI -6 to 14), the difference between morphine and dexketoprofen in reducing pain was 11.2 ± 4.7 (95% CI 2 to 21). At least one adverse effect occurred in 8.7% (n=4) of the cases in the paracetamol group, 15.5% (n=7) of the morphine group, and 8.7% (n=4) of the dexketoprophen group (p=0.482). Intravenous paracetamol, dexketoprofen and morphine are not superior to each other for the treatment of mechanical LBP in ED.

  8. The Influence of Polyethylene Glycol Solution on the Dissolution Rate of Sustained Release Morphine.

    Science.gov (United States)

    Hodgman, Michael; Holland, Michael G; Englich, Ulrich; Wojcik, Susan M; Grant, William D; Leitner, Erich

    2016-12-01

    Whole bowel irrigation (WBI) is a management option for overdose of medications poorly adsorbed to activated charcoal, with modified release properties, or for body packers. Polyethylene glycol (PEG) is a mixture of ethylene oxide polymers of varying molecular weight. PEG with an average molecular weight of 3350 g/mol is used for WBI. PEG electrolyte lavage solution has been shown in vitro to hasten the dissolution of acetaminophen. The impact of PEG on the pharmacokinetics of extended release pharmaceuticals is unknown. Lower average molecular weight PEG mixtures are used as solvents and excipients. We sought to investigate the impact of PEG on the release of morphine from several extended release morphine formulations. An in vitro gastric model was developed. To test the validity of our model, we first investigated the previously described interaction of ethanol and Avinza®. Once demonstrated, we then investigated the effect of PEG with several extended release morphine formulations. In the validation portion of our study, we confirmed an ethanol Avinza® interaction. Subsequently, we did not observe accelerated release of morphine from Avinza® or generic extended release morphine in the presence of PEG. The use of PEG for gastric decontamination following ingestion of these extended release morphine formulations is unlikely to accelerate morphine release and aggravate intoxication.

  9. Successful management of a difficult cancer pain patient by appropriate adjuvant and morphine titration

    Directory of Open Access Journals (Sweden)

    Shiv PS Rana

    2011-01-01

    Full Text Available Morphine has been used for many years to relieve cancer pain. Oral morphine (in either immediate release or modified release form remains the analgesic of choice for moderate or severe cancer pain. The dose of oral morphine is titrated up to achieve adequate relief from pain with minimal side effects. Antidepressant and anticonvulsant drugs, when used in addition to conventional analgesics, give excellent relief from cancer pain. Most cancer pain responds to pharmacological measures with oral morphine but some pain like neuropathic and bony pain, pain in children and elderly age group, and advanced malignancy pain are very difficult to treat. Here, we report the management of a similar patient of severe cancer pain and the difficulty that we came across during dose titration of oral morphine and adjuvant analgesic.

  10. Detrimental effects of rat mesenchymal stromal cell pre-treatment in a model of acute kidney rejection

    Directory of Open Access Journals (Sweden)

    Martina eSeifert

    2012-07-01

    Full Text Available Mesenchymal stromal cells (MSC have shown immunomodulatory and tissue repair potential including partial tolerance induction by pre-treatment of donor-specific cells in a rat heart transplantation model. Very recently, we could show that autologous MSC attenuated ischemia reperfusion injury in a highly mismatched donor-recipient rat kidney transplant model. Therefore, we investigated donor-specific MSC pre-treatment in this rat kidney transplantation model to study whether graft function could be improved, or if tolerance could be induced.Donor- and recipient-type MSC or PBS as a control were injected i.v. four days before kidney transplantation. Mycophenolate mofetil (MMF immunosuppression (20 mg/kg body weight was applied for 7 days. Kidney grafts and spleens were harvested between days 8-10 and analyzed by quantitative RT-PCR and immunohistology. In addition, creatinine levels in the blood were measured and serum was screened for the presence of donor-specific antibodies.Surprisingly, application of both donor- and recipient-specific MSC resulted in enhanced humoral immune responses verified by intragraft B cell infiltration and complement factor C4d deposits. Moreover, signs of inflammation and rejection were generally enhanced in both MSC-treated groups relative to PBS control group. Additionally, pre-treatment with donor-specific MSC significantly enhanced the level of donor-specific antibody formation when compared with PBS- or recipient-MSC-treated groups. Pre-treatment with both MSC types resulted in a higher degree of kidney cortex tissue damage and elevated creatinine levels at the time point of rejection. Thus, MSC pre-sensitization in this model impairs the allograft outcome.Our data from this pre-clinical kidney transplantation model indicate that pre-operative MSC administration may not be optimal in kidney transplantation and caution must be exerted before moving forward with clinical studies in order to avoid adverse effects.

  11. Determination of morphine, codeine and 6-monoacetylmorphine in saliva of substance-abuse patients using HPLC/MS methods

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    Milovanović Vesna

    2012-01-01

    Full Text Available Background/Aim. Saliva represents an alternative specimen for substances abuse determination in toxicology. Hence, the aim of this study was to optimize a method for saliva specimen preparation for heroin metabolites, morphine and 6-monoacetylmorphine (6-mam, and codeine determination by liquid chromatography-mass spectrometry (LC/MS, and to apply this method on saliva samples taken from the patients. Methods. Saliva specimen was prepared using liqiud/liquid extraction of morphine, codeine and 6- mam by mixture of chloroform and isopropanol (9 : 1; v/v. Extracts were analysed by HPLC/MS technique: separation column Waters Spherisorb® 5 μm, ODS2, 4.6 × 100 mm; mobile phase: ammonium acetate : acetonitile (80 : 20; v/v, mobile phase flow rate 0.3 mL/min; mass detection range: 100-400 m/z. Regression and correlation analyses were performed with the probalility level of 0.05. Concentrations of morphine, codeine and 6-mam were determined in saliva samples of the patients with “opiates” in urine identified by the test strips. Results. Calibration for each analysed substance was done in the concentration range from 0.1 to 1 mg/L and the coefficient of correlation was R2 > 0.99. We obtained following calibration curves: y = 385531x + 14584; y = 398036x + 31542; and y = 524162x - 27105, for morphine, codeine and 6-mam, respectively. Recovery for morphine and codeine determination was 99%, while for 6- mam it was 94%. Limits of detection and quantification of a proposed method were 0.01 mg/L and 0.05 mg/L, respectively. Concentration of morphine in the saliva of the heroin users ranged between 0.54 and 5.82 mg/L, concentration of codeine between 0.05 and 5.33, and 6-mam between 0.01 and 0.68 mg/L. A statistically significant correlation between codeine and 6-mam concentrations was obtained. Conclusion. A proposed HPLC/MS method for morphine, codeine and 6-mam determination in saliva is accurate, simple, cheap and suitable for routine analysis and

  12. Influence of surface pre-treatment on the electronic levels in silicon MaWCE nanowires.

    Science.gov (United States)

    Venturi, Giulia; Castaldini, Antonio; Schleusener, Alexander; Sivakov, Vladimir; Cavallini, Anna

    2015-05-15

    Deep level transient spectroscopy (DLTS) was performed on n-doped silicon nanowires grown by metal-assisted wet chemical etching (MaWCE) with gold as the catalyst in order to investigate the energetic scheme inside the bandgap. To observe the possible dependence of the level scheme on the processing temperature, DLTS measurements were performed on the nanowires grown on a non-treated Au/Si surface and on a thermally pre-treated Au/Si surface. A noticeable modification of the configuration of the energy levels was observed, induced by the annealing process. Based on our results on these MaWCE nanowires and on literature data about deep levels in bulk silicon, some hypotheses were advanced regarding the identification of the defects responsible of the energy levels revealed.

  13. Strain differences in the response to morphine on incorporation of 3H-lysine into rat brain protein

    International Nuclear Information System (INIS)

    Ford, D.H.; Rhines, R.K.; Levi, M.A.

    1977-01-01

    The effect of morphine on the specific activity (SA) of lysine in the plasma free amino acid (FFA) fraction and in the cerebral cortical FAA and protein fractions, as well as on the specific accumulation and incorporation, was determined in male Sprague-Dawley and Wistar rats at various time intervals after intravenous injection of drug and amino acid into unanesthetized animals. The lysine SA was higher in Sprague-Dawley than in Wistar rats in the plasma and brain FAA fraction and in the protein fraction. In the SD strain, morphine decreased the SA of plasma FAA significantly, but had only slight effects in the Wistar strain. In the cortical gray matter, morphine elevated the SA of lysine significantly in both strains. SA of the lysine in cerebral cortical protein increased in both strains with time. When the data for the free amino acids were expressed in terms of specific accumulation, the observed rates were higher in the Sprague-Dawley animals and reached a point of maximal concentration, which was not observed in animals of the Wistar strain. Morphine elevated the levels of specific accumulation of lysine into the cortical free amino acid pool in both strains of rat. It is concluded that Sprague-Dawley and Wistar rats are not equivalent in relation to the accumulation of an amino acid in the brain FAA pool from the plasma and that the effect of morphine on specific incorporation of lysine into brain protein is greater in Wistar rats. (author)

  14. Interactive Effects of Morphine on HIV Infection: Role in HIV-Associated Neurocognitive Disorder

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    Pichili Vijaya Bhaskar Reddy

    2012-01-01

    Full Text Available HIV epidemic continues to be a severe public health problem and concern within USA and across the globe with about 33 million people infected with HIV. The frequency of drug abuse among HIV infected patients is rapidly increasing and is another major issue since injection drug users are at a greater risk of developing HIV associated neurocognitive dysfunctions compared to non-drug users infected with HIV. Brain is a major target for many of the recreational drugs and HIV. Evidences suggest that opiate drug abuse is a risk factor in HIV infection, neural dysfunction and progression to AIDS. The information available on the role of morphine as a cofactor in the neuropathogenesis of HIV is scanty. This review summarizes the results that help in understanding the role of morphine use in HIV infection and neural dysfunction. Studies show that morphine enhances HIV-1 infection by suppressing IL-8, downregulating chemokines with reciprocal upregulation of HIV coreceptors. Morphine also activates MAPK signaling and downregulates cAMP response element-binding protein (CREB. Better understanding on the role of morphine in HIV infection and mechanisms through which morphine mediates its effects may help in devising novel therapeutic strategies against HIV-1 infection in opiate using HIV-infected population.

  15. Influence of Pre-trimethylindium flow treatment on blue light emitting diode

    International Nuclear Information System (INIS)

    Xu, Bing; Zhao, Jun Liang; Dai, Hai Tao; Wang, Shu Guo; Lin, Ray-Ming; Chu, Fu-Chuan; Huang, Chou-Hsiung; Yu, Sheng-Fu; Sun, Xiao Wei

    2014-01-01

    The effects of Pre-trimethylindium (TMIn) flow treatment prior to quantum well growth on blue light emitting diode properties were investigated. High-resolution X-ray diffraction indicated that Pre-TMIn flow treatment did not change the composition of indium in quantum wells, but influenced electrical and optical properties of blue light emitting diode. Electroluminescence exhibited redshift with increasing TMIn treatment time. Though, the forward voltage became a little larger with longer Pre-TMIn treatment time due to the slight phase separation and indium aggregation, the efficiency droop of the device was improved effectively. - Highlights: • Pre-trimethylindium treatment can lead to longer wavelength. • External quantum efficiency can be improved effectively. • Electrical properties are not decreased using Pre-trimethylindium treatment

  16. Influence of Pre-trimethylindium flow treatment on blue light emitting diode

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Bing; Zhao, Jun Liang [Tianjin Key Laboratory of Low Dimensional Materials Physics and Preparing Technology, School of Science, Tianjin University, Tianjin 300072 (China); Dai, Hai Tao, E-mail: htdai@tju.edu.cn [Tianjin Key Laboratory of Low Dimensional Materials Physics and Preparing Technology, School of Science, Tianjin University, Tianjin 300072 (China); Wang, Shu Guo [Tianjin Key Laboratory of Low Dimensional Materials Physics and Preparing Technology, School of Science, Tianjin University, Tianjin 300072 (China); Lin, Ray-Ming, E-mail: rmlin@mail.cgu.edu.tw [Graduate Institute of Electronic Engineering and Green Technology Research Center, Chang Gung University, Taoyuan 333, Taiwan (China); Chu, Fu-Chuan; Huang, Chou-Hsiung [Graduate Institute of Electronic Engineering and Green Technology Research Center, Chang Gung University, Taoyuan 333, Taiwan (China); Yu, Sheng-Fu [Institute of Microelectronics and Department of Electrical Engineering, Center for Micro/Nano Science and Technology, Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan 70101, Taiwan (China); Sun, Xiao Wei, E-mail: xwsun@sustc.edu.cn [South University of Science and Technology of China, Shenzhen, Guangdong (China)

    2014-01-31

    The effects of Pre-trimethylindium (TMIn) flow treatment prior to quantum well growth on blue light emitting diode properties were investigated. High-resolution X-ray diffraction indicated that Pre-TMIn flow treatment did not change the composition of indium in quantum wells, but influenced electrical and optical properties of blue light emitting diode. Electroluminescence exhibited redshift with increasing TMIn treatment time. Though, the forward voltage became a little larger with longer Pre-TMIn treatment time due to the slight phase separation and indium aggregation, the efficiency droop of the device was improved effectively. - Highlights: • Pre-trimethylindium treatment can lead to longer wavelength. • External quantum efficiency can be improved effectively. • Electrical properties are not decreased using Pre-trimethylindium treatment.

  17. Combined intra-articular glucocorticoid, bupivacaine and morphine reduces pain and convalescence after diagnostic knee arthroscopy

    DEFF Research Database (Denmark)

    Rasmussen, Sten; Lorentzen, Jan S; Larsen, Allan S

    2002-01-01

    We studied the effect of intra-articullar saline vs. bupivacaine + morphine or bupivacaine morphine + methylprednisolone after diagnostic knee arthroscopy. In a double-blind randomized study, 60 patients undergoing diagnostic knee arthroscopy without a therapeutic procedure were allocated to groups...... receiving intra-articular saline, intra-articular bupivacaine 150 mg + morphine 4 mg or the same dose of bupivacaine + morphine + intra-articular methylprednisolone 40 mg at the end of arthroscopy during general anesthesia. All patients were instructed to resume normal activities immediately after...

  18. Comparison between C-FOS Expression in Male and Female Mice During Morphine Withdrawal in the Presence and Absence of Acute Administration of Matricaria Recutita

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    Kesmati Mahnaz

    2009-06-01

    Full Text Available Background: There are some evidences that indicate there are sexual differences in drug abuse and response to synthetic and herbal drugs. It has been shown that the expression of C-FOS increases in many areas of brain during morphine withdrawal. Concerning the sedative effect of Matricaria recutita extract, the aim of this study was to compare expression of C-FOS transcription factor during morphine withdrawal with and without acute administration of Matricaria recutita on male and female adult mice.Materials and Methods: This study was done at Shahid Chamran University of Ahvaz in 2007 on NMRI mice. Male and female mice were assigned into 8 groups (morphine + saline; morphine + naloxone; morphine + Matricaria recutita + naloxone; and morphine + saline + naloxone. To develop morphine dependency, increasing doses of morphine (20, 40, 80 mg/kg injected subcutaneously for 4 days. Mice received a final morphine injection (40 mg/kg 3hours prior to naloxone (5 mg/kg on the day of testing (day 4. Matricaria recutita extract whit a dose of 30 mg/kg was administered intraperitoneally 5 minutes before naloxone injection. In cellular study, 90minute after naloxone injection, mice were decapitated and their brains were separated, then mRNA was extracted from brain tissue. Using DIG-labeled DNA probe of C-FOS, beta-actin and dot blot technique, expression of C-FOS was analyzed by Zero Dscan software. Statistical evaluation of data was performed using student t-test and ANOVA with one factor followed by Duncan test in SPSS software. P values less than 0.05 were considered significant. Results: The rate of expression of C-FOS increased in male mice but decreased significantly in female mice after naloxone-precipitated abstinence P<0.01(. Matricaria recutita attenuated the rate of expression of C-FOS in male mice but it showed synergistic effect on it in female mice P<0.05(.Conclusion: It seems that the cellular processes involving morphine dependency and

  19. A comparison of detomidine in combination with saline, morphine or methadone in horses submitted to experimental oral stimuli

    Directory of Open Access Journals (Sweden)

    Rafael Costa Guilhen

    2015-12-01

    Full Text Available This study aimed to compare the sedative and cardiopulmonary effects of detomidine in combination with saline, morphine or methadone and to determine whether the addition of these opioids increases the degree of sedation in horses submitted to experimental oral stimuli. In a blinded, randomized, experimental study, six adult mares were evaluated using a crossover design with at least 15 days between trials: 10?g/kg detomidine in combination with saline (D/SAL, 0.1mg/kg morphine (D/ MORPH or 0.1mg/kg methadone (D/METH. The degree of sedation, response to oral stimuli and cardiopulmonary parameters were monitored for 120 minutes. Parametric data were analyzed using the ANOVA and Tukey’s tests, and non- parametric data were analyzed with the Kruskal-Wallis and Friedman’s tests with the post-Dunn test (P<0.05. The degree of sedation was significantly greater for the D/SAL than for the D/MORPH and D/METH treatments at 30 min. The horses´ responses to the oral stimuli decreased significantly following all treatments at 5 and 30 min from baseline values. The heart rate, respiratory rate, arterial pH and blood gas variables were all similar among the treatment groups. Mean arterial blood pressure was significantly higher in the D/MORPH group when compared with the D/SAL group between 75 and 120 min. It was concluded that all treatments provided sedative effects with mild cardiopulmonary changes. However the addition of morphine or methadone to detomidine did not improve the degree of sedation in horses submitted to experimental oral stimuli.

  20. Reverse of Acute and Chronic Morphine Tolerance by Lithocholic Acid via Down-regulating UGT2B7

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    Zizhao Yang

    2016-11-01

    Full Text Available Lithocholic acid (LCA deposited in human livers always induces drastic pains which need analgesic drug, like morphine to release. Our research showed that LCA can effectively inhibit uridine 5'-diphospho-glucuronosyltransferase 2B7 (UGT2B7 in morphine tolerance-like human normal liver cells, HL-7702, then increase μ-opioid receptor (MOR and calcium-calmodulin dependent protein kinase IIα (CaMKIIα expression. In vivo assay, UGT2B7 was significantly repressed in the livers of acute or chronic morphine tolerance mice pretreated with LCA (10, 50 and 100 mg/kg, p.o.. To investigate the connections between LCA function performance and changes of UGT2B7 enzymatic activity in mice livers, two morphine metabolites, morphine-3-glucuronide (M3G and morphine-6-glucuronide (M6G were quantified by solid phase extraction (SPE-HPLC-MS/MS. The result indicated no matter in acute or chronic morphine tolerance, the concentrations of M3G and M6G were all decreased, the later one fell even more. Besides that, 50mg/kg of LCA administration can prevent auto-phosphorylation of CaMKIIα at Thr286 in acute or chronic morphine tolerance mice prefrontal cortexes (mPFCs due to synthesis increase of cyclic adenosine monophosphate (cAMP. As a consequence, UGT2B7 depression mediated by LCA can affect its selective catalysis ability to morphine, that may be responsible to acute or chronic morphine tolerance alleviation. These findings might assist to modify antinociception of morphine in clinic.

  1. [Effects of morphine on pupillary light reflex in monkeys].

    Science.gov (United States)

    Meng, Zhi-Qiang; Zhang, Yu-Hua; Chen, Nan-Hui; Miao, Ying-Da; Hu, Xin-Tian; Ma, Yuan-Ye

    2010-06-01

    The pupil size of both human and other animals can be affected by light. Many kinds of psychiatrical and psychological disorders, such as drug abuse, associate with abnormal properties of pupillary light reflex. Thus, the properties of pupillary light reflex could serve as an indicator for drug abuse detection. However, the effect of drug abuse on pupillary light reflex is till unclear. To assess the effects of addictive drugs on pupillary light reflex quantificationally, in the present study, we examined the effects of morphine on pupil diameter and pupillary light reflex in rhesus monkeys. By measuring the pupil diameter at different timing points before and after the administration of morphine, we found that morphine administration reduced the diameter of pupil and decreased the constriction rate. Our present results provide an experimental support for applying the properties of pupillary light reflex as a reference in addicts' detection.

  2. Association of contextual cues with morphine reward increases neural and synaptic plasticity in the ventral hippocampus of rats.

    Science.gov (United States)

    Alvandi, Mina Sadighi; Bourmpoula, Maria; Homberg, Judith R; Fathollahi, Yaghoub

    2017-11-01

    Drug addiction is associated with aberrant memory and permanent functional changes in neural circuits. It is known that exposure to drugs like morphine is associated with positive emotional states and reward-related memory. However, the underlying mechanisms in terms of neural plasticity in the ventral hippocampus, a region involved in associative memory and emotional behaviors, are not fully understood. Therefore, we measured adult neurogenesis, dendritic spine density and brain-derived neurotrophic factor (BDNF) and TrkB mRNA expression as parameters for synaptic plasticity in the ventral hippocampus. Male Sprague Dawley rats were subjected to the CPP (conditioned place preference) paradigm and received 10 mg/kg morphine. Half of the rats were used to evaluate neurogenesis by immunohistochemical markers Ki67 and doublecortin (DCX). The other half was used for Golgi staining to measure spine density and real-time quantitative reverse transcription-polymerase chain reaction to assess BDNF/TrkB expression levels. We found that morphine-treated rats exhibited more place conditioning as compared with saline-treated rats and animals that were exposed to the CPP without any injections. Locomotor activity did not change significantly. Morphine-induced CPP significantly increased the number of Ki67 and DCX-labeled cells in the ventral dentate gyrus. Additionally, we found increased dendritic spine density in both CA1 and dentate gyrus and an enhancement of BDNF/TrkB mRNA levels in the whole ventral hippocampus. Ki67, DCX and spine density were significantly correlated with CPP scores. In conclusion, we show that morphine-induced reward-related memory is associated with neural and synaptic plasticity changes in the ventral hippocampus. Such neural changes could underlie context-induced drug relapse. © 2017 Society for the Study of Addiction.

  3. Effect of extradural morphine on somatosensory evoked potentials to dermatomal stimulation

    DEFF Research Database (Denmark)

    Lund, C; Selmar, P; Hansen, O B

    1987-01-01

    The effect of the extradural (L2-3) administration of morphine 6 mg on early (less than 0.5 s) somatosensory evoked cortical potentials (SEP) to electrical stimulation of the L1- and S1-dermatomes was examined in eight patients. Extradural morphine did not influence SEP amplitude. SEP latency did...

  4. Role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat.

    Science.gov (United States)

    Haghparast, Abbas; Soltani-Hekmat, Ava; Khani, Abbas; Komaki, Alireza

    2007-10-29

    Neurons in the nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, project to medullary nucleus raphe magnus (NRM), which is a key medullary relay for descending pain modulation and is critically involved in opioid-induced analgesia. Previous studies have shown that antinociceptive response of CnF-microinjected morphine can be modulated by the specific subtypes of glutamatergic receptors within the CnF. In this study, we evaluated the role of NMDA and kainate/AMPA receptors that are widely distributed within the NRM on morphine-induced antinociception elicited from the CnF. Hundred and five male Wistar rats weighing 250-300 g were used. Morphine (10, 20 and 40 microg) and NMDA receptor antagonist, MK-801 (10 microg) or kainate/AMPA receptor antagonist, DNQX (0.5 microg) in 0.5 microl saline were stereotaxically microinjected into the CnF and NRM, respectively. The latency of tail-flick response was measured at set intervals (2, 7, 12, 17, 22, 27 min after microinjection) by using an automated tail-flick analgesiometer. The results showed that morphine microinjection into the CnF dose-dependently causes increase in tail-flick latency (TFL). MK-801 microinjected into the NRM, just 1 min before morphine injection into the CnF, significantly attenuated antinociceptive effects of morphine. On the other hand, DNQX microinjected into the NRM, significantly increased TFL after local application of morphine into the CnF. We suggest that morphine related antinociceptive effect elicited from the CnF is mediated, in part, by NMDA receptor at the level of the NRM whereas kainite/AMPA receptor has a net inhibitory influence at the same pathway.

  5. Effects of chronic cocaine, morphine and methamphetamine on the mobility, immobility and stereotyped behaviors in crayfish.

    Science.gov (United States)

    Imeh-Nathaniel, Adebobola; Rincon, Natalia; Orfanakos, Vasiliki Bessie; Brechtel, Leanne; Wormack, Leah; Richardson, Erika; Huber, Robert; Nathaniel, Thomas I

    2017-08-14

    The worth of crayfish as a model system for studies of addiction was not previously recognized because a drug-reward phenomenon had not been documented in this model system. In our previous experiments, we demonstrate that the crayfish natural reward pathways are sensitive to human drugs of abuse. This finding supports crayfish as a suitable model to characterize specific behaviors that are relevant in drug addiction research, and the current study builds on our previous findings. The aim of the present study was to investigate unconditioned neurobehavioral effects of repeated treatment regimens using cocaine, morphine, and methamphetamine for three consecutive days. We analyzed mobility, immobility and characterized stereotypic behaviors following intracardial infusions of 2.0μg/g or 10.0μg/g doses of cocaine, morphine, and methamphetamine for three days. The results showed that systemic cocaine, morphine, and methamphetamine increased mobility at a low dose of 2.0μg/g more effectively than a high dose of 10.0μg/g, while simultaneously showing that the high dose exerted a more prominent effect in increasing immobility. Moreover, systemic cocaine, morphine, and methamphetamine injections have discerning effects towards a group of defined unconditioned stereotyped behavioral patterns associated with each drug, rather than a shared universal behavioral effect. These findings provide insight into the behavioral and pharmacological basis responsible for the unconditioned effects of these drugs in crayfish. Copyright © 2017. Published by Elsevier B.V.

  6. Dentate gyrus neurogenesis ablation via cranial irradiation enhances morphine self-administration and locomotor sensitization.

    Science.gov (United States)

    Bulin, Sarah E; Mendoza, Matthew L; Richardson, Devon R; Song, Kwang H; Solberg, Timothy D; Yun, Sanghee; Eisch, Amelia J

    2018-03-01

    Adult dentate gyrus (DG) neurogenesis is important for hippocampal-dependent learning and memory, but the role of new neurons in addiction-relevant learning and memory is unclear. To test the hypothesis that neurogenesis is involved in the vulnerability to morphine addiction, we ablated adult DG neurogenesis and examined morphine self-administration (MSA) and locomotor sensitization. Male Sprague-Dawley rats underwent hippocampal-focused, image-guided X-ray irradiation (IRR) to eliminate new DG neurons or sham treatment (Sham). Six weeks later, rats underwent either MSA (Sham = 16, IRR = 15) or locomotor sensitization (Sham = 12, IRR = 12). Over 21 days of MSA, IRR rats self-administered ~70 percent more morphine than Sham rats. After 28 days of withdrawal, IRR rats pressed the active lever 40 percent more than Sham during extinction. This was not a general enhancement of learning or locomotion, as IRR and Sham groups had similar operant learning and inactive lever presses. For locomotor sensitization, both IRR and Sham rats sensitized, but IRR rats sensitized faster and to a greater extent. Furthermore, dose-response revealed that IRR rats were more sensitive at a lower dose. Importantly, these increases in locomotor activity were not apparent after acute morphine administration and were not a byproduct of irradiation or post-irradiation recovery time. Therefore, these data, along with other previously published data, indicate that reduced hippocampal neurogenesis confers vulnerability for multiple classes of drugs. Thus, therapeutics to specifically increase or stabilize hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse. © 2017 Society for the Study of Addiction.

  7. Epidural morphine and detomidine decreases postoperative hindlimb lameness in horses after bilateral stifle arthroscopy.

    Science.gov (United States)

    Goodrich, Laurie R; Nixon, Alan J; Fubini, Susan L; Ducharme, Norm G; Fortier, Lisa A; Warnick, Lorin D; Ludders, John W

    2002-01-01

    To determine whether preoperative epidural administration of morphine and detomidine would decrease postoperative lameness after bilateral stifle arthroscopy in horses. Prospective clinical controlled study. Eight adult horses that had bilateral arthroscopic procedures, including drilling of cartilage and subchondral bone within the femoropatellar joints. Horses were randomly separated into 2 groups. Preoperatively, 4 horses were administered a combination of epidural morphine (0.2 mg/kg) and detomidine (30 microg/kg), and 4 horses were administered an equivalent volume of epidural saline (0.9% NaCl) solution. Postoperative pain was assessed using 6 video recordings made at hourly intervals of each horse at a walk. Assessments began 1 hour after recovery from anesthesia. The recordings were scrambled out of sequence and evaluated by 3 observers, unaware of treatment groups, who scored lameness from 0 to 4. Lameness scores of the 2 groups of horses were compared using a Wilcoxon's rank sum test. Heart and respiratory rates were also measured at each hourly interval and compared between groups using a repeated-measures ANOVA; statistical significance was set at P detomidine significantly decreased lameness and heart rates after bilateral stifle arthroscopy. The greatest decrease was detected at hours 1 and 2 after recovery from anesthesia. We conclude that horses undergoing a painful arthroscopic procedure of the stifle joint benefit from the administration of preoperative epidural morphine and detomidine. Preoperative epidural administration of detomidine and morphine may be useful in decreasing postoperative pain after stifle arthroscopy as well as pain associated with other painful disorders involving the stifle joint, such as septic arthritis and trauma. Copyright 2002 by The American College of Veterinary Surgeons

  8. α-Terpineol attenuates morphine-induced physical dependence and tolerance in mice: role of nitric oxide.

    Science.gov (United States)

    Parvardeh, Siavash; Moghimi, Mahsa; Eslami, Pegah; Masoudi, Alireza

    2016-02-01

    Dependence and tolerance to opioid analgesics are major problems limiting their clinical application. α-Terpineol is a monoterpenoid alcohol with neuroprotective effects which is found in several medicinal plants such as Myrtus communis, Laurus nobilis, and Stachys byzantina. It has been shown that some of these medicinal plants such as S. byzantina attenuate dependence and tolerance to morphine. Since α-terpineol is one of the bioactive phytochemical constituent of these medicinal plants, the present study was conducted to investigate the effects of α-terpineol on morphine-induced dependence and tolerance in mice. The mice were rendered dependent or tolerant to morphine by a 3-day administration schedule. The hot-plate test and naloxone-induced withdrawal syndrome were used to evaluate tolerance and dependence on morphine, respectively. To investigate a possible role for nitric oxide (NO) in the protective effect of α-terpineol, the NO synthase inhibitor, L-N(G)-nitroarginine methyl ester (L-NAME) and NO precursor, L-arginine, were used. Administration of α-terpineol (5, 10, and 20 mg/kg, IP) significantly decreased the number of jumps in morphine dependent animals. Moreover, α-terpineol (20 and 40 mg/kg, IP) attenuated tolerance to the analgesic effect of morphine. The inhibitory effects of α-terpineol on morphine-induced dependence and tolerance were enhanced by pretreatment with L-NAME (10 mg/kg, IP). However, L-arginine (300 mg/kg, IP) antagonized the protective effects of α-terpineol on dependence and tolerance to morphine. These findings indicate that α-terpineol prevents the development of dependence and tolerance to morphine probably through the influence on NO production.

  9. Morphine administration during low ovarian hormone stage results in transient over expression of fear memories in females

    Directory of Open Access Journals (Sweden)

    Emily M Perez-Torres

    2015-05-01

    Full Text Available Acute exposure to morphine after a traumatic event reduces trauma related symptoms in humans and conditioned fear expression in male rats. We aimed to determine whether acute administration of morphine alters consolidation of fear learning and extinction. Male and female rats in proestrus and metaestrus (high and low ovarian hormones respectively underwent fear conditioning and received saline or morphine (2.5 mg/kg s.c.. The next day they underwent extinction. Results showed increased freezing during extinction only in the morphine metaestrus group while morphine did not affect males or proestrus females. Recall of extinction was similar on all groups. On a second experiment, a subset of rats conditioned during metaestrus was administered morphine prior to extinction producing no effects. We then measured mu opioid receptor (MOR expression in the amygdala and periaqueductal gray (PAG at the end of extinction (day 2. In males and proestrus females, morphine caused an increase in MOR in the amygdala but no in the PAG. In metaestrus females, morphine did not change MOR expression in either structure. These data suggests that ovarian hormones may interact with MORs in the amygdala to transiently alter memory consolidation. Morphine given after trauma to females with low ovarian hormones might increase the recall of fear responses, making recovery harder.

  10. Picomolar concentrations of morphine in human urine determined by dansyl derivatization and liquid chromatography-mass spectrometry.

    Science.gov (United States)

    Lamshöft, Marc; Grobe, Nadja; Spiteller, Michael

    2011-04-15

    Morphine is present in varying amounts as an endogenous product in human urine. Derivatization of morphine contained in urine with dansyl chloride yields a known product, which can be quantified by liquid chromatography mass spectrometry with high selectivity and sensitivity. Urine samples of 51 healthy individuals were spiked with stable-isotope labeled morphine, hydrolyzed and subjected to solid phase extraction followed by derivatization of morphine with dansyl chloride. The dansyl derivatives of naturally occurring morphine and deuterated internal standard were then detected by liquid chromatography-triple quadrupole mass spectrometry. Using the [N-CD(3)]-labeled internal standard and solid-phase extraction, a limit of detection of 35 fmol/ml (10 pg/ml) and a limit of quantification of 87.5 fmol/ml (25 pg/ml) was determined for morphine in human urine. This new LC-MS/MS method allowed the detection of endogenous morphine in human urine of 51 volunteers with an average value of 156.4 fmol/ml (44.7 ng/ml). Copyright © 2011 Elsevier B.V. All rights reserved.

  11. PolyMorphine provides extended analgesic-like effects in mice with spared nerve injury

    OpenAIRE

    Lax, Neil C; Chen, Renxun; Leep, Sarah R; Uhrich, Kathryn E; Yu, Lei; Kolber, Benedict J

    2017-01-01

    Morphine is a well-characterized and effective analgesic commonly used to provide pain relief to patients suffering from both acute and chronic pain conditions. Despite its widespread use and effectiveness, one of the major drawbacks of morphine is its relatively short half-life of approximately 4 h. This short half-life often necessitates multiple administrations of the drug each day, which may contribute to both dependence and tolerance to morphine. Here, we tested the analgesic properties ...

  12. Microwave-Assisted Alkali Pre-Treatment, Densification and Enzymatic Saccharification of Canola Straw and Oat Hull.

    Science.gov (United States)

    Agu, Obiora S; Tabil, Lope G; Dumonceaux, Tim

    2017-03-26

    The effects of microwave-assisted alkali pre-treatment on pellets' characteristics and enzymatic saccharification for bioethanol production using lignocellulosic biomass of canola straw and oat hull were investigated. The ground canola straw and oat hull were immersed in distilled water, sodium hydroxide and potassium hydroxide solutions at two concentrations (0.75% and 1.5% w/v) and exposed to microwave radiation at power level 713 W and three residence times (6, 12 and 18 min). Bulk and particle densities of ground biomass samples were determined. Alkaline-microwave pre-treated and untreated samples were subjected to single pelleting test in an Instron universal machine, pre-set to a load of 4000 N. The measured parameters, pellet density, tensile strength and dimensional stability were evaluated and the results showed that the microwave-assisted alkali pre-treated pellets had a significantly higher density and tensile strength compared to samples that were untreated or pre-treated by microwave alone. The chemical composition analysis showed that microwave-assisted alkali pre-treatment was able to disrupt and break down the lignocellulosic structure of the samples, creating an area of cellulose accessible to cellulase reactivity. The best enzymatic saccharification results gave a high glucose yield of 110.05 mg/g dry sample for canola straw ground in a 1.6 mm screen hammer mill and pre-treated with 1.5% NaOH for 18 min, and a 99.10 mg/g dry sample for oat hull ground in a 1.6 mm screen hammer mill and pre-treated with 0.75% NaOH for 18 min microwave-assisted alkali pre-treatments. The effects of pre-treatment results were supported by SEM analysis. Overall, it was found that microwave-assisted alkali pre-treatment of canola straw and oat hull at a short residence time enhanced glucose yield.

  13. "Interaction of different doses of Aspartame with Morphine-induced antinociception in the presence of MK-801, a NMDA antagonist "

    Directory of Open Access Journals (Sweden)

    Abdollahi M

    2002-07-01

    Full Text Available This study was designed to investigate the relative role of sweetness and comparative effects of different taste sensation of the non - caloric sweetener , aspartame on pain and its interaction with MK - 80] as a non - selective MMDA antagonist by formalin - test in mice. The formalin - test was chosen because it measures the response to a long - lasting nociceptive stimulus and closely resembles to the clinical pain. Morphine induced a dose dependent antinociception in the early and late phases of formalin test. Twelve days pretreatment of animals by aspartame ( 0.08% , 0.16% , 0.32% significantly potentiated morphine - induced (1.5-9 mg/kg analgesia in the early phase but significantly antagonized its analgesic effect in the late phase, dose dependently. Aspartame (0.16% alone showed a reduction in pain response . Naloxone (0.4 mg/kg significantly antagonized the antinociceptive effect of morphine in the presence of aspartame (0-0.32% in the early phase. Increasing the dose of aspartame decreased effects of naloxone. MK-801 (0.1 mg/kg as an N- Methyl - D - Aspartate (NMDA antagonist significantly potentiated the effect of aspartame on morphine - induced antinociception in the early phase. In the late phase, naloxone (0.4 mg/kg increased pain response but MK- 801 (0.1 mg/kg induced anti-inflammatory effect significantly. Treatment of animals with MK- 801 alone, significantly induced analgesia in both phases of formalin - test. This effect was potentiated with aspartame dose - dependently. Possible interaction of aspartame with NMDA receptors and its role to facilitate endogenous opioid system are proposed mechanisms of aspartame in modulating morphine - induced antinociception. Furthermore, the resulting association between morphine and aspartame chronic consumption may be explained as an interactive action rather than simple dose combination of both drugs.

  14. Recommended use of morphine in neonates, infants and children based on a literature review

    DEFF Research Database (Denmark)

    Kart, T; Christrup, Lona Louring; Rasmussen, M

    1997-01-01

    The English language literature has been reviewed in order to evaluate the present knowledge on morphine's metabolism and pharmacokinetics in children. The majority of preterm neonates are capable of glucuronidating morphine, but birth weight; gestational and postnatal age influence the glucuroni......The English language literature has been reviewed in order to evaluate the present knowledge on morphine's metabolism and pharmacokinetics in children. The majority of preterm neonates are capable of glucuronidating morphine, but birth weight; gestational and postnatal age influence...... in term neonates aged 0-57 days, and 23.6 +/- 8.5 ml.min-1.kg-1 in infants and children more than 11 days old....

  15. Methyl Parathion Masks Withdrawal from Physical Dependence on Morphine

    OpenAIRE

    Zhu, Hong; Ho, Ing K.; Kramer, Robert E.; Baker, Rodney C.; Rockhold, Robin W.

    2002-01-01

    Abstract: The cholinergic system has been proposed to participate in the development of dependence on opioids. The present study examined effects of dermal pretreatment with methyl parathion (MP), an acetylcholinesterase inhibitor, on the development of physical dependence on morphine. Opioid dependence was induced by continuous intracerebroventricular (i.c.v.) infusion of morphine (26 nmol/μl/h) for 3 days in adult male Sprague-Dawley rats. Each rat received two doses of MP, 12.5 mg/kg, d...

  16. Surface pre-treatment for barrier coatings on polyethylene terephthalate

    Science.gov (United States)

    Bahre, H.; Bahroun, K.; Behm, H.; Steves, S.; Awakowicz, P.; Böke, M.; Hopmann, Ch; Winter, J.

    2013-02-01

    Polymers have favourable properties such as light weight, flexibility and transparency. Consequently, this makes them suitable for food packaging, organic light-emitting diodes and flexible solar cells. Nonetheless, raw plastics do not possess sufficient barrier functionality against oxygen and water vapour, which is of paramount importance for most applications. A widespread solution is to deposit thin silicon oxide layers using plasma processes. However, silicon oxide layers do not always fulfil the requirements concerning adhesion and barrier performance when deposited on films. Thus, plasma pre-treatment is often necessary. To analyse the influence of a plasma-based pre-treatment on barrier performance, different plasma pre-treatments on three reactor setups were applied to a very smooth polyethylene terephthalate film before depositing a silicon oxide barrier layer. In this paper, the influence of oxygen and argon plasma pre-treatments towards the barrier performance is discussed examining the chemical and topological change of the film. It was observed that a short one-to-ten-second plasma treatment can reduce the oxygen transmission rate by a factor of five. The surface chemistry and the surface topography change significantly for these short treatment times, leading to an increased surface energy. The surface roughness rises slowly due to the development of small spots in the nanometre range. For very long treatment times, surface roughness of the order of the barrier layer's thickness results in a complete loss of barrier properties. During plasma pre-treatment, the trade-off between surface activation and roughening of the surface has to be carefully considered.

  17. Surface pre-treatment for barrier coatings on polyethylene terephthalate

    International Nuclear Information System (INIS)

    Bahre, H; Böke, M; Winter, J; Bahroun, K; Behm, H; Hopmann, Ch; Steves, S; Awakowicz, P

    2013-01-01

    Polymers have favourable properties such as light weight, flexibility and transparency. Consequently, this makes them suitable for food packaging, organic light-emitting diodes and flexible solar cells. Nonetheless, raw plastics do not possess sufficient barrier functionality against oxygen and water vapour, which is of paramount importance for most applications. A widespread solution is to deposit thin silicon oxide layers using plasma processes. However, silicon oxide layers do not always fulfil the requirements concerning adhesion and barrier performance when deposited on films. Thus, plasma pre-treatment is often necessary. To analyse the influence of a plasma-based pre-treatment on barrier performance, different plasma pre-treatments on three reactor setups were applied to a very smooth polyethylene terephthalate film before depositing a silicon oxide barrier layer. In this paper, the influence of oxygen and argon plasma pre-treatments towards the barrier performance is discussed examining the chemical and topological change of the film. It was observed that a short one-to-ten-second plasma treatment can reduce the oxygen transmission rate by a factor of five. The surface chemistry and the surface topography change significantly for these short treatment times, leading to an increased surface energy. The surface roughness rises slowly due to the development of small spots in the nanometre range. For very long treatment times, surface roughness of the order of the barrier layer's thickness results in a complete loss of barrier properties. During plasma pre-treatment, the trade-off between surface activation and roughening of the surface has to be carefully considered. (paper)

  18. Spinal cord thyrotropin releasing hormone receptors of morphine tolerant-dependent and abstinent rats

    Energy Technology Data Exchange (ETDEWEB)

    Rahmani, N.H.; Gulati, A.; Bhargava, H.N. (Univ. of Illinois, Chicago (USA))

    1990-07-01

    The effect of chronic administration of morphine and its withdrawal on the binding of 3H-(3-MeHis2)thyrotropin releasing hormone (3H-MeTRH) to membranes of the spinal cord of the rat was determined. Male Sprague-Dawley rats were implanted with either 6 placebo or 6 morphine pellets (each containing 75-mg morphine base) during a 7-day period. Two sets of animals were used. In one, the pellets were left intact at the time of sacrificing (tolerant-dependent) and in the other, the pellets were removed 16 hours prior to sacrificing (abstinent rats). In placebo-pellet-implanted rats, 3H-MeTRH bound to the spinal cord membranes at a single high affinity binding site with a Bmax of 21.3 +/- 1.6 fmol/mg protein, and an apparent dissociation constant Kd of 4.7 +/- 0.8 nM. In morphine tolerant-dependent or abstinent rats, the binding constants of 3H-MeTRH to spinal cord membranes were unaffected. Previous studies from this laboratory indicate that TRH can inhibit morphine tolerance-dependence and abstinence processes without modifying brain TRH receptors. Together with the present results, it appears that the inhibitory effect of TRH on morphine tolerance-dependence and abstinence is probably not mediated via central TRH receptors but may be due to its interaction with other neurotransmitter systems.

  19. Analgesic efficacy of butorphanol and morphine in bearded dragons and corn snakes.

    Science.gov (United States)

    Sladky, Kurt K; Kinney, Matthew E; Johnson, Stephen M

    2008-07-15

    To test the hypothesis that administration of butorphanol or morphine induces antinociception in bearded dragons and corn snakes. Prospective crossover study. 12 juvenile and adult bearded dragons and 13 corn snakes. Infrared heat stimuli were applied to the plantar surface of bearded dragon hind limbs or the ventral surface of corn snake tails. Thermal withdrawal latencies (TWDLs) were measured before (baseline) and after SC administration of physiologic saline (0.9% NaCl) solution (equivalent volume to opioid volumes), butorphanol tartrate (2 or 20 mg/kg [0.91 or 9.1 mg/lb]), or morphine sulfate (1, 5, 10, 20, or 40 mg/kg [0.45, 2.27, 4.5, 9.1, or 18.2 mg/lb]). For bearded dragons, butorphanol (2 or 20 mg/kg) did not alter hind limb TWDLs at 2 to 24 hours after administration. However, at 8 hours after administration, morphine (10 and 20 mg/kg) significantly increased hind limb TWDLs from baseline values (mean +/- SEM maximum increase, 2.7+/-0.4 seconds and 2.8+/-0.9 seconds, respectively). For corn snakes, butorphanol (20 mg/kg) significantly increased tail TWDLs at 8 hours after administration (maximum increase from baseline value, 3.0+/-0.8 seconds); the low dose had no effect. Morphine injections did not increase tail TWDLs at 2 to 24 hours after administration. Compared with doses used in most mammalian species, high doses of morphine (but not butorphanol) induced analgesia in bearded dragons, whereas high doses of butorphanol (but not morphine) induced analgesia in corn snakes.

  20. [Morphine self-administration by rats using a pneumatic syringe].

    Science.gov (United States)

    Akiyama, Y; Takayama, S

    1988-06-01

    An apparatus for drug self-administration by rats using a pneumatic syringe was developed by Weeks. A microliter syringe operated by a pneumatic cylinder supplies an accurate volume of drug solution within one second. When coefficient of variation of infusion volume was compared among pneumatic syringe, infusion pump, and peristaltic pump, pneumatic syringe showed higher accuracy in infusion volume than the other two pumps. Since the infusion speed by a pneumatic syringe is very rapid (less than one second per infusion), the effect of infusion speed on reinforcing property of morphine was investigated. When rats self-administered 0.1, 0.3, 1.0, and 3.0 mg/kg/infusion of morphine by pneumatic syringes, the patterns of self-infusion were more stable, the number of self-infusions and the amount self-administered were larger, and a dose-response relationship was clearer in comparison with those self-infused the same doses of morphine for 5.6 seconds by infusion pumps or peristaltic pumps.

  1. Quaternary naltrexone reverses radiogenic and morphine-induced locomotor hyperactivity

    Energy Technology Data Exchange (ETDEWEB)

    Mickley, G.A.; Stevens, K.E.; Galbraith, J.A.; White, G.A.; Gibbs, G.L.

    1984-04-01

    The present study attempted to determine the relative role of the peripheral and central nervous system in the production of morphine-induced or radiation-induced locomotor hyperactivity of the mouse. Toward this end, we used a quaternary derivative of an opiate antagonist (naltrexone methobromide), which presumably does not cross the blood-brain barrier. Quaternary naltrexone was used to challenge the stereotypic locomotor response observed in these mice after either an i.p. injection of morphine or exposure to 1500 rads /sup 60/Co. The quaternary derivative of naltrexone reversed the locomotor hyperactivity normally observed in the C57BL/6J mouse after an injection of morphine. It also significantly attenuated radiation-induced locomotion. The data reported here support the hypothesis of endorphin involvement in radiation-induced and radiogenic behaviors. However, these conclusions are contingent upon further research which more fully evaluates naltrexone methobromide's capacity to cross the blood-brain barrier.

  2. Mechanism of waste biomass pyrolysis: Effect of physical and chemical pre-treatments

    International Nuclear Information System (INIS)

    Das, Oisik; Sarmah, Ajit K.

    2015-01-01

    To impart usability in waste based biomass through thermo-chemical reactions, several physical and chemical pre-treatments were conducted to gain an insight on their mode of action, effect on the chemistry and the change in thermal degradation profiles. Two different waste biomasses (Douglas fir, a softwood and hybrid poplar, a hardwood) were subjected to four different pre-treatments, namely, hot water pre-treatment, torrefaction, acid (sulphuric acid) and salt (ammonium phosphate) doping. Post pre-treatments, the changes in the biomass structure, chemistry, and thermal makeup were studied through electron microscopy, atomic absorption/ultra violet spectroscopy, ion exchange chromatography, and thermogravimetry. The pre-treatments significantly reduced the amounts of inorganic ash, extractives, metals, and hemicellulose from both the biomass samples. Furthermore, hot water and torrefaction pre-treatment caused mechanical disruption in biomass fibres leading to smaller particle sizes. Torrefaction of Douglas fir wood yielded more solid product than hybrid poplar. Finally, the salt pre-treatment increased the activation energies of the biomass samples (especially Douglas fir) to a great extent. Thus, salt pre-treatment was found to bestow thermal stability in the biomass. - Highlights: • Pre-treatments reduce ash, extractives, alkalines and hemicellulose from biomass. • Torrefaction of Douglas fir yields more solid product than hybrid poplar. • Salt pretreatment significantly increases the activation energy of biomass. • Acid and salt pretreatment bestows thermal stability in biomass.

  3. Mechanism of waste biomass pyrolysis: Effect of physical and chemical pre-treatments

    Energy Technology Data Exchange (ETDEWEB)

    Das, Oisik [Department of Biological Systems Engineering, Washington State University, Pullman 99164-6120, WA (United States); Department of Civil and Environmental Engineering, University of Auckland, Auckland 1142 (New Zealand); Sarmah, Ajit K., E-mail: a.sarmah@auckland.ac.nz [Department of Civil and Environmental Engineering, University of Auckland, Auckland 1142 (New Zealand)

    2015-12-15

    To impart usability in waste based biomass through thermo-chemical reactions, several physical and chemical pre-treatments were conducted to gain an insight on their mode of action, effect on the chemistry and the change in thermal degradation profiles. Two different waste biomasses (Douglas fir, a softwood and hybrid poplar, a hardwood) were subjected to four different pre-treatments, namely, hot water pre-treatment, torrefaction, acid (sulphuric acid) and salt (ammonium phosphate) doping. Post pre-treatments, the changes in the biomass structure, chemistry, and thermal makeup were studied through electron microscopy, atomic absorption/ultra violet spectroscopy, ion exchange chromatography, and thermogravimetry. The pre-treatments significantly reduced the amounts of inorganic ash, extractives, metals, and hemicellulose from both the biomass samples. Furthermore, hot water and torrefaction pre-treatment caused mechanical disruption in biomass fibres leading to smaller particle sizes. Torrefaction of Douglas fir wood yielded more solid product than hybrid poplar. Finally, the salt pre-treatment increased the activation energies of the biomass samples (especially Douglas fir) to a great extent. Thus, salt pre-treatment was found to bestow thermal stability in the biomass. - Highlights: • Pre-treatments reduce ash, extractives, alkalines and hemicellulose from biomass. • Torrefaction of Douglas fir yields more solid product than hybrid poplar. • Salt pretreatment significantly increases the activation energy of biomass. • Acid and salt pretreatment bestows thermal stability in biomass.

  4. Functionally Selective Signaling for Morphine and Fentanyl Antinociception and Tolerance Mediated by the Rat Periaqueductal Gray

    Science.gov (United States)

    Morgan, Michael M.; Reid, Rachel A.; Saville, Kimber A.

    2014-01-01

    Functionally selective signaling appears to contribute to the variability in mechanisms that underlie tolerance to the antinociceptive effects of opioids. The present study tested this hypothesis by examining the contribution of G protein-coupled receptor kinase (GRK)/Protein kinase C (PKC) and C-Jun N-terminal kinase (JNK) activation on both the expression and development of tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray of the rat. Microinjection of morphine or fentanyl into the periaqueductal gray produced a dose-dependent increase in hot plate latency. Microinjection of the non-specific GRK/PKC inhibitor Ro 32-0432 into the periaqueductal gray to block mu-opioid receptor phosphorylation enhanced the antinociceptive effect of morphine but had no effect on fentanyl antinociception. Microinjection of the JNK inhibitor SP600125 had no effect on morphine or fentanyl antinociception, but blocked the expression of tolerance to repeated morphine microinjections. In contrast, a microinjection of Ro 32-0432 blocked the expression of fentanyl, but not morphine tolerance. Repeated microinjections of Ro 32-0432 blocked the development of morphine tolerance and inhibited fentanyl antinociception whether rats were tolerant or not. Repeated microinjections of SP600125 into the periaqueductal gray blocked the development of tolerance to both morphine and fentanyl microinjections. These data demonstrate that the signaling molecules that contribute to tolerance vary depending on the opioid and methodology used to assess tolerance (expression vs. development of tolerance). This signaling difference is especially clear for the expression of tolerance in which JNK contributes to morphine tolerance and GRK/PKC contributes to fentanyl tolerance. PMID:25503060

  5. Comparative Study of Pre-Germination Treatments and their Effects ...

    African Journals Online (AJOL)

    FIRST LADY

    of leaves (10.05) respectively. Pre-germination treatments of seeds soaked in running water (SRW) for 24 hours were found to be more effective in seedlings growth and biomass production. Keywords: Tectona grandis, pre-germination treatment, seed dormancy, seedling growth. Introduction. Tectona grandis is one of the ...

  6. Pre-1989 epidemiological surveys of low-level dose pre-conception irradiation

    International Nuclear Information System (INIS)

    Rose, K.S.B.

    1990-01-01

    Information from 59 pre-1989 epidemiological surveys concerning pre-conception irradiation at doses less than 0.1 Gy has been collated to determine whether any consistent patterns of health effects emerge. The surveys are considered in three groups: childhood malignancies, Down's syndrome and indicators of reproductive damage. Although a pattern is observed for Down's syndrome, no reliable associations are apparent for childhood malignancies (where all surveys pre-date the Gardner survey at Sellafield) or indications of reproductive damage. The twelve surveys of Down's syndrome in relation to maternal pre-conception irradiation received for medical reasons show a pattern consistent with a doubling dose of about 20 mGy. This doubling dose value is, however, not based on individual measurements of ovarian dose and is inconsistent with results from high-level dose surveys. There is no association between paternal irradiation and Down's syndrome. (author)

  7. Predicting Neuroinflammation in Morphine Tolerance for Tolerance Therapy from Immunostaining Images of Rat Spinal Cord.

    Directory of Open Access Journals (Sweden)

    Shinn-Long Lin

    Full Text Available Long-term morphine treatment leads to tolerance which attenuates analgesic effect and hampers clinical utilization. Recent studies have sought to reveal the mechanism of opioid receptors and neuroinflammation by observing morphological changes of cells in the rat spinal cord. This work proposes a high-content screening (HCS based computational method, HCS-Morph, for predicting neuroinflammation in morphine tolerance to facilitate the development of tolerance therapy using immunostaining images for astrocytes, microglia, and neurons in the spinal cord. HCS-Morph first extracts numerous HCS-based features of cellular phenotypes. Next, an inheritable bi-objective genetic algorithm is used to identify a minimal set of features by maximizing the prediction accuracy of neuroinflammation. Finally, a mathematic model using a support vector machine with the identified features is established to predict drug-treated images to assess the effects of tolerance therapy. The dataset consists of 15 saline controls (1 μl/h, 15 morphine-tolerant rats (15 μg/h, and 10 rats receiving a co-infusion of morphine (15 μg/h and gabapentin (15 μg/h, Sigma. The three individual models of astrocytes, microglia, and neurons for predicting neuroinflammation yielded respective Jackknife test accuracies of 96.67%, 90.00%, and 86.67% on the 30 rats, and respective independent test accuracies of 100%, 90%, and 60% on the 10 co-infused rats. The experimental results suggest that neuroinflammation activity expresses more predominantly in astrocytes and microglia than in neuron cells. The set of features for predicting neuroinflammation from images of astrocytes comprises mean cell intensity, total cell area, and second-order geometric moment (relating to cell distribution, relevant to cell communication, cell extension, and cell migration, respectively. The present investigation provides the first evidence for the role of gabapentin in the attenuation of morphine tolerance from

  8. Methyl Parathion Masks Withdrawal from Physical Dependence on Morphine

    Directory of Open Access Journals (Sweden)

    Robin W. Rockhold

    2002-10-01

    Full Text Available Abstract: The cholinergic system has been proposed to participate in the development of dependence on opioids. The present study examined effects of dermal pretreatment with methyl parathion (MP, an acetylcholinesterase inhibitor, on the development of physical dependence on morphine. Opioid dependence was induced by continuous intracerebroventricular (i.c.v. infusion of morphine (26 nmol/μl/h for 3 days in adult male Sprague-Dawley rats. Each rat received two doses of MP, 12.5 mg/kg, dermally, initially, 3 days prior to initiation of i.c.v. morphine infusion and again on the first day of infusion. Withdrawal was precipitated after 3 days of infusion by administering an opioid antagonist, naloxone (48 nmol/5 μl, i.c.v.. Twelve of 23 MP-treated rats exhibited signs of acetylcholinesterase inhibitor intoxication (mild tremors and showed reduced spontaneous locomotor activity (tested by an open field test, prior to naloxone. The brain cholinesterase activity in these 12 rats was 13% of levels in control rats. Eleven rats that did not show toxic signs, exhibited cholinesterase activities that were 20% of control (not significant versus toxic group. The group that showed signs of MP intoxication exhibited a significantly lower incidence of opioid withdrawal jumping, rearing and wet dog shakes compared with the non-toxic group. No differences between quantal withdrawal signs (ptosis, penis-licking, and vocalization were noted between the two groups. The results suggest that toxic inhibition of acetylcholinesterase non-specifically reduces locomotor activity and may obscure certain behavioral signs of withdrawal from opioid dependence. This indicates that caution should be used in interpreting a direct involvement of acetylcholinesterase inhibition in preventing opioid dependence.

  9. Rescue pre-operative treatment with Lugol's solution in uncontrolled Graves' disease.

    Science.gov (United States)

    Calissendorff, Jan; Falhammar, Henrik

    2017-05-01

    Graves' disease is a common cause of hyperthyroidism. Three therapies have been used for decades: pharmacologic therapy, surgery and radioiodine. In case of adverse events, especially agranulocytosis or hepatotoxicity, pre-treatment with Lugol's solution containing iodine/potassium iodide to induce euthyroidism before surgery could be advocated, but this has rarely been reported. All patients hospitalised due to uncontrolled hyperthyroidism at the Karolinska University Hospital 2005-2015 and treated with Lugol's solution were included. All electronic files were carefully reviewed manually, with focus on the cause of treatment and admission, demographic data, and effects of iodine on thyroid hormone levels and pulse frequency. Twenty-seven patients were included. Lugol's solution had been chosen due to agranulocytosis in 9 (33%), hepatotoxicity in 2 (7%), other side effects in 11 (41%) and poor adherence to medication in 5 (19%). Levels of free T4, free T3 and heart rate decreased significantly after 5-9 days of iodine therapy (free T4 53-20 pmol/L, P  = 0.0002; free T3 20-6.5 pmol/L, P  = 0.04; heart rate 87-76 beats/min P  = 0.0007), whereas TSH remained unchanged. Side effects were noted in 4 (15%) (rash n  = 2, rash and vomiting n  = 1, swelling of fingers n  = 1). Thyroidectomy was performed in 26 patients (96%) and one was treated with radioiodine; all treatments were without serious complications. Treatment of uncontrolled hyperthyroidism with Lugol's solution before definitive treatment is safe and it decreases thyroid hormone levels and heart rate. Side effects were limited. Lugol's solution could be recommended pre-operatively in Graves' disease with failed medical treatment, especially if side effects to anti-thyroid drugs have occurred. © 2017 The authors.

  10. The Neurodevelopmental Impact of Neonatal Morphine Administration

    Directory of Open Access Journals (Sweden)

    Stephanie Attarian

    2014-04-01

    Full Text Available Medical management of newborn infants often necessitates recurrent painful procedures, which may alter nociceptive pathways during a critical developmental period and adversely effect neuropsychological outcomes. To mitigate the effects of repeated painful stimuli, opioid administration for peri-procedural analgesia and ICU (intensive care unit sedation is common in the NICU (neonatal intensive care unit. A growing body of basic and animal evidence suggests potential long-term harm associated with neonatal opioid therapy. Morphine increases apoptosis in human microglial cells, and animal studies demonstrate long-term changes in behavior, brain function, and spatial recognition memory following morphine exposure. This comprehensive review examines existing preclinical and clinical evidence on the long-term impacts of neonatal pain and opioid therapy.

  11. Locomotor activity: A distinctive index in morphine self-administration in rats

    OpenAIRE

    Zhang, Jian-Jun; Kong, Qingyao

    2017-01-01

    Self-administration of addictive drugs is a widely used tool for studying behavioral, neurobiological, and genetic factors in addiction. However, how locomotor activity is affected during self-administration of addictive drugs has not been extensively studied. In our present study, we tested the locomotor activity levels during acquisition, extinction and reinstatement of morphine self-administration in rats. We found that compared with saline self-administration (SA), rats that trained with ...

  12. Distinct expression of synaptic NR2A and NR2B in the central nervous system and impaired morphine tolerance and physical dependence in mice deficient in postsynaptic density-93 protein

    Directory of Open Access Journals (Sweden)

    Johns Roger A

    2008-10-01

    Full Text Available Abstract Postsynaptic density (PSD-93, a neuronal scaffolding protein, binds to and clusters N-methyl-D-aspartate receptor (NMDAR subunits NR2A and NR2B at cellular membranes in vitro. However, the roles of PSD-93 in synaptic NR2A and NR2B targeting in the central nervous system and NMDAR-dependent physiologic and pathologic processes are still unclear. We report here that PSD-93 deficiency significantly decreased the amount of NR2A and NR2B in the synaptosomal membrane fractions derived from spinal cord dorsal horn and forebrain cortex but did not change their levels in the total soluble fraction from either region. However, PSD-93 deficiency did not markedly change the amounts of NR2A and NR2B in either synaptosomal or total soluble fractions from cerebellum. In mice deficient in PSD-93, morphine dose-dependent curve failed to shift significantly rightward as it did in wild type (WT mice after acute and chronic morphine challenge. Unlike WT mice, PSD-93 knockout mice also showed marked losses of NMDAR-dependent morphine analgesic tolerance and associated abnormal sensitivity in response to mechanical, noxious thermal, and formalin-induced inflammatory stimuli after repeated morphine injection. In addition, PSD-93 knockout mice displayed dramatic loss of jumping activity, a typical NMDAR-mediated morphine withdrawal abstinence behavior. These findings indicate that impaired NMDAR-dependent neuronal plasticity following repeated morphine injection in PSD-93 knockout mice is attributed to PSD-93 deletion-induced alterations of synaptic NR2A and NR2B expression in dorsal horn and forebrain cortex neurons. The selective effect of PSD-93 deletion on synaptic NMDAR expression in these two major pain-related regions might provide the better strategies for the prevention and treatment of opioid tolerance and physical dependence.

  13. Study Of Morphological Changes Of Uterine Horn Of Surri Mouse Depended To Morphine Before Puberty And DuringPuberty

    Directory of Open Access Journals (Sweden)

    Shadkhast M

    2003-11-01

    Full Text Available : Morphine is the most important alkaloid of opium family which is found as much as ten percent in opium, and is in two types the sulfate morphine and the hydrochloride morphine."nMaterials and Methods: In this study morphological changes of uterus of surri mice due to oral consumption of sulfate morphine were studied. It was shown that, female surri mice following gradually increasing of morphine to water (0.1 and 0.01 mg/ml were depended to morphine. Female surri mice were classified in two age groups before puberty and depended to morphine during puberty. Each age group took morphine for 21 days. After finishing the period, the mice anesthetizing were weighted, then were anesthetizing and uterus was studied the length, width and apparent features."nResults&ConcIusion: In this study it was distinguished that length and width of uterine horn, between experimental and control groups, were significant (P< 0.01. Morphological changes such as anemia, the thinness and fragitidily walls of uterus and filiformity of uterine horns were observed."n"n"n"n"n"n 

  14. Stress-opioid interactions: a comparison of morphine and methadone.

    Science.gov (United States)

    Taracha, Ewa; Mierzejewski, Paweł; Lehner, Małgorzata; Chrapusta, Stanisław J; Kała, Maria; Lechowicz, Wojciech; Hamed, Adam; Skórzewska, Anna; Kostowski, Wojciech; Płaźnik, Adam

    2009-01-01

    The utility of methadone and morphine for analgesia and of methadone for substitution therapy for heroin addiction is a consequence of these drugs acting as opioid receptor agonists.We compared the cataleptogenic and antinociceptive effects of single subcutaneous doses of methadone hydrochloride (1-4 mg/kg) and morphine sulfate (2.5-10 mg/kg) using catalepsy and hot-plate tests, and examined the effects of the highest doses of the drugs on Fos protein expression in selected brain regions in male Sprague-Dawley rats. Methadone had greater cataleptogenic and analgesic potency than morphine. Fos immunohistochemistry revealed substantial effects on the Fos response of both the stress induced by the experimental procedures and of the drug exposure itself. There were three response patterns identified: 1) drug exposure, but not stress, significantly elevated Fos-positive cell counts in the caudate-putamen; 2) stress alone and stress combined with drug exposure similarly elevated Fos-positive cell counts in the nucleus accumbens and cingulate cortex; and 3) methadone and morphine (to a lesser extent) counteracted the stimulatory effect of nonpharmacological stressors on Fos protein expression in the somatosensory cortex barrel field, and Fos-positive cell counts in this region correlated negatively with both the duration of catalepsy and the latency time in the hot-plate test. The overlap between brain regions reacting to nonpharmacological stressors and those responding to exogenous opioids suggests that stress contributes to opioid-induced neuronal activation.

  15. Sludge pre-treatment with pulsed electric fields

    Energy Technology Data Exchange (ETDEWEB)

    Kopplow, O.; Barjenbruch, M.; Heinz, V.

    2003-07-01

    The anaerobic stabilization process depends - among others - on the bio-availability of organic carbon. Through pre-treatment of the sludge which leads to the destruction of micro-organisms and to the setting-free of cell content substances (disintegration), the carbon can be microbially converted better and faster. Moreover, effects on the digestion are likely. However, only little experience is available in the sludge treatment with pulsed electric fields. Laboratory-scale digestion tests have been run to analyse the influence of pulsed electric fields on the properties of sludge, anaerobic degradation, sludge water reload and foaming of digesters. The results will be compared with those of other disintegration methods (high pressure homogenise, thermal treatment). The effect of pre-treatment on the sludge is shown by the COD release. Degrees of disintegration have been achieved up to 20%. The specific energy input was high. The energy consumption has been decreased by initial improvements (pre-heating to 55{sup o}C). The filament bacteria were partially destroyed. The foam reduction in the digesters was marginal. The anaerobic degradation performance has been improved in every case. The degradation rate of organic matter increased about 9%. Due to the increase of degradation, there is a higher reload of the sludge-water with COD and nitrogen compounds. (author)

  16. Behavioral responses to and brain distribution of morphine in mature adult and aged mice

    International Nuclear Information System (INIS)

    Burton, C.K.; Ho, I.K.; Hoskins, B.

    1986-01-01

    Mature adult (3-6 mo old) and aged (2 yr old) male ICR mice were injected with 10 to 100 mg/kg morphine, s.c. The ED50 values for running behavior (as measured using Stoelting activity monitors and having each mouse serve as its own control) representing 5 times control activity was approximately 7.5 mg/kg for aged mice and approximately 17.5 mg/kg for the mature adults. The ED50 values for analgesia 1 hr after morphine administration using the tail-flick method (max. response time = 8 sec) were approx. 70 mg/kg for the aged mice and 15 mg/kg for the mature adults. One hour after injecting 3 H-morphine at doses of 30 and 100 mg/kg, 0.13 and 0.14% of the doses appeared in brains of aged and mature adult mice, respectively. Regional distribution of the morphine was the same for both age groups. Expressed as percent of total brain morphine, it was as follows: cortex, 30%; midbrain, 18%; cerebellum, 17%; medulla, 12%; pons, 9%; striatum, 8% and periaqueductal gray, 6%. Expressed as g morphine/g tissue for the 2 doses, the distribution was; periaqueductal gray, 30 and 80; striatum, 9 and 34; medulla, 6 and 20 pons; 5 and 19; cerebellum, 4 and 13; midbrain 2.5 and 8.5 and cortex, 2 and 8. These results suggest that the differences in response to morphine by the two age groups were due to age-related differences in opioid receptor populations and/or affinities

  17. Behavioral responses to and brain distribution of morphine in mature adult and aged mice

    Energy Technology Data Exchange (ETDEWEB)

    Burton, C.K.; Ho, I.K.; Hoskins, B.

    1986-03-01

    Mature adult (3-6 mo old) and aged (2 yr old) male ICR mice were injected with 10 to 100 mg/kg morphine, s.c. The ED50 values for running behavior (as measured using Stoelting activity monitors and having each mouse serve as its own control) representing 5 times control activity was approximately 7.5 mg/kg for aged mice and approximately 17.5 mg/kg for the mature adults. The ED50 values for analgesia 1 hr after morphine administration using the tail-flick method (max. response time = 8 sec) were approx. 70 mg/kg for the aged mice and 15 mg/kg for the mature adults. One hour after injecting /sup 3/H-morphine at doses of 30 and 100 mg/kg, 0.13 and 0.14% of the doses appeared in brains of aged and mature adult mice, respectively. Regional distribution of the morphine was the same for both age groups. Expressed as percent of total brain morphine, it was as follows: cortex, 30%; midbrain, 18%; cerebellum, 17%; medulla, 12%; pons, 9%; striatum, 8% and periaqueductal gray, 6%. Expressed as g morphine/g tissue for the 2 doses, the distribution was; periaqueductal gray, 30 and 80; striatum, 9 and 34; medulla, 6 and 20 pons; 5 and 19; cerebellum, 4 and 13; midbrain 2.5 and 8.5 and cortex, 2 and 8. These results suggest that the differences in response to morphine by the two age groups were due to age-related differences in opioid receptor populations and/or affinities.

  18. Varied behavioral responses induced by morphine in the tree shrew: a possible model for human opiate addiction

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    Fang eShen

    2014-09-01

    Full Text Available Tree shrews represent a suitable animal model to study the pathogenesis of human diseases as they are phylogenetically close to primates and have a well-developed central nervous system that possesses many homologies with primates. Therefore, in our study, we investigated whether tree shrews can be used to explore the addictive behaviors induced by morphine. Firstly, to investigate the psychoactive effect of morphine on tree shrews’ behavior, the number of jumping and shuttling, which represent the vertical and horizontal locomotor activity respectively, was examined following the injection of different dosage of morphine. Our results showed intramuscular (IM injection of morphine (5 or 10 mg/kg significantly increased the locomotor activity of tree shrews 30-60 min post-injection. Then, using the conditioned place preference/aversion (CPP/CPA paradigm, we found morphine-conditioned tree shrews exhibited place preference in the morphine-paired chamber on the test day. In addition, naloxone-precipitated withdrawal induced place aversion in the chronic morphine-dependent tree shrews. We evaluated the craving for morphine drinking by assessing the break point that reflects the maximum effort animals will expend to get the drug. Our data showed the break point was significantly increased when compared to the baseline on the 1st, 7th and 14th day after the abstinence. Moreover, in the intravenous morphine self-administration experiment, tree shrews conditioned with morphine responded on the active lever significantly more frequently than on the inactive lever after training. These results suggest that tree shrew may be a potential candidate for study the addictive behaviors and the underling neurological mechanisms.

  19. Differential regulation of morphine antinociceptive effects by endogenous enkephalinergic system in the forebrain of mice

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    Sun Wei-Zen

    2008-09-01

    Full Text Available Abstract Background Mice lacking the preproenkephalin (ppENK gene are hyperalgesic and show more anxiety and aggression than wild-type (WT mice. The marked behavioral changes in ppENK knock-out (KO mice appeared to occur in supraspinal response to painful stimuli. However the functional role of enkephalins in the supraspinal nociceptive processing and their underlying mechanism is not clear. The aim of present study was to compare supraspinal nociceptive and morphine antinociceptive responses between WT and ppENK KO mice. Results The genotypes of bred KO mice were confirmed by PCR. Met-enkephalin immunoreactive neurons were labeled in the caudate-putamen, intermediated part of lateral septum, lateral globus pallidus, intermediated part of lateral septum, hypothalamus, and amygdala of WT mice. Met-enkephalin immunoreactive neurons were not found in the same brain areas in KO mice. Tail withdrawal and von Frey test results did not differ between WT and KO mice. KO mice had shorter latency to start paw licking than WT mice in the hot plate test. The maximal percent effect of morphine treatments (5 mg/kg and 10 mg/kg, i.p. differed between WT and KO mice in hot plate test. The current source density (CSD profiles evoked by peripheral noxious stimuli in the primary somatosenstory cortex (S1 and anterior cingulate cortex (ACC were similar in WT and KO mice. After morphine injection, the amplitude of the laser-evoked sink currents was decreased in S1 while the amplitude of electrical-evoked sink currents was increased in the ACC. These differential morphine effects in S1 and ACC were enhanced in KO mice. Facilitation of synaptic currents in the ACC is mediated by GABA inhibitory interneurons in the local circuitry. Percent increases in opioid receptor binding in S1 and ACC were 5.1% and 5.8%, respectively. Conclusion The present results indicate that the endogenous enkephalin system is not involved in acute nociceptive transmission in the spinal cord

  20. Morphine versus Nalbuphine for Open Gynaecological Surgery: A Randomized Controlled Double Blinded Trial

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    Shiv Akshat

    2014-01-01

    Full Text Available Introduction. Pain is the commonest morbidity after open surgical procedures. The most effective treatment of postoperative pain is opioid therapy. Morphine, the commonly used opioid, is associated with many side effects including respiratory depression, sedation, postoperative nausea vomiting, and pruritus. Nalbuphine, on the other hand, is known to cause less respiratory depression. Thus this study was undertaken to compare the intraoperative and postoperative analgesic efficacy and side effect profile of the two drugs. Methodology. 60 patients undergoing open gynaecological surgery were randomized to receive either morphine (Group M or nalbuphine (Group N in the intraoperative and postoperative period. Intraoperative analgesic efficacy (measured by need for rescue analgesics, postoperative pain by visual analogue scale, and side effects like postoperative nausea, vomiting, sedation, respiratory depression, and pruritus were compared in both groups. Intraoperative and postoperative heart rate and blood pressure were also compared between the groups. Results. Need for intraoperative analgesia was significantly more in Group N (P=0.023. Postoperative VAS scores were significantly different between the groups at various time points; however, none of the patients required any rescue analgesia. The incidence of various side effects was not significantly different between the groups. The haemodynamic profile of patients was comparable between the groups in both intraoperative and postoperative period. Conclusion. Nalbuphine provides less effective intraoperative analgesia than morphine in patients undergoing open gynaecological surgery under general anaesthesia. Both drugs, however, provided similar postoperative analgesia and had similar haemodynamic and side effect profile.

  1. Electroencephalographic Changes Associated with Antinociceptive Actions of Lidocaine, Ketamine, Meloxicam, and Morphine Administration in Minimally Anaesthetized Dogs

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    Ubedullah Kaka

    2015-01-01

    Full Text Available Effects of ketamine and lidocaine on electroencephalographic (EEG changes were evaluated in minimally anaesthetized dogs, subjected to electric stimulus. Six dogs were subjected to six treatments in a crossover design with a washout period of one week. Dogs were subjected to intravenous boluses of lidocaine 2 mg/kg, ketamine 3 mg/kg, meloxicam 0.2 mg/kg, morphine 0.2 mg/kg and loading doses of lidocaine 2 mg/kg followed by continuous rate infusion (CRI of 50 and 100 mcg/kg/min, and ketamine 3 mg/kg followed by CRI of 10 and 50 mcg/kg/min. Electroencephalogram was recorded during electrical stimulation prior to any drug treatment (before treatment and during electrical stimulation following treatment with the drugs (after treatment under anaesthesia. Anaesthesia was induced with propofol and maintained with halothane at a stable concentration between 0.85 and 0.95%. Pretreatment median frequency was evidently increased (P<0.05 for all treatment groups. Lidocaine, ketamine, and morphine depressed the median frequency resulting from the posttreatment stimulation. The depression of median frequency suggested evident antinociceptive effects of these treatments in dogs. It is therefore concluded that lidocaine and ketamine can be used in the analgesic protocol for the postoperative pain management in dogs.

  2. Self-administration of morphine into the lateral hypothalamus in the mouse.

    Science.gov (United States)

    Cazala, P; Darracq, C; Saint-Marc, M

    1987-07-28

    BALB/c mice were chronically and unilaterally implanted with a guide cannula, the tip of which was positioned 1 mm above the lateral hypothalamus (LH). On each experimental day, a stainless-steel injection cannula was inserted into the LH, and self-administration of morphine or vehicle in this brain area was studied by using a spatial discrimination test in a Y-maze. In a first experiment, we observed that when mice had access to morphine (0.1 microgram by injection) they rapidly discriminated the reinforced arm from the neutral arm of the maze in order to self administer, with increasing frequency, the drug into the LH. In contrast when only vehicle was present, the two arms were no longer discriminated. In a second experiment we compared the effects of 3 doses of morphine (0.1 microgram, 0.05 microgram and 0.025 microgram by injection); optimal discrimination was obtained with the lowest dose used. In a third experiment we observed that subcutaneous injections of naloxone (4 mg/kg) progressively reduced the number of self-administrations of morphine into the LH, a result which suggests that this response is dependent on an opiate receptor mechanism.

  3. Alterations in brain Protein Kinase A activity and reversal of morphine tolerance by two fragments of native Protein Kinase A inhibitor peptide (PKI).

    Science.gov (United States)

    Dalton, George D; Smith, Forrest L; Smith, Paul A; Dewey, William L

    2005-04-01

    Two peptide fragments of native Protein Kinase A inhibitor (PKI), PKI-(6-22)-amide and PKI-(Myr-14-22)-amide, significantly reversed low-level morphine antinociceptive tolerance in mice. The inhibition of Protein Kinase A (PKA) activity by both peptide fragments was then measured in specific brain regions (thalamus, periaqueductal gray (PAG), and medulla) and in lumbar spinal cord (LSC), which in previous studies have been shown to play a role in morphine-induced analgesia. In drug naive animals, cytosolic PKA activity was greater than particulate PKA activity in each region, while cytosolic and particulate PKA activities were greater in thalamus and PAG compared to medulla and LSC. The addition of both peptides to homogenates from each region completely abolished cytosolic and particulate PKA activities in vitro. Following injection into the lateral ventricle of the brain of drug naive mice and morphine-tolerant mice, both peptides inhibited PKA activity in the cytosolic, but not the particulate fraction of LSC. In addition, cytosolic and particulate PKA activities were inhibited by both peptides in thalamus. These results demonstrate that the inhibition of PKA reverses morphine tolerance. Moreover, the inhibition of PKA activity in specific brain regions and LSC from morphine-tolerant mice by PKI analogs administered i.c.v. is evidence that PKA plays a role in morphine tolerance.

  4. Research Paper: Cross State-dependent Learning Interaction Between Scopolamine and Morphine in Mice: The Role of Dorsal Hippocampus

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    Morteza Maleki

    2017-05-01

    Conclusion: The current study findings indicated a cross state-dependent learning between SCO and morphine at CA1 level. Therefore, it seems that muscarinic and opioid receptors may act reciprocally on modulation of passive avoidance memory retrieval, at the level of dorsal hippocampus, in mice.

  5. Morphine potentiates seizures induced by GABA antagonists and attenuates seizures induced by electroshock in the rat.

    Science.gov (United States)

    Foote, F; Gale, K

    1983-11-25

    In a naloxone-reversible, dose-dependent manner, morphine (10-50 mg/kg i.p.) protected against seizures induced by maximal electroshock and increased the incidence and severity of seizures induced by bicuculline, in rats. Morphine also potentiated seizures induced by isoniazid and by picrotoxin. Thus, opiate activity influences the expression of seizures in contrasting ways depending upon the mode of seizure induction. Since morphine consistently potentiated seizures induced by interference with GABA transmission, it appears that GABAergic systems may be of particular significance for the elucidation of the varied effects of morphine on seizure susceptibility.

  6. A comparison of epidural buprenorphine plus detomidine with morphine plus detomidine in horses undergoing bilateral stifle arthroscopy.

    Science.gov (United States)

    Fischer, Berit L; Ludders, John W; Asakawa, Makoto; Fortier, Lisa A; Fubini, Susan L; Nixon, Alan J; Radcliffe, Rolfe M; Erb, Hollis N

    2009-01-01

    To compare the analgesic efficacy of buprenorphine plus detomidine with that of morphine plus detomidine when administered epidurally in horses undergoing bilateral stifle arthroscopy. Prospective, randomized, blinded clinical trial. Twelve healthy adult horses participating in an orthopedic research study. Group M (n = 6) received morphine (0.2 mg kg(-1)) and detomidine (0.15 mg kg(-1)) epidurally; group B (n = 6) received buprenorphine (0.005 mg kg(-1)) and detomidine (0.15 mg kg(-1)) epidurally. Horses received one of two epidural treatments following induction of general anesthesia for bilateral stifle arthroscopy. Heart rate (HR), mean arterial blood pressure (MAP), end-tidal CO(2) (Pe'CO(2)), and end-tidal isoflurane concentrations (E'Iso%) were recorded every 15 minutes following epidural administration. Post-operative assessment was performed at 1, 2, 3, 6, 9, 12, and 24 hours after standing; variables recorded included HR, respiratory rate (f(R)), abdominal borborygmi, defecation, and the presence of undesirable side effects. At the same times post-operatively, each horse was videotaped at a walk and subsequently assigned a lameness score (0-4) by three ACVS diplomates blinded to treatment and who followed previously published guidelines. Nonparametric data were analyzed using Wilcoxon's rank-sum test. Inter- and intra-rater agreement were determined using weighted kappa coefficients. Statistical significance was set at p detomidine injected epidurally produced analgesia similar in intensity and duration to that of morphine plus detomidine injected epidurally.

  7. Cholecystokinin receptor-1 mediates the inhibitory effects of exogenous cholecystokinin octapeptide on cellular morphine dependence

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    Wen Di

    2012-06-01

    Full Text Available Abstract Background Cholecystokinin octapeptide (CCK-8, the most potent endogenous anti-opioid peptide, has been shown to regulate the processes of morphine dependence. In our previous study, we found that exogenous CCK-8 attenuated naloxone induced withdrawal symptoms. To investigate the precise effect of exogenous CCK-8 and the role of cholecystokinin (CCK 1 and/or 2 receptors in morphine dependence, a SH-SY5Y cell model was employed, in which the μ-opioid receptor, CCK1/2 receptors, and endogenous CCK are co-expressed. Results Forty-eight hours after treating SH-SY5Y cells with morphine (10 μM, naloxone (10 μM induced a cAMP overshoot, indicating that cellular morphine dependence had been induced. The CCK receptor and endogenous CCK were up-regulated after chronic morphine exposure. The CCK2 receptor antagonist (LY-288,513 at 1–10 μM inhibited the naloxone-precipitated cAMP overshoot, but the CCK1 receptor antagonist (L-364,718 did not. Interestingly, CCK-8 (0.1-1 μM, a strong CCK receptor agonist, dose-dependently inhibited the naloxone-precipitated cAMP overshoot in SH-SY5Y cells when co-pretreated with morphine. The L-364,718 significantly blocked the inhibitory effect of exogenous CCK-8 on the cAMP overshoot at 1–10 μM, while the LY-288,513 did not. Therefore, the CCK2 receptor appears to be necessary for low concentrations of endogenous CCK to potentiate morphine dependence in SH-SY5Y cells. An additional inhibitory effect of CCK-8 at higher concentrations appears to involve the CCK1 receptor. Conclusions This study reveals the difference between exogenous CCK-8 and endogenous CCK effects on the development of morphine dependence, and provides the first evidence for the participation of the CCK1 receptor in the inhibitory effects of exogenous CCK-8 on morphine dependence.

  8. Decreased Serum 25-Hydroxycalciferol Levels in Pre-diabetic Adults

    International Nuclear Information System (INIS)

    Ain, Q. A.; Khan, D. A.; Ijaz, A.; Khan, F. A.; Latif, A.

    2016-01-01

    Objective: To determine the serum 25-hydroxycalciferol levels [25(OH)D] in adults with pre-diabetes and normoglycaemia to examine a possible association of vitamin D deficiency with pre-diabetes. Study Design: Case control study. Place and Duration of Study: Armed Forces Institute of Pathology, Rawalpindi, from November 2012 to July 2013. Methodology: A total of 272 adults including 136 pre-diabetics and 136 normoglycaemics of either gender aged 20 years and above were consecutively inducted. Patients with diabetes mellitus, pregnancy, rickets and osteomalacia, ischemic heart disease, chronic kidney disease and chronic liver disease were excluded. Fasting Plasma Glucose (FPG) was estimated with hexokinase method on Modular p800 Roche chemistry analyzer while serum 25(OH)D was measured on Diasorin Liaison immunoassay analyzer using the chemiluminescent technique. Mean 25(OH)D levels in pre-diabetic and normoglycaemic groups were compared using Mann-Whitney U test. Spearman's correlation coefficient 'rs' was determined between serum 25(OH)D and FPG. Odds ratio for vitamin D deficiency was also calculated. Results: Mean serum 25(OH)D level was low in pre-diabetics (23.2 nmol/L) as compared to normoglycaemics (29 nmol/L; p=0.001). Serum 25(OH)D level had inverse correlation with FPG (rs = -0.448, p=0.000). There was also significant association of vitamin D deficiency with pre-diabetes compared with normoglycaemia (OR: 2.21, p= 0.016; 95 percentage CI: 1.15-4.27). Conclusion: Vitamin D deficiency with pre-diabetes suggested that vitamin D may have an important role in pathogenesis of pre-diabetes. (author)

  9. Central neuraxial opioid analgesia after caesarean section: comparison of epidural diamorphine and intrathecal morphine.

    Science.gov (United States)

    Caranza, R; Jeyapalan, I; Buggy, D J

    1999-04-01

    In a prospective, randomized, double-blind study in 55 women undergoing elective caesarean section under spinal anaesthesia, we compared epidural diamorphine 3 mg (2 distinct boluses, group ED) with single-dose intrathecal morphine 0.2 mg (group SM), in terms of analgesic efficacy, patient satisfaction and side-effects at 2, 3, 4, 8, 12, 16, 24 and 28 h postoperatively. There were no significant differences between groups in pain (assessed by 100 mm visual analogue scale), incidence of pruritus, sedation or respiratory depression measured by continuous pulse oximetry. However, time to first request for supplementary oral analgesia was longer in SM than in ED (mean +/- SD: 22.3+/-12.0 h vs. 13.8+/-6.5 h, P=0.04). The incidence of nausea or vomiting was significantly higher in SM than ED (73% vs. 41%, P=0.01). In ED, the mean +/- SD time to requirement of the second bolus was 6.7+/-3.2 h. There was a high level of satisfaction in both groups. We conclude that two boluses of epidural diamorphine 3 mg and single-dose intrathecal morphine 0.2 mg provide satisfactory analgesia after caesarean section, but spinal morphine was associated with both delayed requirement for supplementary analgesia and a higher incidence of nausea and vomiting.

  10. Potentiation of Morphine-Induced Antinociception by Propranolol: The Involvement of Dopamine and GABA Systems

    Directory of Open Access Journals (Sweden)

    Elham A. Afify

    2017-11-01

    Full Text Available Tolerance to the analgesic effect of morphine is a major clinical problem which can be managed by co-administration of another drug. This study investigated the ability of propranolol to potentiate the antinociceptive action of morphine and the possible mechanisms underlying this effect. Antinociception was assessed in three nociceptive tests (thermal, hot plate, (visceral, acetic acid, and (inflammatory, formalin test in mice and quantified by measuring the percent maximum possible effect, the percent inhibition of acetic acid-evoked writhing response, and the area under the curve values of number of flinches for treated mice, respectively. The study revealed that propranolol (0.25–20 mg/Kg, IP administration did not produce analgesia in mice. However, 10 mg/Kg propranolol, enhanced the antinociceptive effect of sub-analgesic doses of morphine (0.2, 1, and 2 mg/Kg, IP in the three nociceptive tests. It also shifted the dose response curve of morphine to the left. The combined effect of propranolol and morphine was attenuated by haloperidol (D2 receptor antagonist, 1.5 mg/Kg, IP, and bicuculline (GABAA receptor antagonist, 2 mg/Kg, IP. Repeated daily administration of propranolol (10 mg/Kg, IP did not alter the nociceptive responses in the three pain tests, but it significantly potentiated morphine-induced antinociception in the hot plate, acetic acid-evoked writhing, and in the second phase of formalin tests. Together, the data suggest that a cross-talk exists between the opioidergic and adrenergic systems and implicate dopamine and GABA systems in this synergistic effect of morphine-propranolol combination. Propranolol may serve as an adjuvant therapy to potentiate the effect of opioid analgesics.

  11. Attenuation of Morphine-Induced Tolerance and Dependence by Pretreatment with Cerebrolysin in Male rats.

    Science.gov (United States)

    Ghavimi, Hamed; Darvishi, Sara; Ghanbarzadeh, Saeed

    2018-01-01

    Dependence and tolerance to morphine are major problems which limit its chronic clinical application. This study was aimed to investigate the attenuation effect of Cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,), on the development of Morphine-induced dependence and tolerance. Male Wistar rats were selected randomly and divided into different groups (n=8) including: a control group, groups received additive doses of morphine (5-25 mg/kg, ip, at an interval of 12 h until tolerance completion), and groups pretreated with Cerebrolysin (40, 80 and 160 mg/kg, ip, before morphine administration). Development of tolerance was assessed by tail-flick test and the attenuation effect of Cerebrolysin on morphine-induced dependence was evaluated after injection of naloxone (4 mg/kg, ip, 12 h after the morning dose of morphine). Seven distinct withdrawal signs including: jumping, rearing, genital grooming, abdominal writhing, wet dog shake and teeth grinding were recorded for 45 min and total withdrawal score (TWS) was calculated. Results showed that administration of Cerebrolysin could prolonged development (10 and 14 days in administration of 80 mg/kg and 160 mg/kg Cerebrolysin) and completion (4, 10 and 14 days in administration of 40, 80 and 160 mg/kg Cerebrolysin, respectively) of tolerance. Results also indicated that administration of Cerebrolysin (40, 80 and 160 mg/kg) could significantly decreased the TWS value (62±2, 77±4 and 85±6%, respectively). In conclusion, it was found that pretreatment with Cerebrolysin could attenuated morphine-induced tolerance and dependence. © Georg Thieme Verlag KG Stuttgart · New York.

  12. Comparison of Morphine Suppository and Diclofenac Suppository for Pain Management After Elective Caesarean Section

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    Atossa Mahdavi

    2016-12-01

    Full Text Available This study investigated efficacy and side effects of Morphine suppository for pain management after the first elective caesarean delivery in comparison to Diclofenac suppository. One hundred women aged 18-40 with term pregnancies undergoing elective caesarean section for the first time participated in this prospective project. Exclusion criteria included drug sensitivity, fetal malformations or defects, and complications during the cesarean operation. After same spinal anesthesia and same surgical techniques and in the recovery room patients consecutively received 100 mg diclofenac suppository or 10 mg morphine suppository. The pain severity was rated by “Numerical Rating Scale.” There was not the difference between two groups in terms of basal information. Pain score was significantly different between two groups in the first 12 hours (5.66 ±1.36 in morphine group and 3.63±0.96 in diclofenac group but not in the second 12 hour period. Considering pain scores every two hours in first 12 hours and every 4 hours in second 12 hours, morphine group had higher scores in comparison to diclofenac group. Also, the morphine group required pethidine injection sooner than the other group. The time giving first pethidine injection was 3.28±2.16 hours after operation in morphine group and 5.24±4.07 hours after operation (P<0.05. This study demonstrated that diclofenac suppository in comparison to morphine suppository decreased subjective pain scores in the first twenty-four hours after elective caesarean section which reached statistical significance in the first twelve hours. Although in diclofenac group, pethidine injection was prescribed significantly later.

  13. Serum Magnesium Levels in Non-Pregnant, Pregnant And Pre ...

    African Journals Online (AJOL)

    The objective of this study was to compare the serum magnesium levels in normal pregnancy and pregnancy complicated by pre-eclampsia since magnesium has been implicated in the pathogenesis of vascular dysfunction. We measured serum magnesium levels in patients with pre-eclampsia (n=36), patients with normal ...

  14. Intrathecal morphine for postoperative analgesia in patients with idiopathic scoliosis undergoing posterior spinal fusion.

    Science.gov (United States)

    Tripi, Paul A; Poe-Kochert, Connie; Potzman, Jennifer; Son-Hing, Jochen P; Thompson, George H

    2008-09-15

    A retrospective study of postoperative pain management with intrathecal morphine. Identify the dosing regimen of intrathecal morphine that safely and effectively provides postoperative analgesia with minimal complications in patients with idiopathic scoliosis undergoing posterior spinal fusion (PSF) and segmental spinal instrumentation (SSI). Postoperative pain after surgery for idiopathic scoliosis is a concern. Intrathecal morphine has been used to decrease pain. However, the most appropriate dose has not been determined. We retrospectively analyzed 407 consecutive patients with idiopathic scoliosis who underwent PSF and SSI at our institution from 1992 through 2006. Patients were divided into 3 groups based on the intrathecal morphine dose: no dose (n = 68); moderate dose of 9 to 19 microg/kg, mean 14 microg/kg (n = 293); and high dose of 20 microg/kg or greater, mean 24 microg/kg (n = 46). Data included demographics, Wong-Baker visual analog scale postoperative pain scores, postoperative intravenous morphine requirements, time to first rescue dose of intravenous morphine, and postoperative complications of pruritus, nausea/vomiting, respiratory depression, and pediatric intensive care unit (PICU) admission. The demographics of the 3 study groups showed no statistical differences. The mean Wong-Baker visual analog scale pain score in the post anesthesia care unit was 5.2, 0.5, and 0.2, and the mean time to first morphine rescue was 6.6, 16.7, and 22.9 hours, respectively. In the first 48 postoperative hours, respiratory depression occurred in 1 (1.5%), 8 (2.7%), and 7 (15.2%) patients, whereas PICU admission occurred in 0 (0%), 6 (2%), and 8 (17.4%) patients, respectively. The majority of PICU admissions were the result of respiratory depression. Frequency of pruritus and nausea/vomiting was similar in all 3 groups. Intrathecal morphine in the moderate dose range of 9 to 19 microg/kg (mean 14 microg/kg), provides safe and effective postoperative analgesia in the

  15. Efficacy of intravenous paracetamol and dexketoprofen on postoperative pain and morphine consumption after a lumbar disk surgery.

    Science.gov (United States)

    Tunali, Yusuf; Akçil, Eren F; Dilmen, Ozlem Korkmaz; Tutuncu, Ayse C; Koksal, Guniz Meyanci; Akbas, Sedat; Vehid, Hayriye; Yentur, Ercument

    2013-04-01

    We compared the analgesic effects of intravenous (IV) paracetamol with that of dexketoprofen on postoperative pain and morphine consumption during the first 24 hour after a lumbar disk surgery. This prospective, placebo-controlled, double blind study investigated the analgesic effects of IV paracetamol and dexketoprofen on postoperative pain, morphine consumption, and morphine-related side effects after a lumbar disk surgery. Sixty American Society of Anesthesiologists 1 or 2 status patients scheduled for elective lumbar disk surgery under general anesthesia were included in the study. Patients were treated using patient-controlled analgesia with morphine for 24 hours after a lumbar disk surgery and randomized to receive IV paracetamol 1 g, dexketoprofen 50 mg, or isotonic saline (placebo). The primary endpoint was pain intensity measured by the visual analogue scale, and secondary endpoints were morphine consumption and related side effects. Pain intensity was lower in the dexketoprofen group (P=0.01) but not in the paracetamol group (P=0.21) when compared with the control group. Cumulative morphine consumption and morphine-related side effects did not reveal significant differences between the groups. The study showed that pain intensity during 24 hours after the lumbar disk surgery was significantly lowered by dexketoprofen, but not with paracetamol, as a supplemental analgesic to morphine patient-controlled analgesia when compared with controls.

  16. Comparison of transversus abdominis plane block vs spinal morphine for pain relief after Caesarean section.

    LENUS (Irish Health Repository)

    McMorrow, R C N

    2012-02-01

    BACKGROUND: Transversus abdominis plane (TAP) block is an alternative to spinal morphine for analgesia after Caesarean section but there are few data on its comparative efficacy. We compared the analgesic efficacy of the TAP block with and without spinal morphine after Caesarean section in a prospective, randomized, double-blinded placebo-controlled trial. METHODS: Eighty patients were randomized to one of four groups to receive (in addition to spinal anaesthesia) either spinal morphine 100 microg (S(M)) or saline (S(S)) and a postoperative bilateral TAP block with either bupivacaine (T(LA)) 2 mg kg(-1) or saline (T(S)). RESULTS: Pain on movement and early morphine consumption were lowest in groups receiving spinal morphine and was not improved by TAP block. The rank order of median pain scores on movement at 6 h was: S(M)T(LA) (20 mm)morphine consumption at 6 h was: S(M)T(S) (4.0 mg)morphine-but not TAP block-improved analgesia after Caesarean section. The addition of TAP block with bupivacaine 2 mg kg(-1) to spinal morphine did not further improve analgesia.

  17. Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine.

    Science.gov (United States)

    Zwicker, Jill G; Miller, Steven P; Grunau, Ruth E; Chau, Vann; Brant, Rollin; Studholme, Colin; Liu, Mengyuan; Synnes, Anne; Poskitt, Kenneth J; Stiver, Mikaela L; Tam, Emily W Y

    2016-05-01

    To examine the relationship between morphine exposure and growth of the cerebellum and cerebrum in very preterm neonates from early in life to term-equivalent age, as well as to examine morphine exposure and brain volumes in relation to neurodevelopmental outcomes at 18 months corrected age (CA). A prospective cohort of 136 very preterm neonates (24-32 weeks gestational age) was serially scanned with magnetic resonance imaging near birth and at term-equivalent age for volumetric measurements of the cerebellum and cerebrum. Motor outcomes were assessed with the Peabody Developmental Motor Scales, Second Edition and cognitive outcomes with the Bayley Scales of Infant and Toddler Development, Third Edition at 18 months CA. Generalized least squares models and linear regression models were used to assess relationships between morphine exposure, brain volumes, and neurodevelopmental outcomes. A 10-fold increase in morphine exposure was associated with a 5.5% decrease in cerebellar volume, after adjustment for multiple clinical confounders and total brain volume (P = .04). When infants exposed to glucocorticoids were excluded, the association of morphine was more pronounced, with an 8.1% decrease in cerebellar volume. Morphine exposure was not associated with cerebral volume (P = .30). Greater morphine exposure also predicted poorer motor (P growth. Morphine exposure in very preterm neonates is independently associated with impaired cerebellar growth in the neonatal period and poorer neurodevelopmental outcomes in early childhood. Alternatives to better manage pain in preterm neonates that optimize brain development and functional outcomes are urgently needed. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Sex differences in locomotor effects of morphine in the rat

    OpenAIRE

    Craft, Rebecca M.; Clark, James L.; Hart, Stephen P.; Pinckney, Megan K.

    2006-01-01

    Sex differences in reinforcing, analgesic and other effects of opioids have been demonstrated; however, the extent to which sex differences in motoric effects of opioids contribute to apparent sex differences in their primary effects is not known. The goal of this study was to compare the effects of the prototypic mu opioid agonist morphine on locomotor activity in male vs. female rats. Saline or morphine (1-10 mg/kg) was administered s.c. to adult Sprague-Dawley rats, which were placed into ...

  19. Age-related postoperative morphine requirements in children following major surgery--an assessment using patient-controlled analgesia (PCA)

    DEFF Research Database (Denmark)

    Hansen, Tom Giedsing; Henneberg, Steen Winther; Hole, P

    1996-01-01

    To investigate if small children require less morphine for postoperative analgesia than do older children and adolescents we analysed the morphine consumption pattern of 28 consecutive children on intravenous patient-controlled analgesia (PCA) following major surgery. The median age-specific morp......To investigate if small children require less morphine for postoperative analgesia than do older children and adolescents we analysed the morphine consumption pattern of 28 consecutive children on intravenous patient-controlled analgesia (PCA) following major surgery. The median age...

  20. Long-term stability of morphine hydrochloride in 0.9% NaCl infusion polyolefin bags after freeze-thaw treatment and in polypropylene syringes at 5 degrees C + 3 degrees C.

    Science.gov (United States)

    Hecq, J-D; Godet, M; Gillet, P; Jamart, J; Galanti, L

    2014-01-01

    The aim of this study was to investigate the long-term stability of morphine hydrochloride in 0.9% NaCI infusion polyolefin bags and polypropylene syringes after storage at 5 degrees C + 3 degrees C and to evaluate the influence of initial freezing and microwave thawing on this stability. Ten polyolefin bags and five polypropylene syringes containing 100 mL of 1 mg/mL of morphine hydrochloride solution in 0.9% NaCI were prepared under aseptic conditions. Five polyolefin bags were frozen at -20 degrees C for 90 days before storage. Immediately after the preparation and after thawing, 2 mL of each bag were withdrawn for the initial concentration measurements. All polyolefin bags and polypropylene syringes were then refrigerated at 5 degrees C + 3 degrees C for 58 days during which the morphine concentrations were measured periodically by high-performance liquid chromatography using a reversed-phase column, naloxone as internal standard, a mobile phase consisting of 5% acetonitrile and 95% of KH2PO4 buffer (pH 3.50), and detection with diode array detector at 254 nm. Visual and microscopic observations and spectrophotometric and pH measurements were also performed. Solutions were considered stable if the concentration remained superior to 90% of the initial concentration. The degradation products peaks were not quantitatively significant and were resolved from the native drug. Polyolefin bag and polypropylene syringe solutions were stable when stored at 5 degrees C + 3 degrees C during these 58 days. No color change or precipitation in the solutions was observed. The physical stability was confirmed by visual, microscopic, and spectrophotometric inspection. There was no significant change in pH during storage. Freezing and microwave thawing didn't influence the infusion stability. Morphine hydrochloride infusions may be prepared in advance by centralized intravenous additive service, frozen in polyolefin bags, and microwave thawed before storage under refrigeration

  1. Relative oral bioavailability of morphine and naltrexone derived from crushed morphine sulfate and naltrexone hydrochloride extended-release capsules versus intact product and versus naltrexone solution: a single-dose, randomized-sequence, open-label, three-way crossover trial in healthy volunteers.

    Science.gov (United States)

    Johnson, Franklin K; Stark, Jeffrey G; Bieberdorf, Frederick A; Stauffer, Joe

    2010-06-01

    Morphine sulfate/sequestered naltrexone hydrochloride (HCl) (MS-sNT) extended-release fixed-dose combination capsules, approved by the US Food and Drug Administration (FDA) in August 2009 for chronic moderate to severe pain, contain extended-release morphine pellets with a sequestered core of the opioid antagonist naltrexone. MS-sNT was designed so that if the product is tampered with by crushing, the naltrexone becomes bioavailable to mitigate morphine-induced subjective effects, rendering the product less attractive for tampering. The primary aim of this study was to compare the oral bioavailability of naltrexone and its metabolite 6-beta-naltrexol, derived from crushed pellets from MS-sNT capsules, to naltrexone solution. This study also assessed the relative bioavailability of morphine from crushed pellets from MS-sNT capsules and that from the whole, intact product. This single-dose, randomized-sequence, open-label, 3-period, 3-treatment crossover trial was conducted in healthy volunteers. Adults admitted to the study center underwent a 10-hour overnight fast before study drug administration. Each subject received all 3 of the following treatments, 1 per session, separated by a 14-day washout: tampered pellets (crushed for >or=2 minutes with a mortar and pestle) from a 60-mg MS-sNT capsule (60 mg morphine/2.4 mg naltrexone); 60-mg whole, intact MS-sNT capsule; and oral naltrexone HCl (2.4 mg) solution. Plasma concentrations of naltrexone and 6-beta-naltrexol were measured 0 to 168 hours after administration. Morphine pharmaco-kinetics of crushed and whole pellets were determined 0 to 72 hours after administration. The analysis of relative bioavailability was based on conventional FDA criteria for assuming bioequivalence; that is, 90% CIs for ratios of geometric means (natural logarithm [In]-transformed C(max) and AUC) fell within the range of 80% to 125%. Subjects underwent physical examinations, clinical laboratory tests, and ECG at screening and study

  2. Attitudes of Polish physicians and medical students toward breaking bad news, euthanasia and morphine administration in cancer patients.

    Science.gov (United States)

    Leppert, Wojciech; Majkowicz, Mikolaj; Forycka, Maria

    2013-12-01

    Medical students and physicians should possess basic knowledge concerning medical ethics and palliative care. The aim of the study was to explore the knowledge on the end-of-life ethics and palliative care in third-year medical students and physicians during internal medicine specialty training and their attitude towards breaking bad news and euthanasia. A voluntary and anonymous questionnaire survey with the participation of 401 students and 217 physicians filled after lectures concerning ethics for medical students and after palliative medicine course for physicians during internal medicine specialty training. A total of 28 % students and 24 % physicians (p = 0.282) were ready to reveal full information to advanced cancer patients. A total of 82 % of students and 90 % of physicians (p = 0.008) would not practice euthanasia; 67 % of students and 75 % of physicians (p = 0.039) were opponents of euthanasia legalisation. A total of 70 % doctors and 23 % students indicated oral as the most preferable route of morphine administration. A total of 74 % physicians and 43 % students stated that there is no maximal dose of morphine; 64 % of doctors and 6 % of students indicated constipation as a constant adverse effect of morphine. Breaking bad news is a significant difficulty for both students and physicians. There is a small percentage of those tending to practice euthanasia and bigger accepting its legalisation with fewer physicians than students. In contrast to medical students, the majority of physicians have knowledge concerning chronic morphine use in the treatment of cancer patients.

  3. Toll-like receptor 4 mutant and null mice retain morphine-induced tolerance, hyperalgesia, and physical dependence.

    Directory of Open Access Journals (Sweden)

    Theresa Alexandra Mattioli

    Full Text Available The innate immune system modulates opioid-induced effects within the central nervous system and one target that has received considerable attention is the toll-like receptor 4 (TLR4. Here, we examined the contribution of TLR4 in the development of morphine tolerance, hyperalgesia, and physical dependence in two inbred mouse strains: C3H/HeJ mice which have a dominant negative point mutation in the Tlr4 gene rendering the receptor non-functional, and B10ScNJ mice which are TLR4 null mutants. We found that neither acute antinociceptive response to a single dose of morphine, nor the development of analgesic tolerance to repeated morphine treatment, was affected by TLR4 genotype. Likewise, opioid induced hyperalgesia and opioid physical dependence (assessed by naloxone precipitated withdrawal were not altered in TLR4 mutant or null mice. We also examined the behavioural consequence of two stereoisomers of naloxone: (- naloxone, an opioid receptor antagonist, and (+ naloxone, a purported antagonist of TLR4. Both stereoisomers of naloxone suppressed opioid induced hyperalgesia in wild-type control, TLR4 mutant, and TLR4 null mice. Collectively, our data suggest that TLR4 is not required for opioid-induced analgesic tolerance, hyperalgesia, or physical dependence.

  4. Intermittent morphine treatment induces a long-lasting increase in cholinergic modulation of GABAergic synapses in nucleus accumbens of adult rats

    NARCIS (Netherlands)

    de Rover, M.; Lodder, J.C.; Schoffelmeer, A.N.M.; Brussaard, A.B.

    2005-01-01

    Repeated exposure to drugs of abuse causes persistent behavioral sensitization and associated adaptations of striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Microdialysis and neurochemical studies suggest that intermittent morphine

  5. Naloxone Induces Frequent Jumping after Chronic Morphine and Methamphetamine Co-Administration in Rats

    Directory of Open Access Journals (Sweden)

    Gholamreza Kaka

    2014-02-01

    Full Text Available Combined use of an opioid with a psychostimulant is popular among drug abusers. Such “polydrug use” may increase drug effects or attenuate adverse effects of either drug alone. We proposed that a combination of methamphetamine (meth and morphine may change physical opioid withdrawal symptoms. Adult male rats were chronically injected with cumulative subcutaneous (s.c. doses of morphine, meth or a combination of both drugs within five days. On day six, a challenge dose of the same drug was injected. Two hours later, precipitated withdrawal symptoms were scored within 30 minutes after naloxone (1mg/kg, i.p. injection. Both frequency and incidence of jumping significantly increased in combined treated animals (P<0.05. The sole emergent symptom in combined treated animals was digging which we consider as another escaping behavior in addition to jumping. Our findings imply that combined use of meth and morphine may exacerbate averseness of morphine withdrawal which may cause more intense opioid dependence

  6. Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine

    Directory of Open Access Journals (Sweden)

    Rodríguez-Muñoz María

    2009-03-01

    Full Text Available Abstract Background Although the systemic administration of cannabinoids produces antinociception, their chronic use leads to analgesic tolerance as well as cross-tolerance to morphine. These effects are mediated by cannabinoids binding to peripheral, spinal and supraspinal CB1 and CB2 receptors, making it difficult to determine the relevance of each receptor type to these phenomena. However, in the brain, the CB1 receptors (CB1Rs are expressed at high levels in neurons, whereas the expression of CB2Rs is marginal. Thus, CB1Rs mediate the effects of smoked cannabis and are also implicated in emotional behaviors. We have analyzed the production of supraspinal analgesia and the development of tolerance at CB1Rs by the direct injection of a series of cannabinoids into the brain. The influence of the activation of CB1Rs on supraspinal analgesia evoked by morphine was also evaluated. Results Intracerebroventricular (icv administration of cannabinoid receptor agonists, WIN55,212-2, ACEA or methanandamide, generated a dose-dependent analgesia. Notably, a single administration of these compounds brought about profound analgesic tolerance that lasted for more than 14 days. This decrease in the effect of cannabinoid receptor agonists was not mediated by depletion of CB1Rs or the loss of regulated G proteins, but, nevertheless, it was accompanied by reduced morphine analgesia. On the other hand, acute morphine administration produced tolerance that lasted only 3 days and did not affect the CB1R. We found that both neural mu-opioid receptors (MORs and CB1Rs interact with the HINT1-RGSZ module, thereby regulating pertussis toxin-insensitive Gz proteins. In mice with reduced levels of these Gz proteins, the CB1R agonists produced no such desensitization or morphine cross-tolerance. On the other hand, experimental enhancement of Gz signaling enabled an acute icv administration of morphine to produce a long-lasting tolerance at MORs that persisted for more than

  7. Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression

    Directory of Open Access Journals (Sweden)

    Liu S

    2018-04-01

    Full Text Available Su Liu,1,2,* Jun-Li Yao,1,3,* Xin-Xin Wan,1,* Zhi-Jing Song,1 Shuai Miao,1,2 Ye Zhao,1,2 Xiu-Li Wang,1,2 Yue-Peng Liu4 1Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; 2Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; 3Department of Anesthesiology, Xuzhou Children’s Hospital, Xuzhou, Jiangsu, China; 4Center of Clinical Research and Translational Medicine, Lianyungang Oriental Hospital, Lianyungang, Jiangsu, China *These authors contributed equally to this work Purpose: Preventing opioid-induced hyperalgesia and tolerance continues to be a major clinical challenge, and the underlying mechanisms of hyperalgesia and tolerance remain elusive. Here, we investigated the role of sonic hedgehog (Shh signaling in opioid-induced hyperalgesia and tolerance. Methods: Shh signaling expression, behavioral changes, and neurochemical alterations induced by morphine were analyzed in male adult CD-1 mice with repeated administration of morphine. To investigate the contribution of Shh to morphine-induced hyperalgesia (MIH and tolerance, Shh signaling inhibitor cyclopamine and Shh small interfering RNA (siRNA were used. To explore the mechanisms of Shh signaling in MIH and tolerance, brain-derived neurotrophic factor (BDNF inhibitor K252 and anti-BDNF antibody were used. Results: Repeated administration of morphine produced obvious hyperalgesia and tolerance. The behavioral changes were correlated with the upregulation and activation of morphine treatment-induced Shh signaling. Pharmacologic and genetic inhibition of Shh signaling significantly delayed the generation of MIH and tolerance and associated neurochemical changes. Chronic morphine administration also induced upregulation of BDNF. Inhibiting BDNF effectively delayed the generation of MIH and tolerance. The upregulation of BDNF induced by morphine was significantly suppressed by inhibiting Shh

  8. The effect of O-1602, an atypical cannabinoid, on morphine-induced conditioned place preference and physical dependence.

    Science.gov (United States)

    Alavi, Mohaddeseh Sadat; Hosseinzadeh, Hossein; Shamsizadeh, Ali; Roohbakhsh, Ali

    2016-06-01

    Previous studies show that some non-CB1/non-CB2 effects of cannabinoids are mediated through G protein coupled receptor 55 (GPR55). As this receptor is activated by some of cannabinoid receptor ligands and is involved in the modulation of pain, it was hypothesized that this receptor may also interact with opioids. This study examined the effect of atypical cannabinoid O-1602 as a GPR55 agonist on morphine-induced conditioned place preference (CPP) and physical dependence. We used a biased CPP model to evaluate the effect of O-1602 (0.2, 1 and 5mg/kg, intraperitoneal; ip) on the acquisition and expression of morphine-induced CPP in male mice. The locomotor activities of mice were also recorded. Moreover, repeated administration of morphine (50, 50 and 75mg/kg/day) for three days, induced physical dependence. The withdrawal signs such as jumps and diarrhea were precipitated by administration of naloxone (5mg/kg, ip). The effect of O-1602 on the development of morphine physical dependence was assessed by injection of O-1602 (0.2, 1 and 5mg/kg) before morphine administrations. Morphine (40mg/kg, subcutaneous; sc), but not O-1602 (5mg/kg) elicited significant preference in the post-conditioning phase. O-1602 at the doses of 0.2 and 1mg/kg, but not 5mg/kg reduced acquisition of morphine CPP with an increase in locomotor activity at the dose of 5mg/kg. O-1602 at the doses of 0.2, 1 and 5mg/kg also reduced expression of morphine CPP with an increase in locomotor activity at the dose of 5mg/kg. O-1602 had a significant inhibitory effect on development of morphine-induced physical dependence at the dose of 5mg/kg by decreasing jumps and diarrhea during withdrawal syndrome. The present results indicate that O-1602 decreased acquisition and expression of morphine CPP and inhibited development of morphine-induced physical dependence. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  9. Bioavailability of morphine, methadone, hydromorphone, and oxymorphone following buccal administration in cats.

    Science.gov (United States)

    Pypendop, B H; Ilkiw, J E; Shilo-Benjamini, Y

    2014-06-01

    Buccal administration of buprenorphine is commonly used to treat pain in cats. It has been argued that absorption of buprenorphine through the buccal mucosa is high, in part due to its pKa of 8.24. Morphine, methadone, hydromorphone, and oxymorphone have a pKa between 8 and 9. This study characterized the bioavailability of these drugs following buccal administration to cats. Six healthy adult female spayed cats were used. Buccal pH was measured prior to drug administration. Morphine sulfate, 0.2 mg/kg IV or 0.5 mg/kg buccal; methadone hydrochloride, 0.3 mg/kg IV or 0.75 mg/kg buccal; hydromorphone hydrochloride, 0.1 mg/kg IV or 0.25 mg/kg buccal; or oxymorphone hydrochloride, 0.1 mg/kg IV or 0.25 mg/kg buccal were administered. All cats received all treatments. Arterial blood was sampled immediately prior to drug administration and at various times up to 8 h thereafter. Bioavailability was calculated as the ratio of the area under the time-concentration curve following buccal administration to that following IV administration, each indexed to the administered dose. Mean ± SE (range) bioavailability was 36.6 ± 5.2 (12.7-49.5), 44.2 ± 7.9 (18.7-70.5), 22.4 ± 6.9 (6.4-43.4), and 18.8 ± 2.0 (12.9-23.5)% for buccal administration of morphine, methadone, hydromorphone, and oxymorphone, respectively. Bioavailability of methadone was significantly higher than that of oxymorphone. © 2013 John Wiley & Sons Ltd.

  10. Improving enzymatic saccharification of cassava stem using peroxide and microwave assisted pre-treatment techniques

    Directory of Open Access Journals (Sweden)

    Sudha A.

    2017-01-01

    Full Text Available The effectiveness of microwave assisted alkali (MAA and alkaline hydrogen peroxide (AHP pre-treatment methods in improving the enzymatic saccharification of cassava stem was investigated. Ground cassava stems were by MAA method by varying microwave power, NaOH concentration and pre-treatment time. AHP method was performed at various H2O2 concentrations, pre-treatment temperatures and times. The results showed that reducing sugar yield was higher from MAA pretreated stem when compared with AHP pre-treatment, which demonstrated that MAA pre-treatment was effective in releasing sugars. SEM studies on the pre-treated samples revealed extensive distortion of fibres in MAA pre-treated than AHP pre-treated samples, which showed pores and cracks in the fibrous structure. Spectral studies showed the change in the chemical structure of pre-treated samples. The work revealed that the studied pre-treatment methods were effective in improving the enzymatic saccharification of cassava stem.

  11. Opioid tolerance in periaqueductal gray neurons isolated from mice chronically treated with morphine.

    Science.gov (United States)

    Bagley, Elena E; Chieng, Billy C H; Christie, MacDonald J; Connor, Mark

    2005-09-01

    The midbrain periaqueductal gray (PAG) is a major site of opioid analgesic action, and a significant site of cellular adaptations to chronic morphine treatment (CMT). We examined mu-opioid receptor (MOP) regulation of voltage-gated calcium channel currents (I(Ca)) and G-protein-activated K channel currents (GIRK) in PAG neurons from CMT mice. Mice were injected s.c. with 300 mg kg(-1) of morphine base in a slow release emulsion three times over 5 days, or with emulsion alone (vehicles). This protocol produced significant tolerance to the antinociceptive effects of morphine in a test of thermal nociception. Voltage clamp recordings were made of I(Ca) in acutely isolated PAG neurons and GIRK in PAG slices. The MOP agonist DAMGO (Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol enkephalin) inhibited I(Ca) in neurons from CMT mice (230 nM) with a similar potency to vehicle (150 nM), but with a reduced maximal effectiveness (37% inhibition in vehicle neurons, 27% in CMT neurons). Inhibition of I(Ca) by the GABA(B) agonist baclofen was not altered by CMT. Met-enkephalin-activated GIRK currents recorded in PAG slices were significantly smaller in neurons from CMT mice than vehicles, while GIRK currents activated by baclofen were unaltered. These data demonstrate that CMT-induced antinociceptive tolerance is accompanied by homologous reduction in the effectiveness of MOP agonists to inhibit I(Ca) and activate GIRK. Thus, a reduction in MOP number and/or functional coupling to G proteins accompanies the characteristic cellular adaptations to CMT previously described in PAG neurons.

  12. Optimization of Pre-Treatment Process Parameters to Generate Biodiesel from Microalga

    Directory of Open Access Journals (Sweden)

    Chukwuma Onumaegbu

    2018-03-01

    Full Text Available Cell disruption is an integral part of microalga production process, which improves the release of intracellular products that are essential for biofuel production. In this work, pre-treatment parameters that will enhance the efficiency of lipid production using high-pressure homogenizer on microalgae biomass will be investigated. The high-pressure homogenizer that is considered is a GYB40-10S/GY60-6S; with a pre-treatment pressure of 1000 psi, 2000 psi, and 3000 psi, the number of passes; 1, 2, and 3, a reaction time of 3, 3.5, and 4 h. Pressure and cavitation increase the efficiency of the pre-treatment process of the homogenizer. In addition, homogenization shear force and pressure are the basic significant factors that enhance the efficiency of microalgae cell rupture. Also, the use of modelling to simulate pre-treatment processes (Response Surface Methodology (RSM, Box-Behnken Designs (BBD, and design of experiment (DOE for process optimization will be adopted in this study. The results clearly demonstrate that high-pressure homogenization pre-treatment can effectively disrupt microalga cell walls to enhance lipid recovery efficiency, with a relatively short extraction time, both that are essential for maintaining a good quality of lipids for biofuel production. A maximum of 18% lipid yields were obtained after 3 h of HPH pre-treatment at 3000 psi.

  13. Comparison of epidural butorphanol versus epidural morphine in postoperative pain relief.

    Science.gov (United States)

    Parikh, Geeta P; Veena, Shah R; Vora, Kalpana; Parikh, Beena; Joshi, Anish

    2014-02-01

    Epidural route is preferable for postoperative pain relief in thoraco-abdominal and lower limb surgeries. We aimed to compare epidural butorphanol versus morphine for postoperative analgesia up to 24 hours in open nephrectomy surgery. 80 ASA physical status I and II adult patients were selected for this randomized double blind prospective study. A standard balanced general anesthesia technique was applied for all patients. Epidural catheter was placed in lower thoracic inter-vertebral space before the start of surgery. Injection butorphanol 0.04 mg/kg in group B (n = 40) or morphine 0.06 mg/kg in group M (n = 40) was given in a double blind manner after completion of surgery and before extubation through the epidural catheter. Patients were observed for pain relief by Visual Analogue Scale (VAS) for the next 24 hours. Dose was repeated when VAS was > 4. The onset and peak effect of pain relief, duration of analgesia of 1st dose, frequency of drug administration and side effects if any were observed. The average onset of analgesia was 26.5 +/- 7.61 minutes with butorphanol and 62.5 +/- 13.4 minutes with morphine group which was statistically significant (p < 0.05). The mean peak effect of pain relief following 1st dose was 173 +/- 51.25 minutes with butorphanol and 251 +/- 52.32 minutes with morphine group. The duration of pain relief after 1st dose was statistically significant and was 339.13 +/- 79.57 minutes in group B and 709.75 +/- 72.12 minutes in group M which was gradually increased on repeated dosing in group B while it was almost same in Group M. Number of doses required in 24 hours was significantly higher (p < 0.05) in butorphanol group than morphine group. Somnolence was the main side effect in group B while pruritus was the main side effect with group M. Epidural butorphanol appears to provide safer and faster postoperative analgesia without much untoward effects but its analgesic action is short so more repeated doses are required than morphine via

  14. Pain-relieving properties of topically applied morphine on arterial leg ulcers: a pilot study.

    NARCIS (Netherlands)

    Jansen, M.M.; Horst, J.C. van der; Valk, P.G.M. van der; Kuks, P.F.M.; Zylicz, Z.; Sorge, A.A. van

    2009-01-01

    OBJECTIVE: To assess whether topical morphine is pharmacologically effective in relieving pain from ulcers caused by arterial insufficiency and identify whether this effect is centrally or peripherally mediated. METHOD: The analgesic effect of a topically applied hydrogel containing 0.5% of morphine

  15. Effects of midazolam and morphine on cerebral oxygenation and hemodynamics in ventilated premature infants.

    NARCIS (Netherlands)

    Velden, A.A.E.M. van der; Hopman, J.C.W.; Klaessens, J.H.G.M.; Feuth, A.B.; Sengers, R.C.A.; Liem, K.D.

    2006-01-01

    BACKGROUND: Midazolam sedation and morphine analgesia are commonly used in ventilated premature infants. OBJECTIVES: To evaluate the effects of midazolam versus morphine infusion on cerebral oxygenation and hemodynamics in ventilated premature infants. METHODS: 11 patients (GA 26.6-33.0 weeks, BW

  16. Effect of pre-treatments on seed germination of Parkia biglobosa ...

    African Journals Online (AJOL)

    Effect of pre-treatments on seed germination of Parkia biglobosa (Benth) ... There has been emphasis on the use of indigenous tree species to check land ... out to investigate the most effective pre-sowing treatments to break seed dormancy and to ... Matured seeds of P. biglobosa were collected from farmers at Mbalagh ...

  17. Pre-Session Satiation as a Treatment for Stereotypy During Group Activities.

    Science.gov (United States)

    Rispoli, Mandy; Camargo, Síglia Hoher; Neely, Leslie; Gerow, Stephanie; Lang, Russell; Goodwyn, Fara; Ninci, Jennifer

    2014-05-01

    Individuals with developmental disabilities may engage in automatically reinforced behaviors that may interfere with learning opportunities. Manipulation of motivating operations has been shown to reduce automatically maintained behavior in some individuals. Considering behavioral indicators of satiation may assist in identifying the point at which an abolishing operation has begun to effect behavior. The purpose of this study was to evaluate the effects of pre-session satiation of automatic reinforcement on subsequent levels of stereotypy and activity engagement during group activities for three males ages 5 to 13 years with developmental disabilities. Following functional analyses with analogue conditions, an alternating treatment design compared a pre-session access to stereotypy condition with a no-pre-session access condition prior to group activity sessions. Results indicated that pre-session satiation of the putative reinforcer produced by stereotypy was effective in decreasing stereotypy and increasing activity engagement during subsequent group activities for all participants. These findings add to the literature supporting the effectiveness of abolishing operations to decrease automatically maintained stereotypy. © The Author(s) 2013.

  18. Inhibitory actions of methionine-enkephalin and morphine on the cat carotid chemoreceptors.

    Science.gov (United States)

    McQueen, D S; Ribeiro, J A

    1980-01-01

    1 The effects of intracarotid injections of methionine-enkephalin (Met-enkephalin) and morphine on chemoreceptor activity recorded from the peripheral end of a sectioned carotid sinus nerve have been studied in cats anaesthetized with pentobarbitone. 2 Met-enkephalin caused a rapid, powerful, inhibition of spontaneous chemoreceptor discharge, the intensity and duration of which was dose-dependent. 3 Morphine was a less potent inhibitor of spontaneous chemoreceptor discharge, and the inhibition it evoked was rather variable and tended to be biphasic. Low doses of morphine caused a slight increase in discharge. 4 Naloxone (0.2 mg i.c.) slightly increased spontaneous discharge, greatly reduced the chemo-inhibition caused by morphine, and reduced the inhibitory effect of Met-enkephalin. A higher dose of naloxone (0.8 mg) caused a substantial reduction of the Met-enkephalin effect. 5 Chemo-excitation evoked by intracarotid injections of acetylcholine, CO2-saturated Locke solution, and sodium cyanide were only slightly and somewhat variably reduced following injections of Met-enkephalin, whereas the inhibitory effect of dopamine was potentiated. Following morphine administration, response to acetylcholine and sodium cyanide were reduced slightly, whereas those to CO2 and dopamine were potentiated. 6 Responses to acetylcholine and CO2 were slightly potentiated during infusion of Met-enkephalin (50 micrograms/min, i.c.) and the response to sodium cyanide was slightly reduced. 7 It is concluded that naloxone-sensitive opiate receptors are present in the cat carotid body; when activated they cause inhibition of spontaneous chemoreceptor discharge. The physiological role of these receptors and the identity of any endogenous ligand remains to be established.

  19. Urinary concentrations of morphine and codeine after consumption of poppy seeds.

    Science.gov (United States)

    Thevis, Mario; Opfermann, Georg; Schänzer, Wilhelm

    2003-01-01

    A quantitative analysis of morphine and codeine in human urine was performed after oral intake of cakes containing commercially available poppy seeds in order to estimate the possibility of positive doping results. Therefore, eight products from different manufacturers (poppy seeds or baking mixtures) and origin were obtained and analyzed by gas chromatography-mass spectrometry for the presence of the alkaloids. One selected batch of poppy seeds was used as an ingredient in a typical cake and was the object of an excretion study with nine volunteers. After application, several urine specimens contained morphine with concentrations higher than 1 microg/mL, and peak values of approximately 10.0 microg/mL were detected. Because the International Olympic Committee set a cutoff limit for morphine at 1 microg/mL, high-performance athletes could possibly test positive in doping control after consumption of products containing poppy seeds.

  20. Optimization of Saccharification Conditions of Lignocellulosic Biomass under Alkaline Pre-Treatment and Enzymatic Hydrolysis

    Directory of Open Access Journals (Sweden)

    Rafał Łukajtis

    2018-04-01

    Full Text Available Pre-treatment is a significant step in the production of second-generation biofuels from waste lignocellulosic materials. Obtaining biofuels as a result of fermentation processes requires appropriate pre-treatment conditions ensuring the highest possible degree of saccharification of the feed material. An influence of the following process parameters were investigated for alkaline pre-treatment of Salix viminalis L.: catalyst concentration (NaOH, temperature, pre-treatment time and granulation. For this purpose, experiments were carried out in accordance to the Box-Behnken design for four factors. In the saccharification process of the pre-treated biomass, cellulolytic enzymes immobilized on diatomaceous earth were used. Based on the obtained results, a mathematical model for the optimal conditions of alkaline pre-treatment prediction is proposed. The optimal conditions of alkaline pre-treatment are established as follows: granulation 0.75 mm, catalyst concentration 7%, pre-treatment time 6 h and temperature 65 °C if the saccharification efficiency and cost analysis are considered. An influence of the optimized pre-treatment on both the chemical composition and structural changes for six various lignocellulosic materials (energetic willow, energetic poplar, beech, triticale, meadow grass, corncobs was investigated. SEM images of raw and pre-treated biomass samples are included in order to follow the changes in the biomass structure during hydrolysis.

  1. Lipid profile and levels of homocysteine, leptin, fibrinogen and C-reactive protein in hyperthyroid patients before and after treatment

    Directory of Open Access Journals (Sweden)

    Emine Sütken

    2010-03-01

    Full Text Available Objectives: The present study was carried out to determine whether thyroid hormones affect lipid profile and levels of erithrocyte sedimentation rate (ESR, serum total homocysteine (t-hcy, leptin, fibrinogen, C-reactive protein (CRP in patients with hyperthyroidism.Materials and methods: This study was carried out on 23 hyperthroid subjects (3 men / 20 women, mean age 41.8 ± 2.4 years. Serum levels of homocysteine, leptin, fibrinogen, CRP, total cholesterol (TC, high-density lipoprotein cholesterol (HDL-C, low-density lipoprotein cholesterol (LDL-C and ESR were measured and body mass index (BMI were calculated before and after treatment of hyperthyroidism.Results: Pretreatment t-hcy, TC, LDL-C, HDL-C levels and BMI of patients were significantly lower than those of the post-treatment (p<0.001, for each variable. However, fibrinogen and ESR decreased after the treatment (p<0.001 and p<0.05, respectively. There were no differences in leptin and CRP levels between pre- and post-treatment periods. Pre and post treatment TC and LDL-C levels were negatively correlated with free triiodothyronine (fT3 levels (r=-0.588, p<0.01; r=-0.534, p<0.01; r=-0.543, p<0.01 and r =-0.653, p<0.01, respectively. Pre-treatment HDL-C was inversely correlated with TSH (r=-0.423, p<0.05. Pre-post- treatment LDL-C was negatively correlated with free thyroxine (fT4 levels (r=-0.536, p<0.001 and r=- 0.422, p<0.05 respectively. Pre-treatment TC was inversely correlated with fT4 (r=-0.590, p<0.01.Conclusion: Hyperthyroidism is associated with high plasma fibrinogen and ESR levels. Elevated plasma fibrinogen and ESR levels may be a possible explanation for the high cardiovascular morbidity among hyperthyroidic subjects. These changes may reflect low-grade inflammation or disturbances in coagulation in hyperthyroidism.

  2. Analysis of covariance with pre-treatment measurements in randomized trials under the cases that covariances and post-treatment variances differ between groups.

    Science.gov (United States)

    Funatogawa, Takashi; Funatogawa, Ikuko; Shyr, Yu

    2011-05-01

    When primary endpoints of randomized trials are continuous variables, the analysis of covariance (ANCOVA) with pre-treatment measurements as a covariate is often used to compare two treatment groups. In the ANCOVA, equal slopes (coefficients of pre-treatment measurements) and equal residual variances are commonly assumed. However, random allocation guarantees only equal variances of pre-treatment measurements. Unequal covariances and variances of post-treatment measurements indicate unequal slopes and, usually, unequal residual variances. For non-normal data with unequal covariances and variances of post-treatment measurements, it is known that the ANCOVA with equal slopes and equal variances using an ordinary least-squares method provides an asymptotically normal estimator for the treatment effect. However, the asymptotic variance of the estimator differs from the variance estimated from a standard formula, and its property is unclear. Furthermore, the asymptotic properties of the ANCOVA with equal slopes and unequal variances using a generalized least-squares method are unclear. In this paper, we consider non-normal data with unequal covariances and variances of post-treatment measurements, and examine the asymptotic properties of the ANCOVA with equal slopes using the variance estimated from a standard formula. Analytically, we show that the actual type I error rate, thus the coverage, of the ANCOVA with equal variances is asymptotically at a nominal level under equal sample sizes. That of the ANCOVA with unequal variances using a generalized least-squares method is asymptotically at a nominal level, even under unequal sample sizes. In conclusion, the ANCOVA with equal slopes can be asymptotically justified under random allocation. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Fractalkine/CX3CL1 protects striatal neurons from synergistic morphine and HIV-1 Tat-induced dendritic losses and death

    Directory of Open Access Journals (Sweden)

    Suzuki Masami

    2011-11-01

    Full Text Available Abstract Background Fractalkine/CX3CL1 and its cognate receptor CX3CR1 are abundantly expressed in the CNS. Fractalkine is an unusual C-X3-C motif chemokine that is important in neuron-microglial communication, a co-receptor for HIV infection, and can be neuroprotective. To assess the effects of fractalkine on opiate-HIV interactive neurotoxicity, wild-type murine striatal neurons were co-cultured with mixed glia from the striata of wild-type or Cx3cr1 knockout mice ± HIV-1 Tat and/or morphine. Time-lapse digital images were continuously recorded at 20 min intervals for up to 72 h using computer-aided microscopy to track the same cells repeatedly. Results Co-exposure to Tat and morphine caused synergistic increases in neuron death, dendritic pruning, and microglial motility as previously reported. Exogenous fractalkine prevented synergistic Tat and morphine-induced dendritic losses and neuron death even though the inflammatory mediator TNF-α remained significantly elevated. Antibody blockade of CX3CR1 mimicked the toxic effects of morphine plus Tat, but did not add to their toxicity; while fractalkine failed to protect wild-type neurons co-cultured with Cx3cr1-/--null glia against morphine and Tat toxicity. Exogenous fractalkine also normalized microglial motility, which is elevated by Tat and morphine co-exposure, presumably limiting microglial surveillance that may lead to toxic effects on neurons. Fractalkine immunofluorescence was expressed in neurons and to a lesser extent by other cell types, whereas CX3CR1 immunoreactivity or GFP fluorescence in cells cultured from the striatum of Cx3cr1-/- (Cx3cr1GFP/GFP mice were associated with microglia. Immunoblotting shows that fractalkine levels were unchanged following Tat and/or morphine exposure and there was no increase in released fractalkine as determined by ELISA. By contrast, CX3CR1 protein levels were markedly downregulated. Conclusions The results suggest that deficits in fractalkine

  4. Influence of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference in rats.

    Science.gov (United States)

    Gawel, Kinga; Labuz, Krzysztof; Jenda, Malgorzata; Silberring, Jerzy; Kotlinska, Jolanta H

    2014-07-15

    The influence of systemic administration of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference (CPP) was examined in rats. Additionally, this study aimed to compare the effects of donepezil, which selectively inhibits acetylcholinesterase, and rivastigmine, which inhibits both acetylcholinesterase and butyrylcholinesterase on morphine reward. Morphine-induced CPP (unbiased method) was induced by four injections of morphine (5 mg/kg, i.p.). Donepezil (0.5, 1, and 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5, and 1 mg/kg, i.p.) were given 20 min before morphine during conditioning phase and 20 min before the expression or reinstatement of morphine-induced CPP. Our results indicated that both inhibitors of cholinesterase attenuated the acquisition and expression of morphine CPP. The results were more significant after rivastigmine due to a broader inhibitory spectrum of this drug. Moreover, donepezil (1 mg/kg) and rivastigmine (0.5 mg/kg) attenuated the morphine CPP reinstated by priming injection of 5mg/kg morphine. These properties of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist but not scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. All effects of cholinesterase inhibitors were observed at the doses that had no effects on locomotor activity of animals. Our results suggest beneficial role of cholinesterase inhibitors in reduction of morphine reward and morphine-induced seeking behavior. Finally, we found that the efficacy of cholinesterase inhibitors in attenuating reinstatement of morphine CPP provoked by priming injection may be due to stimulation of nicotinic acetylcholine receptors. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. [Pre- and post-surgical orthodontic treatment of mandibular asymmetry and prognathism].

    Science.gov (United States)

    Chen, Song; Chen, Yang-xi; Hu, Jing

    2005-01-01

    The purpose of this study was to analyze the pre- and post surgical orthodontic treatment of mandibular asymmetry and prognathism in our hospital, and to summarize some helpful experiences for future clinical work. The data were derived from 21 adults aged from 19 - 28 years who had severe mandibular asymmetry and prognathism. The ANB angle of all patients is from -3 degrees to -8 degrees. The value of wits of all patients is from -7 mm to -14 mm. The deviation of chin point of all patients is from 3 mm to 7 mm. The duration of pre- and post-surgical orthodontic treatment was 10-20 months (mean 18 months) and 5-10 months (mean 7.5 months), respectively. The keys in pre-surgical orthodontic treatment include (1) three dimensional dental decompensation; (2) arch form and transverse discrepancy correction; (3) model surgery and the splint making. The main objective of post surgical orthodontic treatment is to detail the occlusion. Pre- and post surgical orthodontic treatment is essential for the orthognathic treatment of patients with mandibular asymmetry and prognathism.

  6. Effects of casoxin 4 on morphine inhibition of small animal intestinal contractility and gut transit in the mouse

    Directory of Open Access Journals (Sweden)

    Glen S Patten

    2011-02-01

    Full Text Available Glen S Patten1,2, Richard J Head1, Mahinda Y Abeywardena1,21CSIRO Preventative Health National Research Flagship, Adelaide, Australia; 2CSIRO Food and Nutritional Sciences, Adelaide, AustraliaBackground and aims: Chronic opioid analgesia has the debilitating side-effect of constipation in human patients. The major aims of this study were to: 1 characterize the opioid-specific antagonism of morphine-induced inhibition of electrically driven contraction of the small intestine of mice, rats, and guinea pigs; and 2 test if the oral delivery of small milk-derived opioid antagonist peptides could block morphine-induced inhibition of intestinal transit in mice.Methods: Mouse, rat, and guinea pig intact ileal sections were electrically stimulated to contract and inhibited with morphine in vitro. Morphine inhibition was then blocked by opioid subtype antagonists in the mouse and guinea pig. Using a polymeric dye, Poly R-478, the opioid antagonists casoxin 4 and lactoferroxin A were tested orally for blocking activity of morphine inhibition of gut transit in vivo by single or double gavage techniques.Results: The guinea pig tissue was more sensitive to morphine inhibition compared with the mouse or the rat (IC50 [half maximal inhibitory concentration] values as nmol/L ± SEM were 34 ± 3, 230 ± 13, and 310 ± 14 respectively (P < 0.01. The inhibitory influence of opioid agonists (IC50 in electrically driven ileal mouse preparations were DADLE ([D-Ala2, D-Leu5]-enkephalin ≥ met-enkephalin ≥ dynorphin A ≥ DAMGO ([D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin > morphine > morphiceptin as nmol/L 13.9, 17.3, 19.5, 23.3, 230, and 403 respectively. The mouse demonstrated predominantly Κ- and δ-opioid receptor activity with a smaller µ-opioid receptor component. Both mouse and guinea pig tissue were sensitive to casoxin 4 antagonism of morphine inhibition of contraction. In contrast to naloxone, relatively high oral doses of the µ-opioid receptor antagonists

  7. Application of ceramic membranes for seawater reverse osmosis (SWRO) pre-treatment

    KAUST Repository

    Hamad, Juma; Ha, Changwon; Kennedy, Maria Dolores; Amy, Gary L.

    2013-01-01

    and particulate fouling materials (algae, suspended and colloidal particles). Also, a pre-treatment barrier reduces organics and provides better feed water quality for RO membranes. MF and UF pre-treatment prior to SWRO provides Low Silt Density Index (SDI) values

  8. A voltammetric sensor based on NiO/CNTs ionic liquid carbon paste electrode for determination of morphine in the presence of diclofenac

    International Nuclear Information System (INIS)

    Sanati, Afsaneh L.; Karimi-Maleh, Hassan; Badiei, Alireza; Biparva, Pourya; Ensafi, Ali A.

    2014-01-01

    A novel ionic liquid modified NiO/CNTs carbon paste electrode (IL/NiO/CNTCPE) had been fabricated by using hydrophilic ionic liquid 1-methyl-3-butylimidazolium chloride [MBIDZ]Cl as a binder. The cyclic voltammogram showed an irreversible oxidation peak at 0.61 V (vs. Ag/AgCl sat ), which corresponded to the oxidation of morphine. Compared to common carbon paste electrode, the electrochemical response was greatly improved for morphine electrooxidation. This modified electrode exhibited a potent and persistent electron mediating behavior followed by well separated oxidation peaks of morphine and diclofenac. Detection limit of morphine was found to be 0.01 μM using square wave voltammetry (SWV) method. The proposed sensor was successfully applied for the determination of morphine in human urine and pharmaceutical samples. - Graphical abstract: Diclofenac as a nonsteroidal anti-inflammatory drug has been shown to decrease morphine consumption after operation in adults. The addition of regular doses of diclofenac may reduce the need for morphine after abdominal surgery. Therefore, in this study we describe a sensitive electrochemical sensor for simultaneous determination of morphine and diclofenac. - Highlights: • Electrochemical behavior of morphine study using modified carbon paste electrode • The sensor resolved the overlap of morphine and diclofenac • This sensor is also used for the determination of morphine in real samples

  9. A voltammetric sensor based on NiO/CNTs ionic liquid carbon paste electrode for determination of morphine in the presence of diclofenac

    Energy Technology Data Exchange (ETDEWEB)

    Sanati, Afsaneh L. [Department of Chemistry, Graduate University of Advanced Technology, Kerman (Iran, Islamic Republic of); Karimi-Maleh, Hassan, E-mail: h.karimi.maleh@gmail.com [Department of Chemistry, Graduate University of Advanced Technology, Kerman (Iran, Islamic Republic of); Badiei, Alireza [School of Chemistry, College of Science, University of Tehran, Tehran (Iran, Islamic Republic of); Biparva, Pourya [Department of Basic Sciences, Sari Agricultural Sciences and Natural Resources University, Sari (Iran, Islamic Republic of); Ensafi, Ali A. [Department of Chemistry, Isfahan University of Technology, Isfahan 84156-83111 (Iran, Islamic Republic of)

    2014-02-01

    A novel ionic liquid modified NiO/CNTs carbon paste electrode (IL/NiO/CNTCPE) had been fabricated by using hydrophilic ionic liquid 1-methyl-3-butylimidazolium chloride [MBIDZ]Cl as a binder. The cyclic voltammogram showed an irreversible oxidation peak at 0.61 V (vs. Ag/AgCl{sub sat}), which corresponded to the oxidation of morphine. Compared to common carbon paste electrode, the electrochemical response was greatly improved for morphine electrooxidation. This modified electrode exhibited a potent and persistent electron mediating behavior followed by well separated oxidation peaks of morphine and diclofenac. Detection limit of morphine was found to be 0.01 μM using square wave voltammetry (SWV) method. The proposed sensor was successfully applied for the determination of morphine in human urine and pharmaceutical samples. - Graphical abstract: Diclofenac as a nonsteroidal anti-inflammatory drug has been shown to decrease morphine consumption after operation in adults. The addition of regular doses of diclofenac may reduce the need for morphine after abdominal surgery. Therefore, in this study we describe a sensitive electrochemical sensor for simultaneous determination of morphine and diclofenac. - Highlights: • Electrochemical behavior of morphine study using modified carbon paste electrode • The sensor resolved the overlap of morphine and diclofenac • This sensor is also used for the determination of morphine in real samples.

  10. Oral morphine versus ibuprofen administered at home for postoperative orthopedic pain in children: a randomized controlled trial.

    Science.gov (United States)

    Poonai, Naveen; Datoo, Natasha; Ali, Samina; Cashin, Megan; Drendel, Amy L; Zhu, Rongbo; Lepore, Natasha; Greff, Michael; Rieder, Michael; Bartley, Debra

    2017-10-10

    Oral morphine for postoperative pain after minor pediatric surgery, while increasingly popular, is not supported by evidence. We evaluated whether oral morphine was superior to ibuprofen for at-home management of children's postoperative pain. We conducted a randomized superiority trial comparing oral morphine (0.5 mg/kg) with ibuprofen (10 mg/kg) in children 5 to 17 years of age who had undergone minor outpatient orthopedic surgery (June 2013 to September 2016). Participants took up to 8 doses of the intervention drug every 6 hours as needed for pain at home. The primary outcome was pain, according to the Faces Pain Scale - Revised, for the first dose. Secondary outcomes included additional analgesic requirements, adverse effects, unplanned health care visits and pain scores for doses 2 to 8. We analyzed data for 77 participants in each of the morphine and ibuprofen groups. Both interventions decreased pain scores with no difference in efficacy. The median difference in pain score before and after the first dose of medication was 1 (interquartile range 0-1) for both morphine and ibuprofen ( p = 0.2). For doses 2 to 8, the median differences in pain score before and after the dose were not significantly different between groups. Significantly more participants taking morphine reported adverse effects (45/65 [69%] v. 26/67 [39%], p ibuprofen groups, respectively; p = 0.003). Morphine was not superior to ibuprofen, and both drugs decreased pain with no apparent difference in efficacy. Morphine was associated with significantly more adverse effects, which suggests that ibuprofen is a better first-line option after minor surgery. ClinicalTrials.gov, no. NCT01686802. © 2017 Canadian Medical Association or its licensors.

  11. Comparison of the cardio-respiratory effects of methadone and morphine in conscious dogs.

    Science.gov (United States)

    Maiante, A A; Teixeira Neto, F J; Beier, S L; Corrente, J E; Pedroso, C E B P

    2009-08-01

    The effects of methadone and morphine were compared in conscious dogs. Six animals received morphine sulfate (1 mg/kg) or methadone hydrochloride (0.5 mg/kg [MET0.5] or 1.0 mg/kg [MET1.0]) intravenously (i.v.) in a randomized complete block design. Cardiopulmonary variables were recorded before (baseline), and for 120 min after drug administration. One outlier was not included in the statistical analysis for hemodynamic data. Morphine decreased heart rate (HR) compared to baseline from 30 to 120 min (-15% to -26%), while cardiac index (CI) was reduced only at 120 min (-19%). Greater and more prolonged reductions in HR (-32% to -46%) and in CI (-24% to -52%) were observed after MET1.0, while intermediate reductions were recorded after MET0.5 (-19 to -28% for HR and -17% to -27% for CI). The systemic vascular resistance index (SVRI) was increased after methadone; MET1.0 produced higher SVRI values than MET0.5 (maximum increases: 57% and 165% for MET0.5 and MET1.0, respectively). Compared to morphine, oxygen partial pressure (PaO(2)) was lower (-12% to -13%) at 5 min of methadone (0.5 and 1.0 mg/kg), while carbon dioxide partial pressure (PaCO(2)) did not change significantly. It was concluded that methadone induces cardiovascular changes that are dose-related and is a more potent cardiovascular depressant agent than morphine in conscious dogs.

  12. Performance of seeds Crambe exposed to pre-germination treatments

    International Nuclear Information System (INIS)

    Rocha Cardoso, Rebeca; Costa Nobre, Danubia Aparecida; Santos de Souza David, Andreia Marcia; Ribeiro Amaro, Hugo Tiago; Borghetti, Renato Antonio; Costa, Marcia Regina

    2014-01-01

    Encouraging the production and use of biodiesel, seeds of crambe today constitute one of the best options for the supply of raw material, is also an excellent alternative for autumn-winter crop rotation order. The aim of this study was to evaluate the efficiency of combined pre-germination treatments on the seed behavior of Crambe. From a seed sample of FMS Brilhante cultivar, an experimental design completely randomized with a 2 x 5 factorial arrangement was performed. it was formed from combination of two structural conditions, seeds with or without pericarp, and treatments with or without giberelic acid, being: control (no treatment); seeds pre-soaked in distilled water for 24 hours as control; and seeds pre-soaked in gibberellic acid at 4 % at different concentrations (400, 500 and 600 mg.L"-1). Water content, first count germination, germination, seedling emergence and emergence rate index were determined. From these results it is concluded that removal of the pericarp in seed of Crambe, cultivar FMS brilhante, accelerated the germination rate, however, decreased your final percentage. The pre-soaking in gibberellic acid (400, 500 and 600 mg L"-1) for 24 hours, increased the germination and seed vigor crambe with pericarp.

  13. pre-germination treatments in castor seeds, cultivar IAC 226

    International Nuclear Information System (INIS)

    Costa Nobre, Danubia Aparecida; Gomes Damascena, Joyce; Marcia, Andreia; Santos de Souza, David; Pereira dos Santos, Marlucia; Rodrigues Pereira, Adriana; Goncalves Pereira, Cassio

    2013-01-01

    The present study aimed to evaluate the efficiency of different pre-germination treatments in castor beans, IAC 226. The experimental design was completely randomized in a factorial 4 x 4 (four temperatures and four immersion times), with four replications. Pre-germination treatments were: immersion in water at room temperature (25 Celsius degrade) and immersion in hot water at temperatures of 60, 70 and 80 Celsius degrade for 2, 4, 6 and 8 minutes. Water content of the seeds was determined before treatments. Before and after each treatment, seeds were subjected to germination test; 20-30 Celsius degrade alternating temperature, determining the percentages of normal and abnormal seedlings, dormant and dead seeds. Independent of time, immersion in 70 Celsius degrade, water was the most efficient treatment for accelerating germination of castor bean cultivar IAC 226.

  14. Automated radiosynthesis of [{sup 11}C]morphine for clinical investigation

    Energy Technology Data Exchange (ETDEWEB)

    Fan Jinda [Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110 (United States); Meissner, Konrad [Department of Anesthesiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110 (United States); Gaehle, Gregory G.; Li Shihong [Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110 (United States); Kharasch, Evan D. [Department of Anesthesiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110 (United States); Mach, Robert H. [Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110 (United States); Tu Zhude, E-mail: tuz@mir.wustl.ed [Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110 (United States)

    2011-02-15

    To meet a multiple-dose clinical evaluation of the P-gp modulation of [{sup 11}C]morphine delivery into the human brain, radiosynthesis of [{sup 11}C]morphine was accomplished on an automated system by N-methylation of normorphine with [{sup 11}C]CH{sub 3}I. A methodology employing optimized solid phase extraction of the HPLC eluent was developed. Radiosynthesis took 45 min with a radiochemical yield ranging from 45% to 50% and specific activity ranging from 20 to 26 Ci/{mu}mol (decay corrected to end-of-bombardment); radiochemical and chemical purities were >95% (n=28).

  15. Morphine Reward Promotes Cue-Sensitive Learning: Implication of Dorsal Striatal CREB Activity

    Directory of Open Access Journals (Sweden)

    Mathieu Baudonnat

    2017-05-01

    Full Text Available Different parallel neural circuits interact and may even compete to process and store information: whereas stimulus–response (S–R learning critically depends on the dorsal striatum (DS, spatial memory relies on the hippocampus (HPC. Strikingly, despite its potential importance for our understanding of addictive behaviors, the impact of drug rewards on memory systems dynamics has not been extensively studied. Here, we assessed long-term effects of drug- vs food reinforcement on the subsequent use of S–R vs spatial learning strategies and their neural substrates. Mice were trained in a Y-maze cue-guided task, during which either food or morphine injections into the ventral tegmental area (VTA were used as rewards. Although drug- and food-reinforced mice learned the Y-maze task equally well, drug-reinforced mice exhibited a preferential use of an S–R learning strategy when tested in a water-maze competition task designed to dissociate cue-based and spatial learning. This cognitive bias was associated with a persistent increase in the phosphorylated form of cAMP response element-binding protein phosphorylation (pCREB within the DS, and a decrease of pCREB expression in the HPC. Pharmacological inhibition of striatal PKA pathway in drug-rewarded mice limited the morphine-induced increase in levels of pCREB in DS and restored a balanced use of spatial vs cue-based learning. Our findings suggest that drug (opiate reward biases the engagement of separate memory systems toward a predominant use of the cue-dependent system via an increase in learning-related striatal pCREB activity. Persistent functional imbalance between striatal and hippocampal activity could contribute to the persistence of addictive behaviors, or counteract the efficiency of pharmacological or psychotherapeutic treatments.

  16. Influences of mechanical pre-treatment on the non-biological treatment of municipal wastewater by forward osmosis

    DEFF Research Database (Denmark)

    Hey, Tobias; Zarebska, Agata; Bajraktari, Niada

    2016-01-01

    municipal wastewater treatment without the biological treatment step, including the effects of different pre-treatment configurations, e.g., direct membrane filtration before forward osmosis. Forward osmosis was tested using raw wastewater and wastewater subjected to different types of mechanical pre-treatment......, e.g., microsieving and microfiltration permeation, as a potential technology for municipal wastewater treatment. Forward osmosis was performed using thin-film-composite, Aquaporin Inside(TM) and HTI membranes with NaCl as the draw solution. Both types of forward osmosis membranes were tested......-sized wastewater treatment plants....

  17. Fluoxetine, a selective inhibitor of serotonin uptake, potentiates morphine analgesia without altering its discriminative stimulus properties or affinity for opioid receptors

    International Nuclear Information System (INIS)

    Hynes, M.D.; Lochner, M.A.; Bemis, K.G.; Hymson, D.L.

    1985-01-01

    The analgesic effect of morphine in the rat tail jerk assay was enhanced by the serotonin uptake inhibitor, fluoxetine. Tail jerk latency was not affected by fluoxetine alone. Morphine's affinity for opioid receptors labeled in vitro with 3 H-naloxone or 3 H-D-Ala 2 -D-Leu 5 -enkephalin was not altered by fluoxetine, which has no affinity for these sites at concentrations as high as 1000 nM. In rats trained to discriminate morphine from saline, fluoxetine at doses of 5 or 10 mg/kg were recognized as saline. Increasing the fluoxetine dose to 20 mg/kg did not result in generalization to either saline or morphine. The dose response curve for morphine generalization was not significantly altered by fluoxetine doses of 5 or 10 mg/kg. Those rats treated with the combination of morphine and 20 mg/kg of fluoxetine did not exhibit saline or morphine appropriate responding. Fluoxetine potentiates the analgesic properties of morphine without enhancing its affinity for opioid receptors or its discriminative stimulus properties. 30 references, 2 figures, 2 tables

  18. Meta-Analysis of the Ease of Care From the Nurses' Perspective Comparing Fentanyl Iontophoretic Transdermal System (ITS) Vs Morphine Intravenous Patient-Controlled Analgesia (IV PCA) in Postoperative Pain Management.

    Science.gov (United States)

    Pestano, Cecile R; Lindley, Pam; Ding, Li; Danesi, Hassan; Jones, James B

    2017-08-01

    The aim of this meta-analysis was to compare the ease of care (EOC) of fentanyl iontophoretic transdermal system (ITS) vs the morphine intravenous patient-controlled analgesia (IV PCA) as assessed by the nurse. Meta-analysis of three phase 3B randomized active-comparator trials. This meta-analysis according to Cochrane's approach assessed EOC using a validated nurse questionnaire (22 items grouped into three subscales, which include time efficiency, convenience, and satisfaction) in adult patients treated with fentanyl ITS or morphine IV PCA for postoperative pain management. The weighted mean difference (WMD) between treatments was calculated. EOC analyses were based on responses to questionnaires from 848 (fentanyl ITS) and 761 (morphine IV PCA) nurses. Fentanyl ITS was reported to provide significant advantages compared with morphine IV PCA in terms of nurses' overall EOC (WMD = -0.57, P PCA. Copyright © 2016 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.

  19. Morphine analgesia and cerebral opiate receptors: a developmental study

    International Nuclear Information System (INIS)

    Auguy-Valette, A.; Pontonnier, G.; Cros, J.; Gouarderes, C.; Gout, R.

    1978-01-01

    Development of the analgesic response to morphine and ontogenesis of central opiate receptors were analyzed in rats 5 to 120 days old. The analgesic effect of morphine increased until day 15, after which it decreased to reach a plateau at about day 30. With phenoperidine, on the other hand, the analgesic effect increased until day 15, remained constant between day 15 and day 30 after which it decreased slowly. The ratio of the amounts of morphine in blood over those in brain increased about 3 fold between day 15 and day 30. Opiate receptors were detected in the brain of newborn rats; stereospecific binding of [ 3 H]-naloxone at 10 and 50 nM indicated the presence of low and high affinity binding sites. The number of [ 3 H]-naloxone binding sites increased rapidly during the second and third week after birth. Their affinity for several opiates remained constant throughout development. These results indicate that the analgesic activity of opiates varies with age: until day 15, the analgesic effect of opiates increases in parallel with the number of opiate brain receptors. Then, the formation of the blood brain barrier introduces an additional step in the regulation of opiate activity. (author)

  20. Preservation of Retina Ganglion Cell Function by Morphine in a Chronic Ocular-Hypertensive Rat Model

    OpenAIRE

    Husain, Shahid; Abdul, Yasir; Crosson, Craig E.

    2012-01-01

    Morphine, a broad range opioid-receptors agonist, provides retina neuroprotection against glaucomatous injury in chronic experimental rat model. Morphine-induced retina neuroprotection in glaucoma model is mediated partly via inhibition of TNF-alpha production and caspase-3 and caspase-8 activation.

  1. Diagnostic accuracy of pre-treatment biopsy for grading cutaneous mast cell tumours in dogs.

    Science.gov (United States)

    Shaw, T; Kudnig, S T; Firestone, S M

    2018-06-01

    Mast cell tumours (MCTs) are common tumours of the canine skin, and are estimated to represent up to 20% of all skin tumours in dogs. Tumour grade has a major impact on the incidence of local recurrence and metastatic potential. In addition to helping the clinician with surgical planning, knowledge of the tumour grade also assists in proper prognostication and client education. For pre-treatment biopsies to be useful, there must exist a high level of correlation between the histopathological grade obtained from the pre-treatment biopsy and the actual histopathological grade from the excisional biopsy. The aim of this study was to determine concordance of tumour grade between various biopsy techniques (wedge, punch, needle core) and the "gold standard" excisional biopsy method. We found an overall concordance rate of 96% based on the Patnaik grading system, and an overall concordance rate of 92% based on the Kiupel grading system. The accuracy of the various biopsy techniques (wedge, punch and needle core) when compared with excisional biopsy was 92%, 100% and 100%, respectively, based on the Patnaik grading system, and 90%, 95% and 100%, respectively, based on the Kiupel grading system. Of the cases with discordant results, the pre-treatment biopsies tended to underestimate the grade of the tumour. Based on these results, we conclude that pre-treatment biopsies are sufficiently accurate for differentiating low-grade from high-grade MCTs, regardless of biopsy technique or tumour location. © 2017 John Wiley & Sons Ltd.

  2. Biochemical and behavioral effects of phospholipase A2 and morphine microinjections in the periaqueductal gray of the rat

    International Nuclear Information System (INIS)

    Reichman, M.; Abood, L.G.; Costanzo, M.

    1985-01-01

    In order to characterize the in vivo action of phospholipase A 2 (PLA 2 ) on opiate receptors and opiate-induced behaviors, the effects of injections of PLA 2 into the periaqueductal gray region (PAG) of the rat were assessed on free fatty acid (FFA) release, opiate-binding levels, and morphine-induced behaviors. Rats received bilateral PAG injections of 2 μg of PLA 2 while anesthetized. One hour later, regions around the cannulae tracts in PLA 2 -treated rats contained over 2.5 times more FFA than saline-injected controls, and 3 H-dihydromorphine binding was reduced on average more than 70%. In another series of experiments, conscious rats were given 2 μg of PLA 2 prior to 10 μg of morphine through cannulae chronically implanted into the PAG. PLA 2 did not significantly attenuate morphine-induced analgesia as measured by the tail-flick test to radiant heat, but did prevent the explosive motor behavior observed following morphine injections alone. PLA 2 by itself did not induce analgesia, but did cause explosive motor behavior 2 hr after the injections. Neither lysophosphatidylcholine nor trypsin resulted in motor seizures following PAG injections. It was concluded that the behavioral effects of PLA 2 result from the unique properties of the enzyme, rather than generalized membrane damage, and that the opioid sites and mechanisms that mediate analgesia are different from those associated with explosive motor behavior. 36 references, 2 figures, 2 tables

  3. Retrospective analysis of the financial break-even point for intrathecal morphine pump use in Korea.

    Science.gov (United States)

    Kim, Eun Kyoung; Shin, Ji Yeon; Castañeda, Anyela Marcela; Lee, Seung Jae; Yoon, Hyun Kyu; Kim, Yong Chul; Moon, Jee Youn

    2017-10-01

    The high cost of intrathecal morphine pump (ITMP) implantation may be the main obstacle to its use. Since July 2014, the Korean national health insurance (NHI) program began paying 50% of the ITMP implantation cost in select refractory chronic pain patients. The aims of this study were to investigate the financial break-even point and patients' satisfaction in patients with ITMP treatment after the initiation of the NHI reimbursement. We collected data retrospectively or via direct phone calls to patients who underwent ITMP implantation at a single university-based tertiary hospital between July 2014 and May 2016. Pain severity, changes in the morphine equivalent daily dosage (MEDD), any adverse events, and patients' satisfaction were determined. We calculated the financial break-even point of ITMP implantation via investigating the patient's actual medical costs and insurance information. During the studied period, 23 patients received ITMP implantation, and 20 patients were included in our study. Scores on an 11-point numeric rating scale (NRS) for pain were significantly reduced compared to the baseline value ( P break-even point was 28 months for ITMP treatment after the NHI reimbursement policy. ITMP provided effective chronic pain management with improved satisfaction and reasonable financial break-even point of 28 months with 50% financial coverage by NHI program.

  4. Rescue pre-operative treatment with Lugol’s solution in uncontrolled Graves’ disease

    Directory of Open Access Journals (Sweden)

    Jan Calissendorff

    2017-04-01

    Full Text Available Background: Graves’ disease is a common cause of hyperthyroidism. Three therapies have been used for decades: pharmacologic therapy, surgery and radioiodine. In case of adverse events, especially agranulocytosis or hepatotoxicity, pre-treatment with Lugol’s solution containing iodine/potassium iodide to induce euthyroidism before surgery could be advocated, but this has rarely been reported. Methods: All patients hospitalised due to uncontrolled hyperthyroidism at the Karolinska University Hospital 2005–2015 and treated with Lugol’s solution were included. All electronic files were carefully reviewed manually, with focus on the cause of treatment and admission, demographic data, and effects of iodine on thyroid hormone levels and pulse frequency. Results: Twenty-seven patients were included. Lugol’s solution had been chosen due to agranulocytosis in 9 (33%, hepatotoxicity in 2 (7%, other side effects in 11 (41% and poor adherence to medication in 5 (19%. Levels of free T4, free T3 and heart rate decreased significantly after 5–9 days of iodine therapy (free T4 53–20 pmol/L, P = 0.0002; free T3 20–6.5 pmol/L, P = 0.04; heart rate 87–76 beats/min P = 0.0007, whereas TSH remained unchanged. Side effects were noted in 4 (15% (rash n = 2, rash and vomiting n = 1, swelling of fingers n = 1. Thyroidectomy was performed in 26 patients (96% and one was treated with radioiodine; all treatments were without serious complications. Conclusion: Treatment of uncontrolled hyperthyroidism with Lugol’s solution before definitive treatment is safe and it decreases thyroid hormone levels and heart rate. Side effects were limited. Lugol’s solution could be recommended pre-operatively in Graves’ disease with failed medical treatment, especially if side effects to anti-thyroid drugs have occurred.

  5. Deletion of the δ opioid receptor gene impairs place conditioning but preserves morphine reinforcement.

    Science.gov (United States)

    Le Merrer, Julie; Plaza-Zabala, Ainhoa; Del Boca, Carolina; Matifas, Audrey; Maldonado, Rafael; Kieffer, Brigitte L

    2011-04-01

    Converging experimental data indicate that δ opioid receptors contribute to mediate drug reinforcement processes. Whether their contribution reflects a role in the modulation of drug reward or an implication in conditioned learning, however, has not been explored. In the present study, we investigated the impact of δ receptor gene knockout on reinforced conditioned learning under several experimental paradigms. We assessed the ability of δ receptor knockout mice to form drug-context associations with either morphine (appetitive)- or lithium (aversive)-induced Pavlovian place conditioning. We also examined the efficiency of morphine to serve as a positive reinforcer in these mice and their motivation to gain drug injections, with operant intravenous self-administration under fixed and progressive ratio schedules and at two different doses. Mutant mice showed impaired place conditioning in both appetitive and aversive conditions, indicating disrupted context-drug association. In contrast, mutant animals displayed intact acquisition of morphine self-administration and reached breaking-points comparable to control subjects. Thus, reinforcing effects of morphine and motivation to obtain the drug were maintained. Collectively, the data suggest that δ receptor activity is not involved in morphine reinforcement but facilitates place conditioning. This study reveals a novel aspect of δ opioid receptor function in addiction-related behaviors. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  6. Sex differences between CRF1 receptor deficient mice following naloxone-precipitated morphine withdrawal in a conditioned place aversion paradigm: implication of HPA axis.

    Directory of Open Access Journals (Sweden)

    Juan-Antonio García-Carmona

    Full Text Available Extinction period of positive affective memory of drug taking and negative affective memory of drug withdrawal, as well as the different response of men and women might be important for the clinical treatment of drug addiction. We investigate the role of corticotropin releasing factor receptor type one (CRF1R and the different response of male and female mice in the expression and extinction of the aversive memory.We used genetically engineered male and female mice lacking functional CRF1R. The animals were rendered dependent on morphine by intraperitoneally injection of increasing doses of morphine (10-60 mg/kg. Negative state associated with naloxone (1 mg/kg s.c.-precipitated morphine withdrawal was examined by using conditioned place aversion (CPA paradigm. No sex differences for CPA expression were found in wild-type (n = 29 or CRF1R knockout (KO mice (n = 29. However, CRF1R KO mice presented less aversion score than wild-type mice, suggesting that CRF1R KO mice were less responsive than wild-type to continuous associations between drug administration and environmental stimuli. In addition, CPA extinction was delayed in wild-type and CRF1R KO male mice compared with females of both genotypes. The genetic disruption of the CRF1R pathway decreased the period of extinction in males and females suggesting that CRF/CRF1R is implicated in the duration of aversive memory. Our results also showed that the increase in adrenocorticotropic hormone (ACTH levels observed in wild-type (n = 11 mice after CPA expression, were attenuated in CRF1R KO mice (n = 10. In addition, ACTH returned to the baseline levels in males and females once CPA extinction was finished.These results suggest that, at least, CPA expression is partially due to an increase in plasma ACTH levels, through activation of CRF1R, which can return when CPA extinction is finished.

  7. The design of a novel, environmentally improved cotton pre-treatment proces

    NARCIS (Netherlands)

    Bouwhuis, G.H. (Gerrit)

    2011-01-01

    The scope of this thesis of Gerrit Bouwhuis, lecturer at Saxion Research Centre for Design and Technology in Enschede is the development of a new industrial applicable pre-treatment process for cotton based on catalysis. The pre-treatment generally consists of desizing, scouring and bleaching. These

  8. Effect of morphine on biliary dynamics. A scintigraphic study with /sup 99m/Tc-HIDA

    Energy Technology Data Exchange (ETDEWEB)

    Pedersen, S.A.; Oester-Joergensen, E.; Kraglund, K.

    1987-01-01

    The effect of morphine on biliary dynamics was studied by cholescintigraphy with /sup 99m/Tc-HIDA. Among 30 normals without morphine injection 3 did not demonstrate intestinal radioactivity after 1 h, whereas all visualized the gallbladder. Eight normals with morphine injection did not demonstrate intestinal radioactivity after 2 h, but all had gallbladder visualization very early. Variables of the time-activity curves from liver areas did not point to impaired uptake or excretion. Morphine-induced increase in resistance to passage from the common duct to the intestines in normals is of a magnitude that forces the total amount of bile to accumulate in the gallbladder. Results from 11 patients after cholecystectomy indicate that the increase in pressure is less than the maximal secretory pressure of the liver. The resorptive capacity and the compliance of the gallbladder enable these events to take place without signs of secondary liver impairment.

  9. Role of Medial Prefrontal Cortex Narp in the Extinction of Morphine Conditioned Place Preference

    Science.gov (United States)

    Blouin, Ashley M.; Han, Sungho; Pearce, Anne M.; Cheng, KaiLun; Lee, JongAh J.; Johnson, Alexander W.; Wang, Chuansong; During, Matthew J.; Holland, Peter C.; Shaham, Yavin; Baraban, Jay M.; Reti, Irving M.

    2013-01-01

    Narp knockout (KO) mice demonstrate an impaired extinction of morphine conditioned place preference (CPP). Because the medial prefrontal cortex (mPFC) has been implicated in extinction learning, we tested whether Narp cells in this region play a role in the extinction of morphine CPP. We found that intracranial injections of adenoassociated virus…

  10. Evaluation of the effect of gabapentin on postoperative analgesia with epidural morphine after abdominal hysterectomy

    Directory of Open Access Journals (Sweden)

    Diptesh Aryal

    2017-07-01

    Full Text Available Background & Objectives: Gabapentin has been used successfully as a non-opioid analgesic adjuvant for postoperative pain management. We hypothesized that the preoperative use of gabapentin prolonged the analgesic effect of epidural morphine without an increase in adverse effects of morphine. Materials & Methods: In a randomized, double blind study sixty ASA PS I and II patients undergoing abdominal hysterectomy were assigned to receive either placebo or gabapentin 1200mg 1 hour before surgery. Postoperatively, 0.125% bupivacaine with morphine 50 µg per kg body weight was used for epidural analgesia. Vital parameters, time to the first request for analgesic, visual analogue scale scoring for pain at rest and during movement, 24-hour morphine consumption, and side effects were studied.Results: The patients were comparable with respect to age, weight, ASA PS, baseline hemodynamic parameters and duration of surgery. Gabapentin significantly decreased the duration of analgesia compared to placebo (1078.26 min Vs. 303.5 min; P value <0.0001. The VAS scores at rest and during movement at 1, 2, 4, 8, 12, and 24h were significantly lower in gabapentin group. The total amount of morphine consumption in 24 h postoperatively was significantly lower in gabapentin group (1.93mg Vs. 6.30mg; P value <0.0001. The incidence of nausea and pruritus was significantly lower with gabapentin. Conclusion: Oral gabapentin 1200 mg as a premedication decreases the dose requirement of epidural morphine and postoperative pain after total abdominal hysterectomy. It also decreases the pain scores at rest and during movement significantly. 

  11. Acupuncture and pharmacopuncture are as effective as morphine or carprofen for postoperative analgesia in bitches undergoing ovariohysterectomy.

    Science.gov (United States)

    Luna, Stelio Pacca Loureiro; Martino, Irene Di; Lorena, Silvia Elaine Rodolfo de Sá; Capua, Maria Luisa Buffo de; Lima, Alfredo Feio da Maia; Santos, Bianca Paiva Costa Rodrigues dos; Brondani, Juliana Tabarelli; Vesce, Giancarlo

    2015-12-01

    To investigate the analgesic effect of acupuncture (AP) or micro-dose pharmacopuncture (PA), using carprofen or morphine, in bitches undergoing ovariohysterectomy (OHE). Thirty five dogs were randomly assigned to five groups after sedation with acepromazine IM: AP, 0.5 mg.kg(-1) of morphine subcutaneously (SC), 4 mg.kg(-1) of carprofen SC, and PA with 0.05 mg.kg(-1) of morphine or 0.4 mg.kg(-1) of carprofen. Anaesthesia was induced with propofol and maintained with isoflurane. Pain was assessed after OHE by a blind observer for 24h, by dynamic visual analogue scale (DIVAS), Glasgow (CMPS-SF), Melbourne (UMPS) and Colorado University pain scale (CSU). Animals reaching 33% of the UMPS score received rescue analgesia with morphine IM. Non parametric data were analysed by Kruskal-Wallis or Friedman tests where applicable, followed by Dunn's test. Parametric data were analysed by two way ANOVA, followed by Tukey test. There were no differences among groups in number of rescue analgesia. Except for the DIVAS score where animals treated with morphine had the lowest score compared with AP and carprofen, at 1h after surgery, there were no other differences among groups. Acupuncture or pharmacopuncture were equally effective as morphine or carprofen to control postoperative pain in bitches undergoing ovariohysterectomy.

  12. Efficacy, Safety, and Feasibility of the Morphine Microdose Method in Community-Based Clinics.

    Science.gov (United States)

    Wilkes, Denise M; Orillosa, Susan J; Hustak, Erik C; Williams, Courtney G; Doulatram, Gulshan R; Solanki, Daneshvari R; Garcia, Eduardo A; Huang, Li-Yen M

    2017-06-13

    The goal of this study was to assess the success of the morphine microdose method in a community pain clinic setting by monitoring follow-up frequency, dose escalation, and monotherapy/polytherapy ratio. The morphine microdose method involves a pretrial reduction or elimination of systemic opioids followed by a period of abstinence. Intrathecal (IT) morphine is then started at doses of less than 0.2 mg per day. Systemic opioid abstinence is then continued after pump implant and IT morphine monotherapy. Retrospective review of medical records. Private and academic pain clinic practices. Chronic noncancer pain patients. We reviewed the charts of 60 patients who had completed a microdose regimen and had an IT pump implanted between June 11, 2008, and October 11, 2014. During IT therapy, dose change over time, pain scores, side effects, max dose, and duration were recorded. The majority of patients (35/60, 58%) were successfully managed solely on morphine microdose monotherapy. These patients did not require additional oral therapy. There was a significant reduction in mean pain scores, from 7.4 ± 0.32 before microdose therapy to 4.8 ± 0.3 after microdose therapy. Microdose therapy achieved analgesia, improved safety, and avoided systemic side effects. The safety of IT therapy was increased by using a lower concentration (2 mg/mL) and lower daily doses (microdose therapy was feasible, safe, and cost-effective in the outpatient setting. 2017 American Academy of Pain Medicine. This work is written by US Government employees and is in the public domain in the US.

  13. Substantially Modified Ratios of Effector to Regulatory T Cells During Chemotherapy in Ovarian Cancer Patients Return to Pre-Treatment Levels at Completion: Implications for Immunotherapy

    International Nuclear Information System (INIS)

    Park, Anthony; Govindaraj, Chindu; Xiang, Sue D.; Halo, Julene; Quinn, Michael; Scalzo-Inguanti, Karen; Plebanski, Magdalena

    2012-01-01

    Ovarian cancer is the leading cause of death from gynaecological malignancy. Despite improved detection and treatment options, relapse rates remain high. Combining immunotherapy with the current standard treatments may provide an improved prognosis, however, little is known about how standard chemotherapy affects immune potential (particularly T cells) over time, and hence, when to optimally combine it with immunotherapy (e.g., vaccines). Herein, we assess the frequency and ratio of CD8+ central memory and effector T cells as well as CD4+ effector and regulatory T cells (Tregs) during the first 18 weeks of standard chemotherapy for ovarian cancer patients. In this pilot study, we observed increased levels of recently activated Tregs with tumor migrating ability (CD4+CD25 hi Foxp3+CD127−CCR4+CD38+ cells) in patients when compared to controls. Although frequency changes of Tregs as well as the ratio of effector T cells to Tregs were observed during treatment, the Tregs consistently returned to pre-chemotherapy levels at the end of treatment. These results indicate T cell subset distributions associated with recurrence may be largely resistant to being “re-set” to healthy control homeostatic levels following standard treatments. However, it may be possible to enhance T effector to Treg ratios transiently during chemotherapy. These results suggest personalized immune monitoring maybe beneficial when combining novel immuno-therapeutics with standard treatment for ovarian cancer patients

  14. Substantially Modified Ratios of Effector to Regulatory T Cells During Chemotherapy in Ovarian Cancer Patients Return to Pre-Treatment Levels at Completion: Implications for Immunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Park, Anthony; Govindaraj, Chindu; Xiang, Sue D., E-mail: Sue.Xiang@monash.edu [Department of Immunology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria 3004 (Australia); Halo, Julene; Quinn, Michael [Department of Oncology, Royal Women’s Hospital, Melbourne, Victoria 3052 (Australia); Scalzo-Inguanti, Karen; Plebanski, Magdalena, E-mail: Sue.Xiang@monash.edu [Department of Immunology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria 3004 (Australia)

    2012-06-18

    Ovarian cancer is the leading cause of death from gynaecological malignancy. Despite improved detection and treatment options, relapse rates remain high. Combining immunotherapy with the current standard treatments may provide an improved prognosis, however, little is known about how standard chemotherapy affects immune potential (particularly T cells) over time, and hence, when to optimally combine it with immunotherapy (e.g., vaccines). Herein, we assess the frequency and ratio of CD8+ central memory and effector T cells as well as CD4+ effector and regulatory T cells (Tregs) during the first 18 weeks of standard chemotherapy for ovarian cancer patients. In this pilot study, we observed increased levels of recently activated Tregs with tumor migrating ability (CD4+CD25{sup hi}Foxp3+CD127−CCR4+CD38+ cells) in patients when compared to controls. Although frequency changes of Tregs as well as the ratio of effector T cells to Tregs were observed during treatment, the Tregs consistently returned to pre-chemotherapy levels at the end of treatment. These results indicate T cell subset distributions associated with recurrence may be largely resistant to being “re-set” to healthy control homeostatic levels following standard treatments. However, it may be possible to enhance T effector to Treg ratios transiently during chemotherapy. These results suggest personalized immune monitoring maybe beneficial when combining novel immuno-therapeutics with standard treatment for ovarian cancer patients.

  15. Efficacy and tolerability of intravenous morphine patient-controlled analgesia (PCA) in women undergoing cesarean delivery.

    Science.gov (United States)

    Andziak, Marta; Beta, Jarosław; Barwijuk, Michal; Issat, Tadeusz; Jakimiuk, Artur J

    2015-06-01

    The aim of the study was to evaluate analgesic efficacy and tolerability of patient-controlled analgesia (PCA) with intravenous morphine. Our observational study included 50 women who underwent a Misgav-Ladach or modified Misgav-Ladach cesarean section. Automated PCA infusion device (Medima S-PCA Syringe Pump, Medima, Krakow, Poland) was used for postoperative pain control. Time of morphine administration or initiation of intravenous patient-controlled analgesia (IV PCA) with morphine was recorded, as well as post-operative pain at rest assessed by a visual analogue scale (VAS). All patients were followed up for 24 hours after discharge from the operating room, taking into account patient records, worst pain score at rest, number of IV PCA attempts, and drug consumption. Median of total morphine doses used during the postoperative period was 42.9mg (IQR 35.6-48.5), with median infusion time of 687.0 min. (IQR 531.0-757.5). Pain severity and total drug consumption improved after the first 3 hours following cesarean delivery (p PCA attempts per patient was 33 (IQR: 24-37), with median of 11 placebo attempts (IQR: 3-27). Patient-controlled analgesia with morphine is an efficient and acceptable analgesic method in women undergoing cesarean section.

  16. Identification of Individuals With Undiagnosed Diabetes and Pre-Diabetes in a Danish Cohort Attending Dental Treatment

    DEFF Research Database (Denmark)

    Holm, Niels-Christian Reimers; Belstrøm, Daniel; Østergaard, Jakob Appel

    2016-01-01

    BACKGROUND AND OBJECTIVE: It is estimated that 3.6% and 13.6% of the Danish population suffer from undiagnosed type 2 diabetes and pre-diabetes, respectively. Periodontitis is an established complication to diabetes. Identification of individuals with diabetes and pre-diabetes is important...... to reduce diabetes-related complications including periodontitis. The objective of the study was to identify individuals with undiagnosed diabetes or pre-diabetes among individuals attending a dental setting for diagnosis and treatment. METHODS: 291 adults with no history of diabetes were included......c levels corresponding to guideline values for diabetes and pre-diabetes respectively. Higher proportions of patients with undiagnosed diabetes and pre-diabetes were observed in the periodontitis group (32.7%) than in the control group (17.4%) (p=0.054). Identification of diabetes and pre-diabetes...

  17. Morphine-augmented cholescintigraphy and acute a calculous cholecystitis in critically ill patients: interest and new way of interpreting

    International Nuclear Information System (INIS)

    Emptaz, A.; Prevot, N.; Dubois, F.; Mahul, P.; Mariat, G.; Jospe, R.; Auboyer, C.; Cuilleron, M.

    2005-01-01

    Introduction: Acute acalculous cholecystitis (AAC) is a serious disease, difficult to diagnose in critically ill patients. The aim of the study was to evaluate the diagnostic performances of abdominal ultrasonography (US) and morphine-augmented cholescintigraphy (MC) and to improve diagnostic strategy in patients of intensive care unit (ICU) with suspected AA C. Methods: We retrospectively studied 82 consecutive ICU patients with suspected AA C. US was positive if the triad of gallbladder distension, gallbladder wall thickening and sludge was found. MC was positive if the gallbladder remained non-visualized after morphine injection. In a second time, other scintigraphic criteria of interpretation were tested, according to the visualization of the gallbladder before or after morphine administration. Treatment was decided on the basis of clinical, laboratory and imaging data. Results: The diagnosis of AAC was retained in 34 patients. US and MC had respectively for the diagnosis of AAC a sensitivity of 20.6 and 70.6%, and a specificity of 95.8 and 100%. Interpreting the MC as positive if the gallbladder remains non-visualized after morphine, as negative if it appears before, and as non-conclusive if visualized after, makes it possible to define respectively patients with high probability (100%), with low probability (7.5%) or with intermediate probability (39%) of AAC. Conclusions: MC is better than US for diagnosing AAC in critically ill patients, having in particular excellent specificity using the classical criteria of interpretation. MC must be thus performed in patients at risk for AAC, determined with clinical, laboratory and eventually echographic findings. To decrease false negative rate of MC, a probability categorical classification is proposed to improve patients' care. (author)

  18. Morphine dependence is attenuated by red ginseng extract and ginsenosides Rh2, Rg3, and compound K

    OpenAIRE

    Yayeh, Taddesse; Yun, Kyunghwa; Jang, Soyong; Oh, Seikwan

    2016-01-01

    Background: Red ginseng and ginsenosides have shown plethoric effects against various ailments. However, little is known regarding the effect of red ginseng on morphine-induced dependence and tolerance. We therefore investigated the effect of red ginseng extract (RGE) and biotransformed ginsenosides Rh2, Rg3, and compound K on morphine-induced dependence in mice and rats. Methods: While mice were pretreated with RGE and then morphine was injected intraperitoneally, rats were infused with g...

  19. Rectal absorption of morphine from controlled release suppositories

    NARCIS (Netherlands)

    Moolenaar, Frits; Meyler, Pim; Frijlink, Erik; Jauw, Tjoe Hang; Visser, Jan; Proost, Johannes

    1995-01-01

    The absorption profiles and bioavailability of morphine in human volunteers (n = 13) were described after oral administration of MS Contin tablets and rectal administration of a newly developed controlled release suppository. By manipulating the viscosity of fatty suppository base an entirely

  20. Pre-eclampsia Diagnosis and Treatment Options: A Review of Published Economic Assessments.

    Science.gov (United States)

    Zakiyah, Neily; Postma, Maarten J; Baker, Philip N; van Asselt, Antoinette D I

    2015-10-01

    Pre-eclampsia is a pregnancy complication affecting both mother and fetus. Although there is no proven effective method to prevent pre-eclampsia, early identification of women at risk of pre-eclampsia could enhance appropriate application of antenatal care, management and treatment. Very little is known about the cost effectiveness of these and other tests for pre-eclampsia, mainly because there is no clear treatment path. The aim of this study was to provide a comprehensive overview of the existing evidence on the health economics of screening, diagnosis and treatment options in pre-eclampsia. We searched three electronic databases (PubMed, EMBASE and the Cochrane Library) for studies on screening, diagnosis, treatment or prevention of pre-eclampsia, published between 1994 and 2014. Only full papers written in English containing complete economic assessments in pre-eclampsia were included. From an initial total of 138 references, six papers fulfilled the inclusion criteria. Three studies were on the cost effectiveness of treatment of pre-eclampsia, two of which evaluated magnesium sulphate for prevention of seizures and the third evaluated the cost effectiveness of induction of labour versus expectant monitoring. The other three studies were aimed at screening and diagnosis, in combination with subsequent preventive measures. The two studies on magnesium sulphate were equivocal on the cost effectiveness in non-severe cases, and the other study suggested that induction of labour in term pre-eclampsia was more cost effective than expectant monitoring. The screening studies were quite diverse in their objectives as well as in their conclusions. One study concluded that screening is probably not worthwhile, while two other studies stated that in certain scenarios it may be cost effective to screen all pregnant women and prophylactically treat those who are found to be at high risk of developing pre-eclampsia. This study is the first to provide a comprehensive overview