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Sample records for repeated morphine administration

  1. Huperzine A inhibits immediate addictive behavior but not behavioral sensitization following repeated morphine administration in rats.

    Science.gov (United States)

    Sun, Jinling; Tian, Lin; Cui, Ruisi; Li, Xinwang

    2017-04-01

    Acetylcholinesterase inhibitors are regarded as promising therapeutic agents to treat addiction. The current study aimed to examine the effects of huperzine A, a cholinesterase inhibitor, on behavioral sensitization induced by repeated morphine administration and relapse induced by contextual conditioning. The present study also assessed whether the state-dependency hypothesis may explain the results. Adult rats were divided into four groups (n=8) and intraperitoneally injected with 0.2, 0.3 or 0.4 mg/kg huperzine A or saline (1 ml/kg, control), for 5 days. The effect of repeated huperzine A administration alone on locomotor activity was assessed. For the experiments that analyzed the development of morphine-induced sensitization, 40 rats were divided into five groups (n=8): Saline+Saline, Saline+Morphine, 0.2, 0.3 and 0.4 mg/kg huperzine A+Morphine. Following a withdrawal period of 7 days, all animals were administered saline or morphine, as appropriate. To test the state-dependency hypothesis, the rats in the Saline+Morphine group were injected with saline and morphine, while the other three groups were administered different doses of huperzine A and morphine. To examine the effect of huperzine A on the expression of morphine-induced sensitization, the rats in huperzine A+Morphine groups were injected with appropriate concentrations of huperzine A, and morphine. The current results indicated that the administration of huperzine A alone did not affect locomotor activity, while higher doses of huperzine A inhibited the addictive behavior induced by morphine at the development phase. Additionally, huperzine A administration during the expression phase of morphine sensitization did not inhibit the relapse induced by administration of saline. Furthermore, 0.4 mg/kg huperzine A inhibited the expression of morphine-induced behavioral sensitization. Therefore, the results of the current study do not support the state-dependency hypothesis.

  2. Morphine Analgesia Modification in Normotensive and Hypertensive Female Rats after Repeated Fluoxetine Administration.

    Science.gov (United States)

    Kosiorek-Witek, Anna; Makulska-Nowak, Helena Elżbieta

    2016-01-01

    The purpose of this investigation was to determine through the use of fluoxetine the effect of administering a serotonin reuptake inhibitor over several days on the antinociceptive action of μ-morphine type opioid receptor agonist. Investigations were performed on rats of both sexes, both the WKY normotensive strains as well as on the SHR genetically conditioned hypertensive strains. Results showed that the efficacy of morphine analgesia is higher in the SHR strain compared to normotensive rats (WKY). Surprisingly, repeated administration of fluoxetine reduced morphine analgesia, with the weakening of opioid antinociceptive action comparable to the duration of serotonin reuptake inhibitor administration. It was also concluded that the antinociceptive action of morphine in female rats and the alteration of its efficacy as a result of fluoxetine premedication for several days depend on oestrus cycle phase. The highest sensitivity of female rats to morphine was reported in the dioestrus and oestrus phases; much lower values were reported for the metoestrus phase.

  3. Repeated administration of dopaminergic agents in the dorsal hippocampus and morphine-induced place preference.

    Science.gov (United States)

    Zarrindast, M-R; Nasehi, M; Rostami, P; Rezayof, A; Fazli-Tabaei, S

    2005-03-01

    The aim of the present experiments was to investigate whether repeated intra-hippocampal CA1 (intra-CA1) administration of dopaminergic agents can affect morphine-induced conditioned place preference (CPP). Effects of repeated intra-CA1 injections of dopamine (DA) receptor agonists and antagonists on morphine-induced CPP in rats were investigated using an unbiased 3-day schedule of place conditioning. Animals receiving once-daily subcutaneous (s.c.) injections of morphine (1-9 mg/kg) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner: the maximum response was observed with 3 mg/kg morphine. Three days' intra-CA1 injections of apomorphine (0.25-1 microg/rat) followed by 5 days free of the drug, significantly decreased morphine CPP (1 and 3 mg/kg, s.c.). Moreover, pre-treatment with the highest dose of apomorphine (1 microg/rat) altered the effect of morphine to an aversive response. The morphine (1 and 3 mg/kg) CPP was also significantly decreased in animals that previously received three intra-CA1 injections of SKF 38393 (2-9 microg/rat), quinpirole (1-3 microg/rat) or sulpiride (1-3 microg/rat), and significantly increased in animals that had previously received three intra-CA1 injections of SCH 23390 (0.02 microg/rat). The 3-day pre-treatment with apomorphine, SKF 38393 or quinpirole reduced locomotor activity in the test session, while SCH 23390 and sulpiride did not have any influence on locomotor activity. It is concluded that repeated injections of DA receptor agents in the dorsal hippocampus, followed by 5 days free of the drugs, can affect morphine reward.

  4. Repeated morphine treatment-mediated hyperalgesia, allodynia and spinal glial activation are blocked by co-administration of a selective cannabinoid receptor type-2 agonist

    OpenAIRE

    Tumati, Suneeta; Largent-Milnes, Tally M.; Keresztes, Attila; Ren, Jiyang; Roeske, William R.; Vanderah, Todd W; Varga, Eva V.

    2012-01-01

    Spinal glial activation has been implicated in sustained morphine-mediated paradoxical pain sensitization. Since activation of glial CB2 cannabinoid receptors attenuates spinal glial activation in neuropathies, we hypothesized that CB2 agonists may also attenuate sustained morphine–mediated spinal glial activation and pain sensitization. Our data indicate that co-administration of a CB2-selective agonist (AM 1241) attenuates morphine (intraperitoneal; twice daily; 6 days)-mediated thermal hyp...

  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. Intrathecal co-administration of ketamine and morphine preventing activation of astrocytes and decreasing releases of IL-1β and IL-6 from spinal cord in rats of morphine tolerance

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Objective: To investigate the effects of intrathecal administration of ketamine, a non-competitive N-methy-D-aspartate receptor antagonist, combined with morphine on the activation of astrocytes and releases of IL-1β and IL-6 from spinal cord in the rats of morphine tolerance. Methods: Twenty-seven Sprague-Dawley male rats were randomly divided into sham-operated, morphine tolerance, and morphine plus ketamine group. The subarachnoid catheterization of all the rats was prepared by the method of Jianping Yang.Morphine 20 μg in 10 μl was administrated intrathecally to induce spinal morphine tolerance once daily for 5 consecutive days. Morphine and ketamine 250 μg in 10 μl total volume was given in morphine plus ketamine group. Three groups all received intrathecal morphine 5 μg in 10 μl for morphine challenge test at 24 h after last administration of the morphine. After morphine challenge test, lumbar spinal tissues were taken for measurement of glial fibrillary acidic protein (GFAP) of astrocyte in lumbar spinal horn cord by immunohistochemistry and IL-1βand IL-6 of spinal cord by ELISA. Results: The decrease of %MPE induced by chronic intrathecal morphine was inhibited by ketamine and hyperalgesia and allodynia induced by morphine-withdrawl were alleviated. The average areas, the average absorbency (-A), the integral absorbency (A) of GFAP immuno-reactive cells in the dorsal horn, and IL-1β and IL-6 of spinal cord were significantly larger in morphine tolerance group than in morphine plus ketamine group. Conclusion: Co-administration of ketamine and morphine enhance antinociceptive effect of morphine and prevent the development of morphine tolerance. Ketamine might attenuate the activation of astrocytes and inhibit the release of IL-1β and IL-6 from spinal cord in repeated intrathecal morphine rats.

  7. The involvement of noradrenergic transmission in the morphine-induced locomotor hyperactivity in mice withdrawn from repeated morphine treatment

    OpenAIRE

    Airio, Juha; Ahtee, Liisa

    1999-01-01

    Our previous studies suggest that in addition to the cerebral dopaminergic systems the noradrenergic ones have a crucial role in the morphine-induced behavioural sensitization in mice. Therefore the effects of α2-adrenoceptor antagonist, idazoxan (1 and 3 mg kg−1, i.p.) on morphine-induced locomotor hyperactivity as well as on morphine-induced changes in cerebral noradrenaline (NA) and striatal dopamine (DA) metabolism were studied in mice withdrawn for 3 days from 5 day repeated morphine tre...

  8. History of cocaine self-administration alters morphine reinforcement in the rat.

    Science.gov (United States)

    Mierzejewski, Pawel; Stefanski, Roman; Bienkowski, Przemyslaw; Kostowski, Wojciech

    2007-05-07

    It has been shown repeatedly that cocaine pre-exposure may sensitise neurochemical and behavioural responses to opioid drugs. The aim of the present study was to investigate effects of a prior history of cocaine self-administration on morphine reinforcement in the rat. Male Sprague-Dawley rats were allowed to acquire intravenous cocaine self-administration (0.3 mg/kg/infusion) for 20 days. When operant responding for cocaine had stabilised, morphine was introduced instead of cocaine in the next self-administration session. One group of cocaine-exposed rats was allowed to respond for 0.56 mg/kg/infusion of morphine (i.e. the dose which was willingly self-administered by drug-naive controls). The second group was allowed to respond for 0.056 mg/kg/infusion of morphine (i.e. the dose which did not maintain self-administration behaviour in the drug-naive rats). The subjects with the history of cocaine self-administration, in contrast to the drug-naive group, did not maintain operant responding for 0.56 mg/kg/infusion of morphine. These rats easily self-administered the ten times lower dose of the opioid (0.056 mg/kg/infusion). An opioid receptor antagonist, naltrexone (1 mg/kg i.p.) restored the positive reinforcing properties of the higher dose of morphine in the cocaine-exposed rats. Concluding, the present results suggest that prior history of cocaine self-administration sensitises rats to the positive reinforcing properties of morphine.

  9. Postnatal morphine administration alters hippocampal development in rats.

    Science.gov (United States)

    Traudt, Christopher M; Tkac, Ivan; Ennis, Kathleen M; Sutton, Leah M; Mammel, Daniel M; Rao, Raghavendra

    2012-01-01

    Morphine is frequently used as an analgesic and sedative in preterm infants. Adult rats exposed to morphine have an altered hippocampal neurochemical profile and decreased neurogenesis in the dentate gyrus of the hippocampus. To evaluate whether neonatal rats are similarly affected, rat pups were injected twice daily with 2 mg/kg morphine or normal saline from postnatal days 3 to 7. On postnatal day 8, the hippocampal neurochemical profile was determined using in vivo (1)H NMR spectroscopy. The mRNA and protein concentrations of specific analytes were measured in hippocampus, and cell division in dentate gyrus was assessed using bromodeoxyuridine. The concentrations of γ-aminobutyric acid (GABA), taurine, and myo-insotol were decreased, whereas concentrations of glutathione, phosphoethanolamine, and choline-containing compounds were increased in morphine-exposed rats relative to control rats. Morphine decreased glutamic acid decarboxylase enzyme levels and myelin basic protein mRNA expression in the hippocampus. Bromodeoxyuridine labeling in the dentate gyrus was decreased by 60-70% in morphine-exposed rats. These results suggest that recurrent morphine administration during brain development alters hippocampal structure.

  10. Effect of repeated morphine withdrawal on spatial learning, memory and serum cortisol level in mice

    OpenAIRE

    Mahdieh Matinfar; Mahsa Masjedi Esfahani; Neda Aslany; Seyyed Hamid Reza Davoodi; Pouya Parsaei; Ghasem Zarei; Parham Reisi

    2013-01-01

    Background: One of the serious problems that opioid addicted people are facing is repeated withdrawal syndrome that is accompanying with a significant stress load for addicts. Therefore, the aim of this study was to evaluate the effects of repeated withdrawal on spatial learning, memory and serum cortisol levels in morphine-dependent mice. Materials and Methods: Male NMRI mice received morphine as daily increasing doses for 3 days. After that, the mice underwent one time or repeated spont...

  11. 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...

  12. Intracerebroventricular administration of riluzole prevents morphine-induced apoptosis in the lumbar region of the rat spinal cord.

    Science.gov (United States)

    Hassanzadeh, Kambiz; Habibi-asl, Bohlool; Roshangar, Leila; Nemati, Mahboob; Ansarin, Masood; Farajnia, Safar

    2010-01-01

    Opiates are the most effective drugs for pain relief. However, the repeated use of opiates induces tolerance to their analgesic effects. It has been shown that this morphine-induced tolerance is associated with apoptosis in the central nervous system. The aim of this study is to evaluate the effects of intracerebroventricular (i.c.v.) administration of riluzole, an anti-glutamatergic drug, on morphine-induced apoptosis in the lumbar region of the rat spinal cord. Animals were given daily injections of morphine and vehicle, morphine and riluzole, or riluzole alone. Nociception was assessed using a hot plate apparatus, and apoptosis was assessed using the in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method. The levels of anti-apoptotic factors Bcl-2 and HSP 70 and the pro-apoptotic agent caspase-3 were evaluated using immunoblotting. The glutamate concentration in the lumbar spinal cord was measured with high performance liquid chromatography (HPLC). The results indicate that the i.c.v. administration of riluzole attenuated morphine tolerance and reduced the number of TUNEL positive cells. Immunoblotting revealed that the levels of the selected anti-apoptotic agents were greater in the treatment groups compared to the controls. Furthermore, the results demonstrated that the administration of riluzole can attenuate the morphine-induced elevation of glutamate in the lumbar spinal cord. In conclusion, i.c.v. administration of riluzole attenuated morphine-induced tolerance to analgesia and apoptosis in addition to preventing the morphine-induced increase of glutamate in the lumbar spinal cord of rats.

  13. 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.

  14. Trans-stilbene oxide administration increased hepatic glucuronidation of morphine but decreased biliary excretion of morphine glucuronide in rats

    Energy Technology Data Exchange (ETDEWEB)

    Fuhrman-Lane, C.; Fujimoto, J.M.

    1982-09-01

    The effect of the inducing agent trans-stilbene oxide (TSO) on the metabolism and biliary excretion of (/sup 14/C)morphine was studied in the isolated in situ perfused rat liver. After administration of morphine by intraportal injection or by the segmented retrograde intrabiliary injection technique, the TSO-treated group showed a marked decrease in the biliary recovery of morphine as its glucuronide conjugate (morphine-3-glucuronide (MG)). However, recovery of MG in the venous outflow of the single pass perfusate was greatly increased. These findings suggested that TSO treatment enhanced the formation of MG from morphine and changed the primary route of hepatic elimination of MG. TSO treatment also decreased the excretion of morphine (as MG) in the bile of anesthetized renal-ligated rats. This decreased biliary function required several days to develop and appeared closely associated with the inductive effect of TSO. After i.v. administration of (/sup 14/C)MG itself, biliary recovery was also markedly decreased in TSO-treated rats. It is postulated that the effect of the TSO treatment led to either a decrease in canalicular transport of MG into bile or an increase in the efficiency of transfer of MG to the blood at the sinusoidal side of the hepatocyte. Regardless of the mechanism, the results indicate the need to study compartmentalization of drug transport and metabolism functions.

  15. Effect of metamizol on morphine pharmacokinetics and pharmacodynamics after acute and subchronic administration in arthritic rats.

    Science.gov (United States)

    Domínguez-Ramírez, Adriana Miriam; Cortés-Arroyo, Alma Rosa; Y de la Peña, Marcela Hurtado; López, José Raúl Medina; López-Muñoz, Francisco Javier

    2010-10-25

    The aim of the present study was to investigate whether metamizol alters the pharmacokinetics of morphine and to determine the relationship between morphine plasma levels and antinociceptive effect produced after co-administration of drugs under acute and subchronic treatments using the pain-induced functional impairment model in rat (PIFIR model). Administration of morphine+metamizol under acute treatment produced a significantly higher antinociceptive effect than that obtained with morphine alone (Pmetamizol combination produced an accumulation of the drug in plasma (Pmetamizol may be explained by a possible enzymatic inhibition of the glucuronosyl-transferase system involved in the metabolism of morphine. This study reveals both a pharmacodynamic and a pharmacokinetic interaction between morphine and metamizol, leading to an increased antinociceptive effect and a delay in tolerance development. Copyright © 2010 Elsevier B.V. All rights reserved.

  16. Dendrosomal nanocurcumin prevents morphine self-administration behavior in rats despite CA1 damage.

    Science.gov (United States)

    Norozi, Jalaleden; Hassanpour-Ezatti, Majid; Alaei, Hojjat A

    2017-01-25

    Dendrosomal nanocurcumin (DNC) is fabricated from esterification of oleic acid and polyethylene glycol residues with curcumin. DNC has shown antioxidant, neuroprotective, and neurogenesis-enhancing effects. In addition, it can attenuate morphine tolerance. Morphine self-administration is associated with neurodegenerative changes of CA1 neurons in the adult hippocampus. The present study evaluated the effect of DNC pretreatment on morphine self-administration and hippocampal damage. Rats were pretreated with DNC (5 and 10 mg/kg, intraperitoneally) 30 min before a morphine self-administration paradigm performed in 2-h/sessions for 12 days under a FR-1 schedule. Pretreatment with both doses of DNC markedly suppressed morphine intake. Morphine self-administration resulted in a 71% reduction in the number of hippocampal CA1 neurons. DNC (5 mg/kg) pretreatment only marginally improved (by 22%) neuronal loss in this area. The data suggest that the effect of DNC on morphine self-administration is largely independent of the CA1 area. A functional restoration and regulation of reward circuit activity by DNC may reduce the motivation for morphine despite CA1 damage.

  17. Prolonged morphine administration alters protein expression in the rat myocardium

    OpenAIRE

    Drastichova Zdenka; Skrabalova Jitka; Neckar Jan; Kolar Frantisek; Novotny Jiri

    2011-01-01

    Abstract Background Morphine is used in clinical practice as a highly effective painkiller as well as the drug of choice for treatment of certain heart diseases. However, there is lack of information about its effect on protein expression in the heart. Therefore, here we aimed to identify the presumed alterations in rat myocardial protein levels after prolonged morphine treatment. Methods Morphine was administered to adult male Wistar rats in high doses (10 mg/kg per day) for 10 days. Protein...

  18. 5α-reductase 1 regulates spinal cord testosterone after morphine administration.

    Science.gov (United States)

    Sharif, Alireza; Shoae-Hassani, Alireza; Sharif, Shiva; Banafshe, Hamid Reza; Mortazavi-Tabatabaei, Seyed Abdolreza; Verdi, Javad

    2013-01-01

    The enzyme 5alpha-reductase 1 (5α-R(1)) that converts testosterone (T) to dihydrotestosterone (DHT) is present in many mammalian tissues including the spinal cord. It is established that morphine administration decreases spinal cord T levels, but the mechanism is still undetermined. Here, we investigated the link between T and the enzyme 5α-R(1) in the spinal cord after morphine administration. For spinal cord steroid extraction, all the animals were killed 30 min, 2 h (acute) and 14 days (chronic) after first drug injection by decapitation. The whole spinal cord was removed and kept frozen at -20°C until T and DHT extraction. The effects of acute and chronic morphine administration on 5α-R(1) expression in the adult male rat spinal cord were evaluated using RT-PCR. Spinal cord T and DHT levels were measured using radioimmunoassay before and after the morphine exposure. Morphine significantly reduced the T concentration after acute and chronic exposure in the spinal cord. In contrast, the 5α-R(1) expression and of course DHT levels increased the following chronic morphine administration. One important reason for the decreasing effect of morphine exposure on the spinal cord T level is due to an increase in the 5α-R(1) levels. We suggest that morphine plays a regulatory role in metabolism of neurosteroids, especially T in the spinal cord via 5α-R(1).

  19. Population Pharmacokinetics of Morphine and Morphine-6-Glucuronide following Rectal Administration -A Dose Escalation Study

    DEFF Research Database (Denmark)

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

    2014-01-01

    data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6 hours, clearance 78 L/h [relative standard error (RSE) 12%] and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed...... that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side...

  20. The Effect of Nicotine Administration on Physical and Psychological Signs of Withdrawal Syndrome Induced by Single or Frequent Doses of Morphine in Rats

    Directory of Open Access Journals (Sweden)

    Mohammad Allahtavakoli

    2012-07-01

    Full Text Available Introduction. Morphine addiction and morphine withdrawal syndrome are the two main problems of today’s human society. The present study has investigated the effects of nicotine on the strength of physical and psychological dependency in single and repeated doses morphine administrated rats. Materials and methods. Male Wistar rats were subjected to morphine consumption with single or frequent dose protocols. In the single dose protocol, rats received only one dose of morphine and 24hrs later they also received one dose of nicotine 30 min prior to injection of naloxone. In the repeated dose protocol, rats received incremental doses of morphine for 7 days and 24hr after the last dose (the 8th day were given naloxone. However, the nicotine regimen of this group was injected 15 min before the morphine injection, for 4 days, from the 4th to the 7th day. Five minutes after naloxone injection, each rat′s behavior was captured for 30 min, and then physical and psychological signs of withdrawal syndrome were recorded. Data were analyzed by ANOVA followed by Tukey tests and p<0.05 was considered as significant difference. Findings. Results showed that the injection of frequent and single doses of morphine lead to morphine dependency. In single dose protocol, nicotine consumption attenuated the signs of withdrawal syndrome, especially weight of excrement and total withdrawal score. In frequent dose protocol, in addition to these effects, nicotine induced weight loss and place aversion. Conclusion. The inhibitory effects of nicotine on signs of withdrawal syndrome may involve a dopaminergic portion of the central nervous system and is mediated by central nicotinic receptors. There is also a cross-dependence between nicotine and morphine.

  1. 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...... in 63 patients receiving intravenous, oral immediate release or oral controlled release morphine on request after hip surgery. The PK-PD relationship between predicted exposure of morphine and morphine consumption was modeled using repeated time to event (RTTE) modeling in NONMEM. To validate the RTTE...... model, a visual predictive check method was developed with simulated morphine consumption given the exposure of preceding morphine administration. Results The probability of requesting morphine was found to be significantly related to the exposure of morphine as well as night/day. Oral controlled...

  2. Ascorbic acid decreases morphine self-administration and withdrawal symptoms in rats.

    Science.gov (United States)

    Alaei, H; Esmaeili, M; Nasimi, A; Pourshanazari, A

    2005-09-01

    Recent studies have indicated that the glutamatergic system is involved in the motivational aspects during the initiation of drug self-administration. Ascorbic acid (AA), an antioxidant vitamin, is released from glutamatergic neurons, and it modulates the synaptic action of dopamine and glutamate. In this study the AA effects on the self-administration of morphine and on the morphine withdrawal syndrome have been investigated. Wistar rats were allowed to self-administer morphine (1 mg/infusion) during 10 consecutive days for 2 h/session. The number of lever pressings was recorded. An intrapritoneal AA injection (500 mg/kg, i.p.), 30 min before morphine self-administration produced a significant decrease in the initiation of morphine self administration during all sessions. After the last test session morphine withdrawal symptom signs (MWS) were recorded after naloxone precipitation. Most of MWS (but not all) were decreased by AA application. In conclusion, AA may change the motivational processes underlying the morphine self-administration.

  3. Rectal administration of nicomorphine in patients improves biological availability of morphine and its glucuronide conjugates.

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    Koopman-Kimenai, P M; Vree, T B; Booij, L H; Dirksen, R

    1994-12-02

    The pharmacokinetics of 30 mg nicomorphine after rectal administration with a suppository are described in 8 patients under combined general and epidural anaesthesia. No nicomorphine or 6-mononicotinoylmorphine could be detected in the serum. Morphine appeared almost instantaneously with a lag-time of 8 min and had a final elimination half-life of 1.48 +/- 0.48 h. Morphine was metabolized to morphine-3-glucuronide and morphine-6-glucuronide. These glucuronide conjugates appeared after a lag-time of 12 min and the half-life of these two glucuronide conjugates was similar: about 2.8 h (P > 0.8). The glucuronide conjugate of 6-mononicotinoylmorphine was not detected. In the urine only morphine and its glucuronides were found. The renal clearance value for morphine was 162 ml.min-1 and for the glucuronides 81 ml.min-1. This study shows that administration of a suppository with 30 mg nicomorphine gives an excellent absolute bioavailability of morphine and its metabolites of 88%. The lipid-soluble prodrug nicomorphine is quickly absorbed and immediately hydrolysed to morphine.

  4. Effect of repeated morphine withdrawal on spatial learning, memory and serum cortisol level in mice

    Directory of Open Access Journals (Sweden)

    Mahdieh Matinfar

    2013-01-01

    Full Text Available Background: One of the serious problems that opioid addicted people are facing is repeated withdrawal syndrome that is accompanying with a significant stress load for addicts. Therefore, the aim of this study was to evaluate the effects of repeated withdrawal on spatial learning, memory and serum cortisol levels in morphine-dependent mice. Materials and Methods: Male NMRI mice received morphine as daily increasing doses for 3 days. After that, the mice underwent one time or repeated spontaneous or pharmacologic (naloxone-precipitated withdrawal. Then spatial learning and memory were investigated by morris water maze test, and at the end trunk blood samples were collected for measurement of serum cortisol levels. Results: The results showed that only repeated spontaneous withdrawal significantly increases escape latency ( P < 0.05, and in other models of withdrawal, spatial learning and memory were intact. The results of probe trial were intact in all groups. Radioimmunoassay showed that serum cortisol levels were increased significantly in all models of withdrawal ( P < 0.05 and P < 0.01 except the repeated spontaneous withdrawal. Conclusion: The results showed that short periods of withdrawal syndrome can increase serum cortisol levels; however they do not affect spatial learning and memory. Nevertheless, repeated spontaneous withdrawal can make learning slow.

  5. Enhanced analgesic effect of morphine-nimodipine combination after intraspinal administration as compared to systemic administration in mice

    Indian Academy of Sciences (India)

    Dilip Verma; Subrata Basu Ray; Ishan Patro; Shashi Wadhwa

    2005-09-01

    Calcium plays an important role in the pathophysiology of pain. A number of studies have investigated the effect of L-type calcium channel blockers on the analgesic response of morphine. However, the results are conflicting. In the present study, the antinociceptive effect of morphine (2.5 g) and nimodipine (1 g) co-administered intraspinally in mice was observed using the tail flick test. It was compared to the analgesic effect of these drugs (morphine – 250 g subcutaneously; nimodipine – 100 g intraperitoneally) after systemic administration. Nimodipine is highly lipophilic and readily crosses the blood brain barrier. Addition of nimodipine to morphine potentiated the analgesic response of the latter when administered through the intraspinal route but not when administered through systemic route. It may be due to direct inhibitory effect of morphine and nimodipine on neurons of superficial laminae of the spinal cord after binding to -opioid receptors and L-type calcium channels respectively.

  6. Prolonged morphine administration alters protein expression in the rat myocardium

    Directory of Open Access Journals (Sweden)

    Drastichova Zdenka

    2011-11-01

    Full Text Available Abstract Background Morphine is used in clinical practice as a highly effective painkiller as well as the drug of choice for treatment of certain heart diseases. However, there is lack of information about its effect on protein expression in the heart. Therefore, here we aimed to identify the presumed alterations in rat myocardial protein levels after prolonged morphine treatment. Methods Morphine was administered to adult male Wistar rats in high doses (10 mg/kg per day for 10 days. Proteins from the plasma membrane- and mitochondria-enriched fractions or cytosolic proteins isolated from left ventricles were run on 2D gel electrophoresis, scanned and quantified with specific software to reveal differentially expressed proteins. Results Nine proteins were found to show markedly altered expression levels in samples from morphine-treaded rats and these proteins were identified by mass spectrometric analysis. They belong to different cell pathways including signaling, cytoprotective, and structural elements. Conclusions The present identification of several important myocardial proteins altered by prolonged morphine treatment points to global effects of this drug on heart tissue. These findings represent an initial step toward a more complex view on the action of morphine on the heart.

  7. Impact of the Timing of Morphine Administration on Lipopolysaccharide-Mediated Lethal Endotoxic Shock in Mice.

    Science.gov (United States)

    Fukada, Tomoko; Kato, Hidehito; Ozaki, Makoto; Yagi, Junji

    2016-05-01

    Sepsis is a serious condition related to systemic inflammation, organ dysfunction, and organ failure. It is a subset of the cytokine storm caused by dysregulation of cytokine production. Morphine influences the severity of infection in vivo and in vitro because it regulates cytokine production. We investigated the immunological function of morphine using a mouse model of septic shock. We treated mice with α-galactosylceramide (2 μg/mouse) to induce lethal endotoxic shock following a challenge with lipopolysaccharide (LPS, 1.5 μg/mouse). This model represents acute lung injury and respiratory failure, and reflects the clinical features of severe septic shock. We evaluated the effect of the timing of morphine (0.8 mg/mouse) administration on the survival rate, cytokine production in vivo, and histological changes of mice with LPS-mediated lethal endotoxic shock. Morphine treatment before LPS challenge suppressed lethal endotoxic shock. In contrast, when we administered after LPS, morphine exacerbated lethal endotoxic shock; hematoxylin and eosin staining revealed a marked increase in the accumulation of infiltrates comprising polymorphonuclear leukocytes and mononuclear cells in the lung; and Elastica van Gieson staining revealed the destruction of alveoli. The plasma levels of tumor necrosis factor-α, interferon-γ, monocyte-chemotactic protein-1, and interleukin-12 in the group treated with morphine after LPS challenge were higher than those treated with morphine before LPS challenge. In conclusion, one of the factors that determine whether morphine exacerbates or inhibits infection is the timing of its administration. Morphine treatment before shock improved the survival rate, and morphine treatment after shock decreased the rate of survival.

  8. Androgens and opiates: testosterone interaction with morphine self-administration in male rats.

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    Cooper, Sarah E; Wood, Ruth I

    2014-05-07

    Abuse of anabolic androgenic steroids (AAS) and opioids intersects in athletics. Evidence from humans and animals suggests that AAS may act in the brain through opioidergic mechanisms, and may potentiate effects of opioids. To determine whether AAS enhance motivation for opioid intake, in this study, male rats were treated chronically for 6 weeks with high levels of testosterone (7.5 mg/kg) or vehicle subcutaneously, and they were tested for morphine self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules. Initially, rats received chronic morphine infusion (16.8-50 mg/kg/day) over 7 days. Subsequently, rats were tested for morphine self-administration (3.2 mg/kg) 6 h/day for 3 days under an FR1 schedule, and for 7 days under a PR 9-4 schedule. Under the FR1 schedule, controls self-administered more morphine (95.9±8.5 mg/kg) than testosterone-treated rats (63.2±7.2 mg/kg; P<0.05). Under the PR schedule, there was no effect of testosterone on morphine intake or operant responding (26.7±5.7 responses vs. 30.9±5.9 responses for vehicle; NS). To determine whether testosterone enhances morphine sedation, additional rats were treated with testosterone or vehicle and evaluated for locomotor behavior and rearing activity over 30 min in response to saline or 10 mg/kg morphine. Morphine inhibited locomotor activity and rearing; testosterone selectively reduced rearing behavior, but did not alter locomotor behavior. These results suggest that testosterone does not increase motivation for morphine.

  9. Selegiline modifies the extinction of responding following morphine self-administration, but does not alter cue-induced reinstatement, reacquisition of morphine reinforcement, or precipitated withdrawal.

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    Grasing, Kenneth; He, Shaunteng; Li, Ning

    2005-01-01

    Selegiline is an irreversible inhibitor of monoamine oxidase (MAO) with psychostimulant and neuroprotective effects which can prevent decreases in dopamine efflux that follow opiate withdrawal. The present study evaluated effects of selegiline treatment on morphine-seeking behavior and morphine reinforcement in Wistar rats (n = 26). In additional animals (n = 30), the ability of single doses of selegiline to modify naloxone-precipitated withdrawal was determined. After pretreatment with noncontingent morphine to establish opiate dependence, rats acquired self-administration of intravenous morphine. Daily intravenous treatment with saline or 2.0mg kg(-1) doses of selegiline was then initiated and continued over 14 days during extinction, reinstatement, and reacquisition of morphine self-administration. To reduce the potential for psychostimulant effects, selegiline was administered approximately 1h following self-administration, extinction, or reinstatement sessions. In some animals (n = 23), effects of saline or selegiline administration on locomotor activity were determined following extinction sessions. Daily selegiline treatment decreased the number of ratios completed and increased response latency during extinction, without modifying these measures during reinstatement or reacquisition of morphine self-administration. Chronic selegiline treatment increased locomotor activity recorded between 4 and 7h after selegiline administration on day 7 of extinction, but otherwise did not alter locomotor activity. Pretreatment with single, 2.0mg kg(-1) doses of selegiline did not modify naloxone-precipitated withdrawal. In conclusion, pretreatment with selegiline produced only a small decrease in responding during extinction of morphine self-administration and did not modify cue-induced reinstatement of morphine-seeking behavior, reacquisition or morphine reinforcement, or precipitated withdrawal.

  10. Effect of dexamethasone on emesis after morphine administration in animal model

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    Mehdi Marjani

    2013-09-01

    Full Text Available  Background & Objective: Morphine is commonly used to relieve moderate to severe pain, but some side effects include vomiting. The Objective of this study was to evaluate the anti-emetic properties of dexamethasone in animal models receiving morphine.   Materials & Methods: In a clinical study fourteen cross breed dogs that were 2 and 4 years old were assigned to two equals groups. The Treatment group received dexamethasone (1 mg/kg intra muscularly, 60 minutes prior to morphine administration. The Control group received 2 cc of saline intra muscularly (IM, 60 minutes prior to morphine administration. After 60 minutes all dogs received morphine (1 mg/kg intra muscularly. After morphine was administrated all dogs were observed for 1 hour to allow assessment of frequency of emesis and time until the onset of the first emetic episode and then they were compared accordingly.   Results: The Mean ± SD for the first emetic episode in the treatment group was 266 ± 49. The same number was  197.6 ± 31.84 in the control group. There was no statistically significant deference for the time of the first emetic episode between treatment and control group (P = 0.23. There was no statistically significant deference for the number of emetic episodes between the treatment and control group (P = 0.16. There was no statistically significant deference for the weight of the dogs between the treatment and control groups (P = 0.95.    Conclusion: in the current study, the administration of dexamethasone 1 hour before administrating morphine was not able to significantly affect the frequency of emetic episodes or the time period before the occurrence of the first emetic episode. 

  11. Phosphoproteomics and Bioinformatics Analyses of Spinal Cord Proteins in Rats with Morphine Tolerance

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    Wen-Jinn Liaw; Cheng-Ming Tsao; Go-Shine Huang; Chin-Chen Wu; Shung-Tai Ho; Jhi-Joung Wang; Yuan-Xiang Tao; Hao-Ai Shui

    2014-01-01

    INTRODUCTION: Morphine is the most effective pain-relieving drug, but it can cause unwanted side effects. Direct neuraxial administration of morphine to spinal cord not only can provide effective, reliable pain relief but also can prevent the development of supraspinal side effects. However, repeated neuraxial administration of morphine may still lead to morphine tolerance. METHODS: To better understand the mechanism that causes morphine tolerance, we induced tolerance in rats at the spinal c...

  12. Morphine and codeine in oral fluid after controlled poppy seed administration.

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    Concheiro, Marta; Newmeyer, Matthew N; da Costa, Jose Luiz; Flegel, Ron; Gorelick, David A; Huestis, Marilyn A

    2015-07-01

    Opiates are an important drug class in drug testing programmes. Ingestion of poppy seeds containing morphine and codeine can yield positive opiate tests and mislead result interpretation in forensic and clinical settings. Multiple publications evaluated urine opiate concentrations following poppy seed ingestion, but only two addressed oral fluid (OF) results; neither provided the ingested morphine and codeine dosage. We administered two 45 g raw poppy seed doses, each containing 15.7 mg morphine and 3.1 mg codeine, 8 h apart to 17 healthy adults. All OF specimens were screened by on-site OF immunoassay Draeger DrugTest 5000, and confirmed with OF collected with Oral-Eze® device and quantified by liquid chromatography-tandem mass spectrometry (1 µg/L morphine and codeine limits of quantification). Specimens (n = 459) were collected before and up to 32 h after the first dose. All specimens screened positive 0.5 h after dosing and remained positive for 0.5-13 h at Draeger 20 µg/L morphine cut-off. Maximum OF morphine and codeine concentrations (Cmax ) were 177 and 32.6 µg/L, with times to Cmax (Tmax ) of 0.5-1 h and 0.5-2.5 h post-dose, respectively. Windows of detection after the second dose extended at least 24 h for morphine and to 18 h for codeine. After both doses, the last morphine positive OF result was 1 h with 40 µg/L 2004 proposed US Substance Abuse and Mental Health Services Administration cut-off, and 0.5 h with 95 µg/L cut-off, recently recommended by the Driving under the Influence of Drugs and Medicines project. Positive OF morphine results are possible 0.5-1 h after ingestion of 15.7 mg of morphine in raw poppy seeds, depending on the cut-off employed.

  13. Regulation of rat MOR-1 gene expression after chronic intracerebroventricular administration of morphine.

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    Zhu, Zhi-Ping; Badisa, Ramesh B; Palm, Donald E; Goodman, Carl B

    2012-02-01

    The µ-opioid receptor is the primary site for the action of morphine. In the present study, we investigated the regulation of the µ-opioid receptor mRNA levels in the locus ceruleus, ventral tegmental area, nucleus accumbens and hypothalamus of the rat brain following intracerebroventricular administration of morphine for 7 days. The isolated mRNA from these regions was subjected to real-time quantitative RT-PCR to determine the regulation of µ-opioid receptor gene expression. It was observed that 7 days of treatment with morphine significantly down-regulated the µ-opioid receptor mRNA levels in the hypothalamus of the brain in comparison to the control group. However, the µ-opioid receptor levels in the locus ceruleus, ventral tegmental area and nucleus accumbens regions remained the same as the control levels. Down-regulation of µ-opioid receptor mRNA levels in the hypothalamus region of the brain indicates the probable role of opioids to influence neuroendocrine function. The results further indicate that cellular adaptation for morphine tolerance is tissue-specific. These findings help us to understand the mechanism of morphine tolerance in various regions of the brain.

  14. The intracerebroventricular (ICV) administration of W-7, a calmodulin inhibitor, attenuates the development of morphine tolerance in rats.

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    Sepehri, Gholamreza; Sheibani, Vahid; Azarang, Afrooz; Shamsizadeh, Ali; Afarinesh, Mohammad Reza; Azizollahi, Saeed; Sepehri, Ehsan

    2010-04-01

    The present study was performed to determine the effect of intracerebroventricular (ICV) administration of W-7, a specific calmodulin inhibitor, on the development of tolerance to antinociceptive effect morphine administration. This study was carried out on male wistar rats, weighing 200-250 g. Morphine was administered daily (15 mg/kg for 8 days). The threshold to thermal nociceptive stimuli was measured by tail-flick test. W-7 (0.25, 0.5 and 1 micromol/rat) was injected through ICV. Maximal possible effect percentage (MPE %) was considered as analgesia index. Our result showed that chronic morphine exposure induced tolerance to its antinociceptive effect and administration of W-7 (0.5 and 1 micromol/rat) decreased the development of tolerance to it. In conclusion these data showed that chronic injection of W-7 inhibited the development of morphine tolerance which indicates that calmodulin and its dependent pathways may play a role in the morphine tolerance processes.

  15. Efficacy of epidural administration of morphine with bupivacaine for orthopaedic surgery in sheep

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    Durej M.; Ledecký V.; Michalák D.; Hluchý M.; Kòazovický D.

    2012-01-01

    The aim of the study was to test the hypothesis that epidural administration of morphine with bupivacaine provides more intense and sufficient perioperative analgesia compared with parenterally administrated butorphanol during orthopaedic surgery. Sheep were assigned to group C (control group, 6 sheep) and group E (epidural, 5 sheep). Sheep from group C were pre-medicated with midazolam (0.3 mg/kg, i.m.) and butorphanol (0.2 mg/kg, i.m.). Propofol was used ...

  16. [Inhibition of morphine intake by antibodies to serotonin-modulating anticonsolidation protein in model of self-administration in rats].

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    Mekhtiev, A A; Rashidova, A M; Muslimov, I A

    2014-01-01

    The article concerns study of effects of polyclonal antibodies to serotonin-modulating anticonsolidation protein (SMAP) being in direct dependence on serotonin level and providing intracellular transduction of serotonergic signal, on positive reinforcement effect of morphine in rats. The task was formed in Wistar male rats in the model of morphine self-administration as a result of pressing of one of two levers attached to the wall, joined to the pump delivering each time 100 μg of morphine directly into the vena jugularis. In the 1st series of studies brain cingulate cortex and hypothalamus were taken from the rats achieved stable level of morphine intake and SMAP level was measured with indirect immune-enzyme assay. It was shown that in the morphine-self-injected rats SMAP level in the cingulate cortex is significantly upregulated (p = 0.01), while in the hypothalamus it was left unchanged. In the 2nd series of studies the rats with stable level of morphine intake were administered intraperitoneally with anti-SMAP rabbit polyclonal antibodies (experimental group) or non-immune γ-globulins (control group). Soon after antibodies administration the animals of the experimental group demonstrated manifold decrease of morphine intake lasted for 8 days (p positive reinforcement effect of morphine. Blockade of SMAP activity with anti-SMAP antibodies in the nerve cells induced sharp decrease of morphine intake due to disturbances of transduction through intracellular serotonin's signal channels.

  17. Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision

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    Angst Martin S

    2008-02-01

    Full Text Available Abstract Background - The chronic use of opioids prior to surgery leads to lowered pain thresholds and exaggerated pain levels after these procedures. Several mechanisms have been proposed to explain this heightened sensitivity commonly termed opioid-induced hyperalgesia (OIH. Most of these proposed mechanisms involve plastic events in the central or peripheral nervous systems. Alterations in the abundance of peripheral mediators of nociception have not previously been explored. Results - In these experiments mice were treated with saline (control or ascending daily doses of morphine to generate a state of OIH followed by hind paw incision. In other experiments morphine treatment was initiated at the time of incision. Both mechanical allodynia and peri-incisional skin cytokine levels were measured. Myeloperoxidase (MPO assays were used to determine neutrophil activity near the wounds. The cytokine production inhibitor pentoxifylline was used to determine the functional significance of the excess cytokines in previously morphine treated animals. Mice treated chronically treated with morphine prior to incision were found to have enhanced skin levels of IL-1β, IL-6, G-CSF, KC and TNFα after incision at one or more time points compared to saline pretreated controls. The time courses of individual cytokines followed different patterns. There was no discernable effect of chronic morphine treatment on wound area neutrophil infiltration. Pentoxifylline reduced cytokine levels and reversed the excess mechanical sensitization caused by chronic morphine administration prior to incision. Morphine treatment initiated at the time of incision did not lead to a generalized enhancement of cytokine production or nociceptive sensitization in excess of the levels observed after incision alone. Conclusion - The enhanced level of nociceptive sensitization seen after incision in animals chronically exposed to morphine is associated with elevated levels of several

  18. Chronic morphine administration induces over-expression of aldolase C with reduction of CREB phosphorylation in the mouse hippocampus.

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    Yang, Hai-Yu; Pu, Xiao-Ping

    2009-05-01

    In recent studies, alterations in the activity and expression of metabolic enzymes, such as those involved in glycolysis, have been detected in morphine-dependent patients and animals. Increasing evidence demonstrates that the hippocampus is an important brain region associated with morphine dependence, but the molecular events occurring in the hippocampus following chronic exposure to morphine are poorly understood. Aldolase C is the brain-specific isoform of fructose-1, 6-bisphosphate aldolase which is a glycolytic enzyme catalyzing reactions in the glycolytic, gluconeogenic, and fructose metabolic pathways. Using Western blot and immunofluorescence assays, we found the expression of aldolase C was markedly increased in the mouse hippocampus following chronic morphine treatment. Naloxone pretreatment before morphine administration suppressed withdrawal jumping, weight loss, and overexpression of aldolase C. CREB is a transcription factor regulated through phosphorylation on Ser133, which is known to play a key role in the mechanism of morphine dependence. When detecting the expression of phosphorylated CREB (p-CREB) in the mouse hippocampus using Western blot and immunohistochemistry, we found CREB phosphorylation was clearly decreased following chronic morphine treatment. Interestingly, laser-confocal microscopy showed that overexpression of aldolase C in mouse hippocampal neurons was concomitant with the decreased immunoreactivity of p-CREB. The results suggest potential links between the morphine-induced alteration of aldolase C and the regulation of CREB phosphorylation, a possible mechanism of morphine dependence.

  19. Morphine and Codeine Concentrations in Human Urine following Controlled Poppy Seeds Administration of Known Opiate Content

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    Smith, Michael L.; Nichols, Daniel C.; Underwood, Paula; Fuller, Zachary; Moser, Matthew A.; LoDico, Charles; Gorelick, David A.; Newmeyer, Matthew N.; Concheiro, Marta; Huestis, Marilyn A.

    2014-01-01

    Opiates are an important component for drug testing due to their high abuse potential. Proper urine opiate interpretation includes ruling out poppy seed ingestion; however, detailed elimination studies after controlled poppy seed administration with known morphine and codeine doses are not available. Therefore, we investigated urine opiate pharmacokinetics after controlled oral administration of uncooked poppy seeds with known morphine and codeine content. Participants were administered two 45g oral poppy seed doses 8h apart, each containing 15.7mg morphine and 3mg codeine. Urine was collected ad libitum up to 32h after the first dose. Specimens were analyzed with the Roche Opiates II immunoassay at 2,000 and 300μg/L cutoffs, and the ThermoFisher CEDIA® Heroin Metabolite (6-acetylmorphine, 6AM) and Lin-Zhi 6AM immunoassays with 10μg/L cutoffs to determine if poppy seed ingestion could produce positive results in these heroin marker assays. In addition, all specimens were quantified for morphine and codeine by GC/MS. Participants (N=22) provided 391 urine specimens over 32h following dosing; 26.6% and 83.4% were positive for morphine at 2,000 and 300μg/L GC/MS cutoffs, respectively. For the 19 subjects who completed the study, morphine concentrations ranged from <300 to 7,522μg/L with a median peak concentration of 5,239μg/L. The median first morphine-positive urine sample at 2,000μg/L cutoff concentration occurred at 6.6h (1.2-12.1), with the last positive from 2.6 to 18h after the second dose. No specimens were positive for codeine at a cutoff concentration of 2,000μg/L, but 20.2% exceeded 300μg/L, with peak concentrations of 658 μg/L (284-1540). The Roche Opiates II immunoassay had efficiencies greater than 96% for the 2000 and 300μg/L cutoffs. The CEDIA 6AM immunoassay had a specificity of 91%, while the Lin-Zhi assay had no false positive results. These data provide valuable information for interpreting urine opiate results. PMID:24887324

  20. Intrathecal Administration of Morphine Decreases Persistent Pain after Cesarean Section: A Prospective Observational Study.

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    Kumi Moriyama

    Full Text Available Chronic pain after cesarean section (CS is a serious concern, as it can result in functional disability. We evaluated the prevalence of chronic pain after CS prospectively at a single institution in Japan. We also analyzed perioperative risk factors associated with chronic pain using logistic regression analyses with a backward-stepwise procedure.Patients who underwent elective or emergency CS between May 2012 and May 2014 were recruited. Maternal demographics as well as details of surgery and anesthesia were recorded. An anesthesiologist visited the patients on postoperative day (POD 1 and 2, and assessed their pain with the Prince Henry Pain Scale. To evaluate the prevalence of chronic pain, we contacted patients by sending a questionnaire 3 months post-CS.Among 225 patients who questionnaires, 69 (30.7% of patients complained of persistent pain, although no patient required pain medication. Multivariate analyses identified lighter weight (p = 0.011 and non-intrathecal administration of morphine (p = 0.023 as determinant factors associated with persistent pain at 3 months. The adjusted odds ratio of intrathecal administration of morphine to reduce persistent pain was 0.424, suggesting that intrathecal administration of morphine could decrease chronic pain by 50%. In addition, 51.6% of patients had abnormal wound sensation, suggesting the development of neuropathic pain. Also, 6% of patients with abnormal wound sensation required medication, yet no patients with persistent pain required medication.Although no effect on acute pain was observed, intrathecal administration of morphine significantly decreased chronic pain after CS.

  1. Proconvulsant effects of tramadol and morphine on pentylenetetrazol-induced seizures in adult rats using different routes of administration.

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    Gholami, Morteza; Saboory, Ehsan; Roshan-Milani, Shiva

    2014-07-01

    Tramadol is frequently used as a pain reliever. However, it has been sometimes noted to have the potential to cause seizures. Because of its dual mechanism of action (both opioid and nonopioid), the adverse effect profile of tramadol can be different in comparison with single-mechanism opioid analgesics, such as morphine. In the present study, the facilitatory effects of tramadol and morphine on pentylenetetrazol-induced seizures using different routes of administration were compared in rats. Adult female rats were divided into six groups and continuously received saline, morphine, or tramadol on a daily basis for 15 days [gavage (PO) or intraperitoneal (IP)]. An increasing dose of morphine and tramadol was used to prevent resistance to repetitive dose (20-125 mg/kg). Following one week of withdrawal period and 30 min before the seizure induction (PTZ=80 mg/kg, IP), each group of rats was further divided into subgroups that received saline, morphine, or tramadol for the second time on the 22nd day of the experiment. Results showed that, while morphine, tramadol, and their administration had different effects on seizure behaviors, both acute and chronic administrations of morphine and tramadol potentiated PTZ-induced seizures. However, there was no significant difference between morphine and tramadol in terms of seizure severity. Effects of morphine and tramadol on PTZ-induced seizures were also stable following one week of withdrawal. In conclusion, this study indicated similar severity in the proconvulsant effect of morphine and tramadol on PTZ-induced seizures, which might depend on their similar effects on GABAergic pathways.

  2. CLINICAL EVALUATION OF EPIDURAL ADMINISTRATION OF MORPHINE, FENTANYL, METHADONE, LIDOCAINE AND LIDOCAINE WITH EPINEPHRINE IN CATTLE

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    A. Tabatabaei Naeine, A. Rezakhani and J. Fazlinia

    2004-01-01

    Full Text Available The purpose of this study was to determine the analgesic efficacy and clinical effects of morphine, fentanyl, methadone, lidocaine, lidocaine with epinephrine and saline (control when injected epidurally into the caudal epidural space in cattle. Epidural analgesia was achieved in five cattle on five successive occasions at weekly intervals. Analgesia was defined as a lack of response to hemostat pressure and pinprick in the skin of the perineal area and ventral aspect of the tail. The results demonstrated that while epidural lidocaine and lidocaine with epinephrine decreased the response to hemostat and pinprick compared to control, there was no reduction in response after the administration of morphine, methadone or fentanyl. Heart rate, pulse and respiratory rates were not significantly altered by any of the drugs. Neither did the drugs produce any change in the electrocardiogram (ECG of the animals.

  3. Phosphoproteomics and bioinformatics analyses of spinal cord proteins in rats with morphine tolerance.

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    Wen-Jinn Liaw

    Full Text Available INTRODUCTION: Morphine is the most effective pain-relieving drug, but it can cause unwanted side effects. Direct neuraxial administration of morphine to spinal cord not only can provide effective, reliable pain relief but also can prevent the development of supraspinal side effects. However, repeated neuraxial administration of morphine may still lead to morphine tolerance. METHODS: To better understand the mechanism that causes morphine tolerance, we induced tolerance in rats at the spinal cord level by giving them twice-daily injections of morphine (20 µg/10 µL for 4 days. We confirmed tolerance by measuring paw withdrawal latencies and maximal possible analgesic effect of morphine on day 5. We then carried out phosphoproteomic analysis to investigate the global phosphorylation of spinal proteins associated with morphine tolerance. Finally, pull-down assays were used to identify phosphorylated types and sites of 14-3-3 proteins, and bioinformatics was applied to predict biological networks impacted by the morphine-regulated proteins. RESULTS: Our proteomics data showed that repeated morphine treatment altered phosphorylation of 10 proteins in the spinal cord. Pull-down assays identified 2 serine/threonine phosphorylated sites in 14-3-3 proteins. Bioinformatics further revealed that morphine impacted on cytoskeletal reorganization, neuroplasticity, protein folding and modulation, signal transduction and biomolecular metabolism. CONCLUSIONS: Repeated morphine administration may affect multiple biological networks by altering protein phosphorylation. These data may provide insight into the mechanism that underlies the development of morphine tolerance.

  4. Spinal cord distribution of sup 3 H-morphine after intrathecal administration: Relationship to analgesia

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    Nishio, Y.; Sinatra, R.S.; Kitahata, L.M.; Collins, J.G. (Yale Univ. School of Medicine, CT (USA))

    1989-09-01

    The distribution of intrathecally administered {sup 3}H-morphine was examined by light microscopic autoradiography in rat spinal cord and temporal changes in silver grain localization were compared with results obtained from simultaneous measurements of analgesia. After tissue processing, radio-activity was found to have penetrated in superficial as well as in deeper layers (Rexed lamina V, VII, and X) of rat spinal cord within minutes after application. Silver grain density reached maximal values at 30 min in every region of cord studied. Radioactivity decreased rapidly between 30 min and 2 hr and then more slowly over the next 24 hr. In rats tested for responses to a thermal stimulus (tail flick test), intrathecal administration of morphine (5 and 15 micrograms) resulted in significant dose dependent analgesia that peaked at 30 min and lasted up to 5 hr (P less than 0.5). There was a close relationship between analgesia and spinal cord silver grain density during the first 4 hr of the study. It is postulated that the onset of spinal morphine analgesia depends on appearance of molecules at sites of action followed by the activation of anti-nociceptive mechanisms.

  5. Central administration of neuropeptide FF and related peptides attenuate systemic morphine analgesia in mice.

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    Fang, Quan; Jiang, Tian-nan; Li, Ning; Han, Zheng-lan; Wang, Rui

    2011-04-01

    Neuropeptide FF (NPFF) belongs to an opioid-modulating peptide family. NPFF has been reported to play important roles in the control of pain and analgesia through interactions with the opioid system. However, very few studies examined the effect of supraspinal NPFF system on analgesia induced by opiates administered at the peripheral level. In the present study, intracerebroventricular (i.c.v.) injection of NPFF (1, 3 and 10 nmol) dose-dependently inhibited systemic morphine (0.12 mg, i.p.) analgesia in the mouse tail flick test. Similarly, i.c.v. administration of dNPA and NPVF, two agonists highly selective for NPFF(2) and NPFF(1) receptors, respectively, decreased analgesia induced by i.p. morphine in mice. Furthermore, these anti-opioid activities of NPFF and related peptides were blocked by pretreatment with the NPFF receptors selective antagonist RF9 (10 nmol, i.c.v.). These results demonstrate that activation of central NPFF(1) and NPFF(2) receptors has the similar anti-opioid actions on the antinociceptive effect of systemic morphine.

  6. Neonatal morphine administration leads to changes in hippocampal BDNF levels and antioxidant enzyme activity in the adult life of rats.

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    Rozisky, J R; Laste, G; de Macedo, I C; Santos, V S; Krolow, R; Noschang, C; Vanzella, C; Bertoldi, K; Lovatel, G A; de Souza, I C C; Siqueira, I R; Dalmaz, C; Caumo, W; Torres, I L S

    2013-03-01

    It is know that repeated exposure to opiates impairs spatial learning and memory and that the hippocampus has important neuromodulatory effects after drug exposure and withdrawal symptoms. Thus, the aim of this investigation was to assess hippocampal levels of BDNF, oxidative stress markers associated with cell viability, and TNF-α in the short, medium and long term after repeated morphine treatment in early life. Newborn male Wistar rats received subcutaneous injections of morphine (morphine group) or saline (control group), 5 μg in the mid-scapular area, starting on postnatal day 8 (P8), once daily for 7 days, and neurochemical parameters were assessed in the hippocampus on postnatal days 16 (P16), 30 (P30), and 60 (P60). For the first time, we observed that morphine treatment in early life modulates BDNF levels in the medium and long term and also modulates superoxide dismutase activity in the long term. In addition, it was observed effect of treatment and age in TNF-α levels, and no effects in lactate dehydrogenase levels, or cell viability. These findings show that repeated morphine treatment in the neonatal period can lead to long-lasting neurochemical changes in the hippocampus of male rats, and indicate the importance of cellular and intracellular adaptations in the hippocampus after early-life opioid exposure to tolerance, withdrawal and addiction.

  7. 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.

  8. Intramuscular administration of morphine reduces mustard-oil-induced craniofacial-muscle pain behavior in lightly anesthetized rats.

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    Han, Seung R; Lee, Min K; Lim, Koang H; Yang, Gwi Y; Jeon, Hye J; Ju, Jin S; Yoon, Young W; Kim, Sung K; Ahn, Dong K

    2008-04-01

    The present study investigated the role of peripheral opioid receptors in mustard oil-induced nociceptive behavior and inflammation in the masseter muscles of lightly anesthetized rats. Experiments were carried out on male Sprague-Dawley rats weighing between 300 and 400 g. After initial anesthesia with sodium pentobarbital (40 mg/kg, i.p.), one femoral vein was cannulated and connected to an infusion pump for the intravenous infusion of sodium pentobarbital. The rate of infusion was adjusted to provide a constant level of anesthesia. Mustard oil (MO, 30 microl) was injected into the mid-region of the left masseter muscle via a 30-gauge needle. Intramuscularly-administered morphine significantly reduced shaking behavior but not MO-induced inflammation. Intramuscular pretreatment with naloxone, an opioid receptor antagonist, reversed antinociception produced by intramuscularly-administered morphine, while intracisternal administration of naloxone did not affect the antinociception of peripheral morphine. Pretreatment with d-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a mu opioid receptor antagonist, but not naltrindole, a delta opioid receptor antagonist, nor norbinaltorphimine (nor-BNI), a kappa opioid receptor antagonist, reversed intramuscularly-administered morphine-induced antinociception. These results indicate that intramuscularly-administered morphine produces antinociception in craniofacial muscle nociception and that this intramuscularly-administered morphine-induced antinociception is mediated by a peripheral mu opioid receptor. Our observations further support the clinical approach of administering opioids in the periphery for the treatment of craniofacial muscle nociception.

  9. Effects of intracerebroventricular administration of ultra low doses of histaminergic drugs on morphine state-dependent memory of passive avoidance in mice.

    Science.gov (United States)

    Khalilzadeh, Azita; Zarrindast, Mohammad-Reza; Djahanguiri, Bijan

    2006-01-06

    The effects of intracerebroventricular (i.c.v.) administration of ultra low doses (ULDs) of histamine, clobenpropit and pyrilamine are studied on morphine state-dependent (STD) memory in mice. Although pre-test administration of different doses of histamine and clobenpropit showed no effect on impairment of memory induced by pre-training morphine, when the above drugs were co-administered with morphine, they inhibited the restoration of memory by morphine. These effects were opposite to microgram doses of the same drugs.

  10. Pharmacokinetics cannot explain the increased effective dose requirement for morphine and midazolam in rats during their extended administration alone or in combination.

    Science.gov (United States)

    Schaller, Stefan J; Alam, Saad M; Mao, Jianren; Zhao, Yanli; Blobner, Manfred; Greenblatt, David J; Martyn, J A Jeevendra

    2017-01-01

    Chronic administration of morphine and midazolam, alone or in combination, can induce tolerance to their effects. Data showed that co-administration of morphine and midazolam increased effective dose requirement of morphine, exceeding that observed with morphine alone. To elucidate the pharmacokinetic component to the tolerance, we administered midazolam (2 mg/kg) and morphine (10 mg/kg) alone or their combination daily to rats for 12 days followed by a pharmacokinetic study on day 13. On the study day, each animal received a single bolus dose of 5 mg/kg morphine, and 2 mg/kg of midazolam 30 s later. Multiple blood samples were obtained for 6 h. Plasma drug concentrations were assayed by mass spectrometry optimized for small samples. Mean morphine clearance was as follows: 22.2, 27.2, 26.0 and 23.4 l/h per kg in the saline-saline, saline-midazolam, saline-morphine and midazolam-morphine groups, respectively. Corresponding midazolam clearances were 32.8, 23.0, 22.2 and 31.1 l/h per kg. ANOVA indicated no significant differences among the four groups in the clearances, half-lives, and volumes of distribution. Morphine and midazolam clearances were significantly correlated (R(2) = 0.48, P midazolam, when administered alone or combination, for extended periods. © 2016 Royal Pharmaceutical Society.

  11. The effects of repeated opioid administration on locomotor activity: II. Unidirectional cross-sensitization to cocaine.

    Science.gov (United States)

    Smith, Mark A; Greene-Naples, Jennifer L; Felder, Jennifer N; Iordanou, Jordan C; Lyle, Megan A; Walker, Katherine L

    2009-08-01

    Sensitization refers to an increase in sensitivity to the effects of a drug and is believed to play a role in the etiology of substance use disorders. Cross-sensitization has been observed between drugs from different pharmacological classes and may play a role in the escalation of drug use in polydrug-abusing populations. The purpose of this study was to examine cross-sensitization between opioids and cocaine and to determine the extent to which cross-sensitization is mediated by an opioid's selectivity for mu, kappa, and delta receptors. Separate groups of rats were treated with opioid receptor agonists and antagonists every other day for 10 days, and the locomotor effects of cocaine were tested 8 days later. The mu agonists, morphine and buprenorphine, and the delta agonist, BW373U86 [(+/-)-4-[(R(*))-[(2S(*),5R(*))-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide hydrochloride], produced cross-sensitization to cocaine, such that repeated administration of these drugs over a 10-day period significantly enhanced cocaine's locomotor effects when tested later. Coadministration of the opioid antagonist naltrexone prevented morphine and buprenorphine from producing cross-sensitization. Coadministration of naltrexone, but not the delta antagonist naltrindole, also prevented BW373U86 from producing cross-sensitization. The kappa agonist spiradoline failed to produce cross-sensitization, but coadministration of spiradoline prevented morphine and buprenorphine from producing cross-sensitization. The ability of spiradoline to block cross-sensitization was itself blocked by the kappa antagonist nor-binaltorphimine. The mixed mu/kappa opioids butorphanol, nalbuphine, and nalorphine did not produce cross-sensitization under any condition examined. These data indicate that agonist activity at mu receptors positively modulates cross-sensitization between opioids and cocaine, whereas agonist activity at kappa receptors negatively modulates

  12. Efficacy of epidural administration of morphine with bupivacaine for orthopaedic surgery in sheep

    Directory of Open Access Journals (Sweden)

    Durej M.

    2012-01-01

    Full Text Available The aim of the study was to test the hypothesis that epidural administration of morphine with bupivacaine provides more intense and sufficient perioperative analgesia compared with parenterally administrated butorphanol during orthopaedic surgery. Sheep were assigned to group C (control group, 6 sheep and group E (epidural, 5 sheep. Sheep from group C were pre-medicated with midazolam (0.3 mg/kg, i.m. and butorphanol (0.2 mg/kg, i.m.. Propofol was used for induction of general anesthesia in both groups. Sheep from group E were pre-medicated with midazolam, but without butorphanol. Sacrococcegeal epidural analgesia with morphine (0.1 mg/kg and bupivacaine (1 mg/kg was performed. We detected a significant increase in heart rate (19%, p=0.021 during surgery in group C. Two hours after surgery, the heart rate was 14.9% lower than prior to surgery in group E (p=0.017. In group E, throughout the surgery, we measured an insignificant increase in respiratory rate of 1.99%. In the same group, 120 minutes post surgery, we measured an increase in respiratory rate of 14.7%, while in group C there was a smaller increase of only 10.9%. The result from both groups was insignificant (p>0.05. The consumption of isoflurane in group C was higher than in group E by 27.3% (p=0.0043. The mean MAC was in group C higher by 27.6% as it was in group E (0.75% ± 0.25, 0.95 ± 0.3 in Group E and C, respectively. This distinction, according to the Mann-Whitney test, was not significant (p=0.329.

  13. Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain.

    Science.gov (United States)

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Heegaard, Anne-Marie; Kreilgaard, Mads; Lund, Trine Meldgaard

    2016-01-20

    Despite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacological interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of morphine and gabapentin in range of different dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7mg/kg), gabapentin (10, 30 and 100mg/kg) or their combination (9 combinations in total) were evaluated in the rat plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58% for the synergistic doses. The finding of dose-dependent synergistic effects highlights that choosing the right dose-dose combination is of importance in postoperative pain therapy. Our results indicate benefit of high doses of gabapentin as adjuvant to morphine. If these findings translate to humans, they might have important implications for the treatment of pain in postoperative patients.

  14. Repeated administration of adenosine increases its cardiovascular effects in rats.

    Science.gov (United States)

    Vidrio, H; García-Márquez, F; Magos, G A

    1987-01-20

    Hypotensive and negative chronotropic responses to adenosine in anesthetized rats increased after previous administration of the nucleoside. Bradycardia after adenosine in the isolated perfused rat heart was also potentiated after repeated administration at short intervals. This self-potentiation could be due to extracellular accumulation of adenosine and persistent stimulation of receptors caused by saturation or inhibition of cellular uptake of adenosine.

  15. Morphine and Codeine in Oral Fluid after Controlled Poppy Seed Administration

    OpenAIRE

    Concheiro, Marta; Newmeyer, Matthew N.; da Costa, Jose Luiz; Flegel, Ron; Gorelick, David A.; Huestis, Marilyn A.

    2014-01-01

    Opiates are an important drug class in drug testing programs. Ingestion of poppy seeds containing morphine and codeine can yield positive opiate tests and mislead result interpretation in forensic and clinical settings. Multiple publications evaluated urine opiate concentrations following poppy seed ingestion, but only 2 addressed oral fluid (OF) results; neither provided the ingested morphine and codeine dosage. We administered two 45g raw poppy seed doses, each containing 15.7mg morphine an...

  16. Olfactory repeated discrimination reversal in rats: effects of chlordiazepoxide, dizocilpine, and morphine.

    Science.gov (United States)

    Galizio, Mark; Miller, Laurence; Ferguson, Adam; McKinney, Patrick; Pitts, Raymond C

    2006-10-01

    Effects of a benzodiazepine (chlordiazepoxide), an N-methyl-D-aspartate receptor antagonist (dizocilpine), and an opiate agonist (morphine) were studied with a procedure designed to assess effects of drugs and other manipulations on nonspatial learning in rats. In each session, rats were exposed to 2 different 2-choice odor-discrimination problems with food reinforcement for correct responses. One problem (performance discrimination) remained the same throughout the study. That is, 1 odor was always correct (S+) and the other was never correct (S-). For the other problem (reversal discrimination), stimuli changed every session. Six different odors were used to program the reversal discrimination; on any given session, S+ was a stimulus that had served as S- the last time it had appeared, S- was a stimulus that had been S+ on its last appearance. Thus, in each session, learning a discrimination reversal could be studied along with the performance of a comparable, but previously learned, discrimination. Chlordiazepoxide interfered with reversal learning at doses that had no effect on the performance discrimination. Morphine and dizocilpine also impaired reversal learning but only at doses that also affected performance of the well-learned performance discrimination.

  17. 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 doses...... of morphine may play a pathogenetic role in the observed behavioural syndrome....

  18. Influence of intracerebroventricular administration of histaminergic drugs on morphine state-dependent memory in the step-down passive avoidance test.

    Science.gov (United States)

    Zarrindast, Mohammad R; Khalilzadeh, Azita; Rezayat, S Mehdi; Sahebgharani, Mousa; Djahanguiri, Bijan

    2005-05-01

    The effects of histaminergic drugs on morphine state-dependent memory of a passive avoidance task were examined in mice. Pre-training administration of morphine (5 mg/kg) led to state-dependent learning with impaired memory recall on the test day which was reversed by pre-test administration of the same dose of the opioid. The pre-test intracerebroventricular (i.c.v.) administration of the H(1) blocker (pyrilamine) prevented the restoration of memory by morphine. The H(2) blocker (ranitidine) was ineffective in this regard and the H(3) blocker (clobenpropit) potentiated the effect of morphine on memory recall. The pre-test i.c.v. administration of histamine alone (5, 10, and 20 microg/mouse) not only mimicked the effect of pre-test morphine treatment, but also increased this action of the opioid. The effect of histamine on memory recall was not changed by the pre-test administration of mu-opioid receptor antagonist, naloxone. In conclusion, the improvement of memory recall by morphine treatment, on the test day, seems to be, at least in part, through the release of histamine followed by the stimulation of H(1) receptors. Histamine by itself, when administered on the test day, mimicked morphine-induced memory improvement by a mechanism independent of the mu-opioid receptors.

  19. Evaluation of analgesic effect of local administration of morphine after iliac crest bone graft harvesting: A double blind study

    Directory of Open Access Journals (Sweden)

    Devinder Singh

    2013-01-01

    Full Text Available Background and Objective: Pain is a complex process influenced by both physiological and psychological factors. In spite of an armamentarium of analgesic drugs and techniques available to combat post-operative pain, appropriate selection, and effective management for relief of post-operative pain still poses unique challenges. The discovery of peripheral opioid receptors has led to growing interest in the use of locally applied opioids (intra-articular, intra-pleural, intra-peritoneal, and perineural for managing acute pain. As bone graft harvesting is associated with significant post-operative pain and there is a paucity of literature on the use of peripheral opioids at the iliac crest bone harvesting site, the present study was planned to evaluate the analgesic efficacy of local administration of morphine after iliac crest bone graft harvesting. Materials and Methods: A total of 60 patients, 20-50 years of age scheduled to undergo elective surgery for delayed and non-union fracture both bone leg with bone grafting under general anaesthesia (GA were randomly assigned to one of the four groups of 15 patients each: group 1: 2.5 ml normal saline (NS +2.5 ml NS infiltrated into the harvest site at 2 sites + 1 ml NS intramuscularly (i/m; Group 2: 2.5 ml NS + 2.5 ml NS infiltrated into the harvest site at 2 sites + 5 mg morphine in 1 ml i/m.; Group 3: 2.5 mg (2.5 ml morphine + 2.5 mg (2.5 ml morphine infiltrated into the harvest site at 2 sites + 1 ml NS i/m; Group 4: 0.5 mg naloxone (2.5 ml +5 mg (2.5 ml morphine infiltrated into the harvest site at 2 sites + 1 ml NS i/m. Pain from the bone graft site and operative site was assessed for 24 h post-operatively. Results: The patients who had received morphine infiltration (Group 3 had significantly less pain scores at the graft site at 4, 6, and 10 post-operative hours. They also had significantly less morphine consumption and overall better pain relief as compared to the other groups. Conclusions

  20. Effect of chronic administration of morphine on the gene expression level of sodium-dependent vitamin C transporters in rat hippocampus and lumbar spinal cord.

    Science.gov (United States)

    Zarebkohan, Amir; Javan, Mohammad; Satarian, Leila; Ahmadiani, Abolhasan

    2009-07-01

    Chronic morphine leads to dependence, tolerance, and neural apoptosis. Vitamin C inhibits the withdrawal syndrome in morphine-dependent subjects and prevents apoptosis in experimental models. Sodium-dependent vitamin C transporter (SVCT) type-2 is the main transporter for carrying vitamin C into the brain and neural cells. The mechanism(s) by which vitamin C inhibits morphine dependence in not understood. SVCT activity determines the vitamin C availably within the nervous system. We have examined the alterations in the expression of SVCT1, SVCT2, and its splice variants in morphine-tolerant rats. Morphine (20 mg/kg) was injected twice/day to male rats for either 7 or 14 days. The development of analgesic tolerance was assessed using tail-flick test. Lumbar spinal cord and the hippocampus were isolated for RNA extraction. Semiquantitative reverse transcriptase-polymerase chain reaction method was used to assess the levels of gene expression. Administration of morphine for 7 or 14 days reduced the expression level of SVCT2 in both hippocampus and dorsal lumbar spinal cord of rats. SVCT2 expression was reduced in vitamin C-, and vitamin C combined with morphine-treated animals. Results did not show SVCT2 splice variation. SVCT1 did not express in control or morphine-treated rats. It seems that reduced expression level of SVCT2 might be involved in the development of morphine side effects such as tolerance and dependency.

  1. Epidural Co-Administration of Dexmedetomidine and Levobupivacaine Improves the Gastrointestinal Motility Function after Colonic Resection in Comparison to Co-Administration of Morphine and Levobupivacaine.

    Directory of Open Access Journals (Sweden)

    Xian-Zhang Zeng

    Full Text Available Gastrointestinal motility may be impaired after intestinal surgery. Epidural morphine is effective in controlling postoperative pain, but can further reduce gastrointestinal motility. Here, we aimed to investigate the effects of epidural dexmedetomidine on gastrointestinal motility in patients undergoing colonic resection. Seventy-four patients undergoing colonic resection were enrolled in this clinical trial and allocated randomly to treatment with dexmedetomidine (D group or morphine (M group. The D group received a loading dose epidural administration of 3 ml dexmedetomidine (0.5 μg kg(-1 and then a continuous epidural administration of 80 μg dexmedetomidine in 150 ml levobupivacaine (0.125% at 3 ml h(-1 for two days. The M group received a loading dose epidural administration of 3 ml morphine (0.03 mg kg(-1 and then a continuous epidural administration of 4.5 mg morphine in 150 ml levobupivacaine at 3 ml h(-1 for two days. Verbal rating score (VRS, postoperative analgesic requirements, side effects related to analgesia, the time to postoperative first flatus (FFL and first feces (FFE were recorded. VRS and postoperative analgesic requirements were not significantly different between treatment groups. In contrast, the time to FFL and time to FFE were significant longer in M group in comparison to D group (P < 0.05. Moreover, patients in M group had a significantly higher incidence of nausea, vomiting, and pruritus (P < 0.05. No patients showed neurologic deficits in either group. In comparison to morphine, epidural dexmedetomidine is safe and beneficial for the recovery of gastrointestinal motility after colonic resection when used as an adjunct with levobupivacaine for postoperative pain control.Chinese Clinical Trial Registry ChiCTR-TRC-14004644.

  2. Epidural Co-Administration of Dexmedetomidine and Levobupivacaine Improves the Gastrointestinal Motility Function after Colonic Resection in Comparison to Co-Administration of Morphine and Levobupivacaine

    Science.gov (United States)

    Zeng, Xian-Zhang; Lu, Zhi-Fang; Lv, Xiang-Qi; Guo, Yue-Ping; Cui, Xiao-Guang

    2016-01-01

    Gastrointestinal motility may be impaired after intestinal surgery. Epidural morphine is effective in controlling postoperative pain, but can further reduce gastrointestinal motility. Here, we aimed to investigate the effects of epidural dexmedetomidine on gastrointestinal motility in patients undergoing colonic resection. Seventy-four patients undergoing colonic resection were enrolled in this clinical trial and allocated randomly to treatment with dexmedetomidine (D group) or morphine (M group). The D group received a loading dose epidural administration of 3 ml dexmedetomidine (0.5 μg kg-1) and then a continuous epidural administration of 80 μg dexmedetomidine in 150 ml levobupivacaine (0.125%) at 3 ml h-1 for two days. The M group received a loading dose epidural administration of 3 ml morphine (0.03 mg kg-1) and then a continuous epidural administration of 4.5 mg morphine in 150 ml levobupivacaine at 3 ml h-1 for two days. Verbal rating score (VRS), postoperative analgesic requirements, side effects related to analgesia, the time to postoperative first flatus (FFL) and first feces (FFE) were recorded. VRS and postoperative analgesic requirements were not significantly different between treatment groups. In contrast, the time to FFL and time to FFE were significant longer in M group in comparison to D group (P < 0.05). Moreover, patients in M group had a significantly higher incidence of nausea, vomiting, and pruritus (P < 0.05). No patients showed neurologic deficits in either group. In comparison to morphine, epidural dexmedetomidine is safe and beneficial for the recovery of gastrointestinal motility after colonic resection when used as an adjunct with levobupivacaine for postoperative pain control. Trial Registration Chinese Clinical Trial Registry ChiCTR-TRC-14004644 PMID:26751791

  3. Pre-injury administration of morphine prevents development of neuropathic hyperalgesia through activation of descending monoaminergic mechanisms in the spinal cord in mice

    Directory of Open Access Journals (Sweden)

    Rashid Md Harunor

    2005-06-01

    Full Text Available Abstract The present study examined whether pre-injury administration of morphine can prevent partial sciatic nerve injury-induced neuropathic pain in mice. We observed that pre-injury administration of subcutaneous (s.c. and intracerebroventricular (i.c.v. morphine dose-dependently prevented the development of both thermal and mechanical hyperalgesia at 7 days following nerve injury in mice. The pre-injury morphine (s.c.-induced analgesia was significantly blocked by pretreatment with naloxone injected s.c. or i.c.v., but not i.t., suggesting that systemic morphine produced the pre-emptying effects mainly by acting at the supra-spinal sites. Since it is believed that activation of descending monoaminergic mechanisms in spinal cord largely contributes to the supra-spinal analgesic effects of morphine, we investigated the involvement of serotonergic and noradrenergic mechanisms in spinal cord in the pre-injury morphine-induced analgesic effects. We found that pre-injury s.c. morphine-induced analgesic effect was significantly blocked by i.t. pretreatment with serotonergic antagonist, methysergide and noradrenergic antagonist, phentolamine. In addition, pre-injury i.t. injection of serotonin uptake inhibitor, fluoxetine and α2-adrenergic agonist, clonidine significantly prevented the neuropathic hyperalgesia. We next examined whether pre-injury morphine prevented the expression of neuronal hyperactivity markers such as c-Fos and protein kinase C γ (PKCγ in the spinal dorsal horn. We found that pre-injury administration of s.c. morphine prevented increased expressions of both c-Fos and PKCγ observed following nerve injury. Similar results were obtained with i.t. fluoxetine and clonidine. Altogether these results suggest that pre-injury administration of morphine might prevent the development of neuropathic pain through activation of descending monoaminergic pain inhibitory pathways.

  4. Pharmacokinetics and pharmacodynamics of metamizol in co-administration with morphine under acute and chronic treatments in arthritic rats.

    Science.gov (United States)

    Carrillo-Calzadilla, Patricia Esmeralda; López-Muñoz, Francisco Javier; Moreno-Rocha, Luis Alfonso; Medina-López, José Raúl; Cortés-Arroyo, Alma Rosa; Domínguez-Ramírez, Adriana Miriam

    2017-06-01

    To investigate the relationship between metamizol pharmacokinetics and the antinociceptive effect produced after subcutaneous administration of metamizol (177.8 mg/kg) alone or in combination with morphine (3.2 mg/kg), under acute and chronic treatments. Antinociception was assessed using the pain-induced functional impairment model in rat (PIFIR). Serial blood samples were collected from the same animals to study the pharmacokinetics of metamizol. The co-administration of the drugs in single dose, confirmed the potentiation of their individual antinociceptive effects. When the drugs were administered alone following the chronic schedule, a pronounced tolerance development to their antinociceptive effects was found, whereas it was significantly attenuated when they were administered together. Metamizol pharmacokinetics was unaltered by the presence of morphine. Plasma concentrations of 4-methylaminoantipyrine, an active metabolite markedly decreased under chronic administration. The mechanism involved in the potentiation of the antinociceptive effect produced by the combination, cannot be explained by the interaction of morphine on metamizol pharmacokinetics. Other pharmacokinetic interactions along with known pharmacodynamic interactions in which metamizol active metabolites contribute, should be considered. The frequency of administration enhances tolerance development and induces metamizol elimination process. © 2017 Royal Pharmaceutical Society.

  5. 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.

  6. Memory enhancement by administration of ginger (Zingiber officinale) extract on morphine-induced memory impairment in male rats

    Institute of Scientific and Technical Information of China (English)

    Ali Gomar; Abdolkarim Hosseini; Naser Mirazi

    2014-01-01

    To study the chronic treatment with hydroethanolic extract of ginger(50,100 and200 mg/kg, p.o) would effect on the passive avoidance learning(PAL) and memory in rat.Methods:The rats were divided into eight groups.On the training trial, the mice received an electric shock when the animals were entered into the dark compartment.Twenty-four hours later,30 min after treatment, theSTL(step-through latency) andTDC(total time in dark compartments) was recorded and defined as the retention trial.Results:The time latency in morphine-treated group was lower than control(P<0.001).Treatment of the animals by100 and200 mg/kg of ginger extract before the training trial increased the time latency at24 hours after the training trial(P<0.01 andP<0.001). Administration of both100 and200 mg/kg doses of the extract in morphine received animal groups before retention trials also increased the time latency than the morphine-treated group groups(P<0.001).Conclusion:The results revealed that the ginger extract attenuated morphine-induced memory impairment.

  7. 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

  8. Acute Morphine Administration Reduces Cell-Mediated Immunity and Induces Reactivation of Latent Herpes Simplex Virus Type 1 in BALB/c Mice

    Institute of Scientific and Technical Information of China (English)

    Shafi Mojadadi; Abbas Jamali; Behzad Khansarinejad; Hoorieh Soleimanjahi; Taravat Bamdad

    2009-01-01

    Acute morphine administration is known to alter the course of herpes simplex virus infection. In this study, the effect of acute morphine administration on the reactivation of latent herpes was investigated in a mouse model. Because of the important role of cytolytic T lymphocyte (CTL) activity in the inhibition of herpes simplex virus type 1 (HSV-1) reactivation, the effect of acute morphine administration on CTL responses was also evaluated. Furthermore, lymphocyte proliferation and IFN-γ production were evaluated for their roles in the induction of the CTL response. The findings showed that acute morphine administration significantly reduced CTL responses, lymphocyte proliferation, and IFN-γ production. Furthermore, acute morphine administration has been shown to reactivate latent HSV-1. Previous studies have shown that cellular immune responses have important roles in the inhibition of HSV reactivation. These findings suggest that suppression of a portion of the cellular immune response after acute morphine administration may constitute one part of the mechanism that induces HSV reactivation. Cellular & Molecular Immunology.

  9. Differential effects of acute morphine administrations on polymorphonuclear cell metabolism in various mouse strains.

    Science.gov (United States)

    Di Francesco, P; Tavazzi, B; Gaziano, R; Lazzarino, G; Casalinuovo, I A; Di Pierro, D; Garaci, E

    1998-01-01

    This paper shows that an acute morphine treatment dose-dependently alters the energetic and oxidative metabolism of polymorphonuclear leukocytes obtained from BALB/c and DBA/2 mice, while phagocytic cells from C57BL/6 were not affected. In sensitive mouse strains, i.e. BALB/c and DBA/2, morphine decreased both ATP concentration and energy charge potential. At the same time, ATP catabolic products, i.e. nucleosides (inosine+adenosine) and oxypurines (hypoxanthine+xanthine+uric acid), significantly increased, indicating an imbalance between energy production and consumption. Morphine treatment also induced malondialdehyde and superoxide anions production in leukocyte cells from sensitive mice. The opiate antagonist naloxone blocked morphine-induced modifications by the lower morphine dose. The same parameters in cells from C57BL/6 mice were not affected. These findings confirm that: i) the phagocytic cells are an important target for the in vivo effects of morphine, and ii) the genotype-dependent variation influences the immunological responsiveness to opiates.

  10. Intracerebroventricular administration of morphine confers remote cardioprotection--role of opioid receptors and calmodulin.

    Science.gov (United States)

    Zhang, Ye; Irwin, Michael G; Lu, Yao; Mei, Bin; Zuo, You-Mei; Chen, Zhi-Wu; Wong, Tak-Ming

    2011-04-10

    The current study aimed to delineate the mechanism of remote preconditioning by intracerebroventricular morphine (RMPC) against myocardial ischemia-reperfusion injury. Male Sprague-Dawley rats were given an intracerebroventricular morphine injection before myocardial ischemia and reperfusion injury. Ischemia-reperfusion injury was achieved by 30min of left coronary artery occlusion followed by 120min of reperfusion. The effects of remote preconditioning by intracerebroventricular morphine preconditioning were also determined upon selective blockade of the δ, κ or μ-opioid receptors, or calmodulin (CaM). The infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining. Remote preconditioning by intracerebroventricular morphine reduced infarct size in the ischemic/reperfused myocardium, and the effect was abolished by the selective blockade of any one of the three δ, κ and μ opioid receptors or CaM. Furthermore, remote preconditioning by intracerebroventricular morphine increased the expression of CaM in the hippocampus and the plasma level of calcitonin gene-related peptide (CGRP). The results of the present study provide evidence that the cardioprotection of remote preconditioning by intracerebroventricular morphine involves not only all three types of opioid receptors in the central nervous system, but also CaM, which releases CGRP, one of the mediators of remote preconditioning.

  11. Changes in ensemble activity of hippocampus CA1 neurons induced by chronic morphine administration in freely behaving mice.

    Science.gov (United States)

    Liu, F; Jiang, H; Zhong, W; Wu, X; Luo, J

    2010-12-15

    The hippocampus plays an important role in the formation of new memories and spatial navigation. Recently, growing evidence supports the view that it is also involved in addiction to opiates and other drugs. Theoretical and experimental studies suggest that hippocampal neural-network oscillations at specific frequencies and unit firing patterns reflect information of learning and memory encoding. Here, using multichannel recordings from the hippocampal CA1 area in behaving mice, we investigated the phase correlations between the theta (4-10 Hz) and gamma (40-100 Hz) oscillations, and the timing of spikes modulated by these oscillations. Local field potentials and single unit recordings in the CA1 area of mice receiving chronic morphine treatment revealed that the power of the theta rhythm was strongly increased; at the same time, the theta frequency during different behavioral states shifted markedly, and the characteristic coupling of theta and gamma oscillations was altered. Surprisingly, though the gamma oscillation frequency changed, the power of gamma lacking theta did not. Moreover, the timing of pyramidal cell spikes relative to the theta rhythm and the timing of interneuron spikes relative to the gamma rhythm changed during chronic morphine administration. Furthermore, these responses were impaired by a selective D1/D5 receptor antagonist intra-hippocampus injection. These results indicate that chronic morphine administration induced the changes of ensemble activity in the CA1 area, and these changes were dependent on local dopamine receptor activation.

  12. A new buprenorphine analogy, thenorphine,inhibits morphine-induced behavioral sensitization in mice

    Institute of Scientific and Technical Information of China (English)

    Wen-liZHAO; Ze-huiGONG; Jian-huiLIANG

    2004-01-01

    AIM: To investigate effects of thenorphine, a new compound of partial agonist of μ-opioid receptor, on the locomotor activity and the behavioral sensitization to morphine in mice. METHODS: Locomotor activity was observed after administration of thenorphine or co-administration of thenorphine and morphine in mice. Mice were induced behavioral sensitization to morphine by intraperitoneal injection of 20 mg/kg morphine once daily for 7 d. Thenorphine was co-administrated with morphine to observe the effects of thenorphine on the development, transfer and expression of morphine-induced behavioral sensitization. RESULTS: A single dose of thenorphine (0.0625, 0.25, and 1.0 mg/kg) could dose-dependently inhibit the locomotor activity in mice (P<0.05), repeated administrations of thenorphine, however, were not able to induce locomotor sensitization, but induced tolerance. Pretreatment with thenorphine 30 min prior to morphine effectively inhibited the psychomotor effect of morphine in mice (P<0.01). Co-administration of thenorphine (0.0625, 0.25, and 1.0 mg/kg) could dose-dependently inhibit the development,transfer, and expression of behavioral sensitization to morphine in mice (P<0.05 or P<0.01). CONCLUSION:Thenorphine inhibited morphine-induced behavioral sensitization in mice, suggesting that thenorphine may be effective against the addiction of opioids.

  13. A new buprenorphine analogy,thenorphine,inhibits morphine-induced behavioral sensitization in mice

    Institute of Scientific and Technical Information of China (English)

    Wen-li ZHAO; Ze-hui GONG; Jian-hui LIANG

    2004-01-01

    AIM: To investigate effects of thenorphine, a new compound of partial agonist of μ-opioid receptor, on the locomotor activity and the behavioral sensitization to morphine in mice. METHODS: Locomotor activity was observed after administration of thenorphine or co-administration of thenorphine and morphine in mice. Mice were induced behavioral sensitization to morphine by intraperitoneal injection of 20 mg/kg morphine once daily for 7 d. Thenorphine was co-administrated with morphine to observe the effects of thenorphine on the development, transfer and expression of morphine-induced behavioral sensitization. RESULTS: A single dose of thenorphine (0.0625, 0.25, and 1.0mg/kg) could dose-dependently inhibit the locomotor activity in mice (P<0.05), repeated administrations of thenorphine, however, were not able to induce locomotor sensitization, but induced tolerance. Pretreatment with thenorphine 30 min prior to morphine effectively inhibited the psychomotor effect of morphine in mice (P<0.01).Co-administration of thenorphine (0.0625, 0.25, and 1.0 mg/kg) could dose-dependently inhibit the development,transfer, and expression of behavioral sensitization to morphine in mice (P<0.05 or P<0.01). CONCLUSION:Thenorphine inhibited morphine-induced behavioral sensitization in mice, suggesting that thenorphine may be effective against the addiction of opioids.

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

    Directory of Open Access Journals (Sweden)

    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

  15. The long-term effects of neonatal morphine administration on the pentylenetetrazol seizure model in rats: the role of hippocampal cholinergic receptors in adulthood.

    Science.gov (United States)

    Saboory, Ehsan; Gholami, Morteza; Zare, Samad; Roshan-Milani, Shiva

    2014-04-01

    Early life exposure to opiates may affect neuropathological conditions, such as epilepsy, during adulthood. We investigated whether neonatal morphine exposure affects pentylenetetrazol (PTZ)-induced seizures in adulthood. Male rats were subcutaneously injected with morphine or saline on postnatal days 8-14. During adulthood, each rat was assigned to 1 of the following 10 sub-groups: saline, nicotine (0.1, 0.5, or 1 μg), atropine (0.25 or 1 μg), oxotremorine M (0.1 or 1 μg), or mecamylamine (2 or 8 μg). An intrahippocampal infusion of the indicated compound was administered 30 min before seizure induction (80 mg/kg PTZ). Compared with the saline/oxotremorine (1 μg), saline/saline, and morphine/saline groups, the morphine/oxotremorine (1 μg) group showed a significantly increased latency to the first epileptic behavior. The duration of tonic-clonic seizures was significantly lower in the morphine/oxotremorine (1 μg) group compared to the saline/saline and morphine/saline groups. The severity of seizure was significantly decreased in the morphine/atropine (1 μg) group than in the saline/atropine (1 μg). Seizure severity was also decreased in the morphine/mecamylamine (2 μg) group than in the saline/mecamylamine (2 μg) group. Latency for death was significantly lower in the morphine/mecamylamine (2 μg) group compared with the saline/mecamylamine (2 μg) group. Mortality rates in the morphine/atropine (1 μg) and morphine/mecamylamine (2 μg) groups were significantly lower than those in the saline/atropine (1 μg) and saline/mecamylamine (2 μg) groups, respectively. Chronic neonatal morphine administration attenuated PTZ-induced seizures, reduced the mortality rate, and decreased the impact of the hippocampal cholinergic system on seizures and mortality rate in adult rats. Neonatal morphine exposure induces changes to μ-receptors that may lead to activation of GABAergic neurons in the hippocampus. This pathway may explain the anti-convulsant effects of

  16. Sleep and GABA levels in the oral part of rat pontine reticular formation are decreased by local and systemic administration of morphine.

    Science.gov (United States)

    Watson, C J; Lydic, R; Baghdoyan, H A

    2007-01-05

    Morphine, a mu-opioid receptor agonist, is a commonly prescribed treatment for pain. Although highly efficacious, morphine has many unwanted side effects including disruption of sleep and obtundation of wakefulness. One mechanism by which morphine alters sleep and wakefulness may be by modulating GABAergic signaling in brain regions regulating arousal, including the pontine reticular nucleus, oral part (PnO). This study used in vivo microdialysis in unanesthetized Sprague-Dawley rat to test the hypothesis that mu-opioid receptors modulate PnO GABA levels. Validation of the high performance liquid chromatographic technique used to quantify GABA was obtained by dialyzing the PnO (n=4 rats) with the GABA reuptake inhibitor nipecotic acid (500 microM). Nipecotic acid caused a 185+/-20% increase in PnO GABA levels, confirming chromatographic detection of GABA and demonstrating the existence of functional GABA transporters in rat PnO. Morphine caused a concentration-dependent decrease in PnO GABA levels (n=25 rats). Coadministration of morphine (100 microM) with naloxone (1 microM), a mu-opioid receptor antagonist, blocked the morphine-induced decrease in PnO GABA levels (n=5 rats). These results show for the first time that mu-opioid receptors in rat PnO modulate GABA levels. A second group of rats (n=6) was used to test the hypothesis that systemically administered morphine also decreases PnO GABA levels. I.v. morphine caused a significant (PPnO GABA levels relative to control i.v. infusions of saline. Finally, microinjections followed by 2 h recordings of electroencephalogram and electromyogram tested the hypothesis that PnO morphine administration disrupts sleep (n=8 rats). Morphine significantly (PPnO.

  17. 吗啡与丁丙诺啡的蛛网膜下腔与皮下联合给药的相互作用%Interaction of combined administration of intrathecal morphine with subcutaneous morphine or buprenorphine

    Institute of Scientific and Technical Information of China (English)

    陈莲华; Alexander NEMIROVSKy; 贡沁燕

    2000-01-01

    AIM: To analyze the mode of interaction of combined administration of intrathecal morphine with subcutaneous morphine or buprenorphine. METHODS: Different groups of rats were scheduled to undergo administration of intrathecal (ith) morphine, subcutaneous (sc) morphine,sc buprenorphine, and the combinations of ith morphine with sc morphine or buprenorphine in a series of dose rarios. Nociceptive responses of hind paws of each animal were measured by means of "plantar stimulation" test.The test latency was converted to the percent of maximal possible effect ( % MPE). RESULT: Morphine ith,morphine sc, buprenorphine sc, as well as combinations in all dose ratios increased the % MPE in a dose-depen-dent manner. Isobolograms showed that the EDs0 points determined for the combinations were plotted significantly left to the theoretical additive line. CONCLUSION:The combination of morphine ith with either morphine sc or buprenorphine sc resulted in a synergistic effect. This interaction might be due to the activation of the synergistic antinociceptive mechanisms between supraspinal and spinal levels.%目的:观察大鼠吗啡与丁丙诺啡(或吗啡)的蛛网膜下腔与皮下联合给药的相互作用.方法:SD大鼠,置人蛛网膜下腔导管.辐射热诱发鼠腿撤退试验测痛阈.分别蛛网膜下腔给予吗啡、皮下注射丁丙诺啡(或吗啡)、蛛网膜下腔给予吗啡与皮下注射丁丙诺啡(或吗啡)的联合给药.结果:单独和联合给药均剂量依赖性地提高鼠痛阈.联合给药的量效曲线的斜率均显著大于吗啡单独给药的曲线斜率.等效线图显示联合给药的ED50均位于理论推测的叠加效应线的左侧.结论:吗啡与丁丙诺啡(或吗啡)的蛛网膜下腔与皮下联合给药呈协同效应.

  18. 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.

  19. Continuous Intrathecal Morphine Administration for Cancer Pain Management Using an Intrathecal Catheter Connected to a Subcutaneous Injection Port: A Retrospective Analysis of 22 Terminal Cancer Patients in Korean Population

    National Research Council Canada - National Science Library

    Kim, Jong Hae; Jung, Jin Yong; Cho, Min Soo

    2013-01-01

    ...) in 22 Korean terminal cancer patients with successful intrathecal morphine trials. Patient demographic data, the duration of intrathecal opioid administration, preoperative numerical pain rating scales (NRS...

  20. Repeated morphine treatment alters polysialylated neural cell adhesion molecule, glutamate decarboxylase-67 expression and cell proliferation in the adult rat hippocampus.

    Science.gov (United States)

    Kahn, Laëtitia; Alonso, Gérard; Normand, Elisabeth; Manzoni, Olivier J

    2005-01-01

    Altered synaptic transmission and plasticity in brain areas involved in reward and learning are thought to underlie the long-lasting effects of addictive drugs. In support of this idea, opiates reduce neurogenesis [A.J. Eisch et al. (2000) Proceedings of the National Academy of Sciences USA, 97, 7579-7584] and enhance long-term potentiation in adult rodent hippocampus [J.M. Harrison et al. (2002) Journal of Neurophysiology, 87, 2464-2470], a key structure of learning and memory processes. Here we studied how repeated morphine treatment and withdrawal affect cell proliferation and neuronal phenotypes in the dentate gyrus-CA3 region of the adult rat hippocampus. Our data showed a strong reduction of cellular proliferation in morphine-dependent animals (54% of control) that was followed by a rebound increase after 1 week withdrawal and a return to normal after 2 weeks withdrawal. Morphine dependence was also associated with a drastic reduction in the expression levels of the polysialylated form of neural cell adhesion molecule (68% of control), an adhesion molecule expressed by newly generated neurons and involved in cell migration and structural plasticity. Polysialylated neural cell adhesion molecule levels quickly returned to normal following withdrawal. In morphine-dependent rats, we found a significant increase of glutamate decarboxylase-67 mRNA transcription (170% of control) in dentate gyrus granular cells which was followed by a marked rebound decrease after 1 week withdrawal and a return to normal after 4 weeks withdrawal. Together, the results show, for the first time, that, in addition to reducing cell proliferation and neurogenesis, chronic exposure to morphine dramatically alters neuronal phenotypes in the dentate gyrus-CA3 region of the adult rat hippocampus.

  1. Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice.

    Science.gov (United States)

    Mika, Joanna; Wawrzczak-Bargiela, Agnieszka; Osikowicz, Maria; Makuch, Wioletta; Przewlocka, Barbara

    2009-01-01

    We have previously demonstrated that glial inhibitors reduce the development of allodynia and hyperalgesia, potentiating the effect of a single morphine dose in a neuropathic pain model. This study explores the effects of two glial activation inhibitors, minocycline and pentoxifylline, on the development of tolerance to morphine in naive and chronic constriction injury (CCI)-exposed mice. Administration of morphine to naive (20 mg/kg; i.p.) and CCI-exposed mice (40 mg/kg; i.p.) twice daily resulted in tolerance to its anti-nociceptive effect after 6 days. Injections of morphine were combined with minocycline (30 mg/kg, i.p.) or pentoxifylline (20 mg/kg, i.p.) administered as two preemptive doses before first morphine administration in naive or pre-injury in CCI-exposed mice, and repeated twice daily 30 min before each morphine administration. With treatment, development of morphine tolerance was delayed by 5 days (from 6 to 11 days), as measured by the tail-flick test in naive and by tail-flick, von Frey, and cold plate tests in CCI-exposed mice. Western blot analysis of CD11b/c and GFAP protein demonstrated that minocycline and pentoxifylline, at doses delaying development of tolerance to morphine analgesia, significantly diminished the morphine-induced increase in CD11b/c protein level. We found that repeated systemic administration of glial inhibitors significantly delays development of morphine tolerance by attenuating the level of this microglial marker under normal and neuropathic pain conditions. Our results support the idea that targeting microglial activation during morphine therapy/treatment is a novel and clinically promising method for enhancing morphine's analgesic effects, especially in neuropathic pain.

  2. Further development of a morphine hydrogel suppository.

    OpenAIRE

    Cole, L.; Hanning, C. D.; Robertson, S.; Quinn, K

    1990-01-01

    1. A sustained release monolithic morphine hydrogel suppository (MHS) was developed and administered to five volunteers. 2. The MHS delivered a mean of 55 mg morphine over 12 h. The mean plasma morphine concentration was 15 ng ml-1 from 2 to 12 h after administration. 3. Plasma morphine concentrations were comparable with those reported for the same dose given orally over the same time period. 4. The morphine hydrogel suppository appears to be an effective means of delivering morphine and may...

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    Fu Zhenyu

    2012-07-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusions 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.

  5. Enhanced ability of TRPV1 channels in regulating glutamatergic transmission after repeated morphine exposure in the nucleus accumbens of rat.

    Science.gov (United States)

    Zhang, Haitao; Jia, Dong; Wang, Yuan; Qu, Liang; Wang, Xuelian; Song, Jian; Heng, Lijun; Gao, Guodong

    2017-04-01

    Glutamatergic projections to nucleus accumbens (NAc) drive drug-seeking behaviors during opioids withdrawal. Modulating glutamatergic neurotransmission provides a novel pharmacotherapeutic avenue for treatment of opioids dependence. Great deals of researches have verified that transient receptor potential vanilloid 1 (TRPV1) channels alters synaptic transmitter release and regulate neural plasticity. In the present study, whole-cell patch clamp recordings were adopted to examine the activity of TRPV1 Channels in regulating glutamate-mediated excitatory postsynaptic currents (EPSCs) in NAc of rat during morphine withdrawal for 3days and 3weeks. The data showed that the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and the amplitudes of evoked excitatory postsynaptic currents (eEPSCs) were increased during morphine withdrawal after applied with capsaicin (TRPV1 agonist). Capsaicin decreased the paired pulse ratio (PPR) and increased sEPSCs frequency but not their amplitudes suggesting a presynaptic locus of action during morphine withdrawal. All these effects were fully blocked by the TRPV1 antagonist Capsazepine. Additionally, In the presence of AM251 (CB1 receptor antagonist), depolarization-induced release of endogenous cannabinoids activated TRPV1 channels to enhance glutamatergic neurotransmission during morphine withdrawal. The functional enhancement of TRPV1 Channels in facilitating glutamatergic transmission was not recorded in dorsal striatum. Our findings demonstrate the ability of TRPV1 in regulating excitatory glutamatergic transmission is enhanced during morphine withdrawal in NAc, which would deepen our understanding of glutamatergic modulation during opioids withdrawal.

  6. Safety of Moxifloxacin following repeated intramuscular administration in Wistar rats

    Directory of Open Access Journals (Sweden)

    K.A. Sadariya

    Full Text Available Moxifloxacin is a novel fourth generation fluoroquinolone with broad spectrum of antibacterial activity. The study was conducted to evaluate the safety of Moxifloxacin (5.0 mg/kg after repeated intramuscular administration at 24 h interval for 14 days in male and female wistar rats. Hematological (Haemoglobin, RBC, WBC, MCV, MCH, MCHC, HCT and DLC, blood biochemical parameters (AST, ALT, ALP, Total Bilirubin, Total Serum Protein, Serum Albumin, Globulin, Serum Creatinine, Urea, Uric acid and Blood glucose and histopathological examination of various tissues were carried out in the present study. Male and female animals of any group did not reveal any clinical symptoms and mortality attributable to the 14 days intramuscular administration of Moxifloxacin. The data were compared by unpaired two tail `t` test using Graph Pad Prism (Version 4.00. All above hematological and blood biochemical parameters were found to fluctuate within normal range during treatment period and the mean values were not significantly differ (p < 0.05 from corresponding control values. Moreover, no gross or microscopic changes were found in the liver, kidney, heart, spleen, stomach, intestine and joint cartilages of the treated wistar rats. Results indicate that daily administration of Moxifloxacin for 14 days seems to be safe and well tolerated in rats. [Veterinary World 2010; 3(10.000: 449-452

  7. The effect of morphine sensitization on extracellular concentrations of GABA in dorsal hippocampus of male rats.

    Science.gov (United States)

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

    2011-11-01

    Repeated, intermittent exposure to drugs of abuse, such as morphine results in response enhancements to subsequent drug treatments, a phenomenon referred to as behavioral sensitization. As persistent neuronal sensitization may contribute to the long-lasting consequences of drug abuse, characterizing the neurochemical mechanisms of sensitization is providing insights into addiction. Although it has been shown that GABAergic systems in the CA1 region of dorsal hippocampus are involved in morphine sensitization, the alteration of extracellular level of GABA in this area in morphine sensitization has not been investigated. In the present study, using the in vivo microdialysis technique, we investigated the effect of morphine sensitization on extracellular GABA concentration in CA1 region of dorsal hippocampus of freely moving rats. Sensitization was induced by subcutaneous (s.c.) injection of morphine, once daily for 3 days followed by 5 days free of the opioid treatment. The results showed that extracellular GABA concentration in CA1 was decreased following acute administration of morphine in non-sensitized rats. However, morphine-induced behavioral sensitization significantly increased the extracellular GABA concentration in this area. The enhancement of GABA in morphine sensitized rats was inhibited by administration of naloxone 30 min before each of three daily doses of morphine. These results suggest an adaptation of the GABAergic neuronal transmission in dorsal hippocampus induced by morphine sensitization and it is implied that opioid receptors may play an important role in this effect.

  8. Increased calcium/calmodulin-dependent protein kinase II activity by morphine-sensitization in rat hippocampus.

    Science.gov (United States)

    Kadivar, Mehdi; Farahmandfar, Maryam; Ranjbar, Faezeh Esmaeli; Zarrindast, Mohammad-Reza

    2014-07-01

    Repeated exposure to drugs of abuse, such as morphine, elicits a progressive enhancement of drug-induced behavioral responses, a phenomenon termed behavioral sensitization. These changes in behavior may reflect long-lasting changes in some of the important molecules involved in memory processing such as calcium/calmodulin-dependent protein kinase II (CaMKII). In the present study, we investigated the effect of morphine sensitization on mRNA expression of α and β isoforms and activity of CaMKII in the hippocampus of male rats. Animals were treated for 3 days with saline or morphine (20mg/kg) and following a washout period of 5 days, a challenge dose of morphine (5mg/kg) were administered. The results indicate that morphine administration in pre-treated animals produces behavioral sensitization, as determined by significant increase in locomotion and oral stereotypy behavior. In addition, repeated morphine treatment increased mRNA expression of both α and β isoforms of CaMKII in the hippocampus. The present study also showed that induction of morphine sensitization significantly increased both Ca2+/calmodulin-independent and Ca2+/calmodulin-dependent activities of CaMK II in the rat hippocampus. However, acute administration of morphine (5mg/kg) did not alter either α and β CaMKII mRNA expression or CaMKII activity in the hippocampus. The stimulation effects of morphine sensitization on mRNA expression and activity of CaMKII were completely abolished by administration of naloxone, 30min prior to s.c. injections of morphine (20mg/kg/day×3 days). Our data demonstrated that induction of morphine sensitization could effectively modulate the activity and the mRNA expression of CaMKII in the hippocampus and this effect of morphine was exerted by the activation of opioid receptors.

  9. Safety of Ketoprofen in Cow calves following repeated intravenous administration

    Directory of Open Access Journals (Sweden)

    R. D. Singh

    2009-06-01

    Full Text Available Ketoprofen is a non steroidal anti-inflammatory drug (NSAID used for its anti-inflammatory,analgesic and antipyretic properties in Veterinary Medicine. The present study was planned to assess safety of ketoprofen (3 mg.kg-1 after repeated intravenous administration at 24 hours interval for five days in six crossbred cow calves (6-12 months age and weighing between 60-122 kg. Ketoprofen in calves was found safe based on evaluation of haematological (Hb, PCV, TLC and DLC, blood biochemical (AKP, ACP, AST, ALT, LDH, Total bilirubin, Serum Creatinine, BUN, Serum total protein, Serum albumin and Blood glucose parameters. [Vet. World 2009; 2(3.000: 105-107

  10. Stereoselective action of (+)-morphine over (−)-morphine in attenuating the (−)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse

    OpenAIRE

    2007-01-01

    We have previously demonstrated that (+)-morphine and (−)-morphine given spinally stereoselectively attenuate the spinally-administered (−)-morphine-produced tail-flick inhibition in the mouse. The phenomenon has been defined as antianalgesia (Wu et al., 2005). Present studies were then undertaken to determine if the systemic administration of (+)-morphine and (−)-morphine also stereoselectively attenuates the systemic (−)-morphine-produced tail-flick inhibition and the effects of (+)-morphin...

  11. Comparison between C-FOS Expression in Male and Female Mice During Morphine Withdrawal in the Presence and Absence of Acute Administration of Matricaria Recutita

    Directory of Open Access Journals (Sweden)

    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

  12. Morphine-induced anxiolytic-like effect in morphine-sensitized mice: involvement of ventral hippocampal nicotinic acetylcholine receptors.

    Science.gov (United States)

    Rezayof, Ameneh; Assadpour, Sara; Alijanpour, Sakineh

    2013-01-01

    In the present study, the effects of repeated intra-ventral hippocampal (intra-VH) microinjections of nicotinic acetylcholine receptor agonist or antagonist on morphine-induced anxiolytic-like behavior were investigated in morphine-sensitized mice using elevated plus-maze. Intraperitoneal (i.p.) administration of different doses of morphine (5, 7.5 and 10mg/kg) increased the percentage of open arm time (%OAT), open arm entries (%OAE), but not locomotor activity, indicating an anxiolytic-like response to morphine. The maximum response was obtained by 7.5mg/kg of the opioid. The anxiety-like behavior which was induced by a lower dose of morphine (5mg/kg) was significantly increased in mice that had previously received once daily injections of morphine (10 and 20mg/kg, i.p.) for 3 days. It should be considered that this treatment also increased locomotor activity in morphine-sensitized mice. Furthermore, the response to an ineffective dose of morphine (5mg/kg, i.p.) in the EPM was significantly increased in the animals that had previously received nicotine for 3 days (0.1, 0.3, 0.5 and 0.7 μg/mouse; intra-VH), 5 min prior to the injections of morphine (5mg/kg/day × 3 days; i.p.). On the other hand, the increase of morphine-induced anxiolytic-like effect in animals that had previously received the 3-day morphine (20mg/kg) was dose dependently suppressed by once daily injections of mecamylamine (0.5, 1 and 2 μg/mouse/day × 3 days; intra-VH). It is important to note that repeated intra-VH administrations of the same doses of nicotine or mecamylamine alone caused no significant change in morphine (5mg/kg)-induced anxiety-like parameters in the EPM. In conclusion, it seems that morphine sensitization affects the anxiety-like behavior in the EPM and the cholinergic system in the ventral hippocampus, via nicotinic receptors, may play an important role in this effect.

  13. 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...

  14. Augmentation of morphine-induced sensitization but reduction in morphine tolerance and reward in delta-opioid receptor knockout mice.

    Science.gov (United States)

    Chefer, V I; Shippenberg, T S

    2009-03-01

    Studies in experimental animals have shown that individuals exhibiting enhanced sensitivity to the locomotor-activating and rewarding properties of drugs of abuse are at increased risk for the development of compulsive drug-seeking behavior. The purpose of the present study was to assess the effect of constitutive deletion of delta-opioid receptors (DOPr) on the rewarding properties of morphine as well as on the development of sensitization and tolerance to the locomotor-activating effects of morphine. Locomotor activity testing revealed that mice lacking DOPr exhibit an augmentation of context-dependent sensitization following repeated, alternate injections of morphine (20 mg/kg; s.c.; 5 days). In contrast, the development of tolerance to the locomotor-activating effects of morphine following chronic morphine administration (morphine pellet: 25 mg: 3 days) is reduced relative to WT mice. The conditioned rewarding effects of morphine were reduced significantly in DOPrKO mice as compared to WT controls. Similar findings were obtained in response to pharmacological inactivation of DOPr in WT mice, indicating that observed effects are not due to developmental adaptations that occur as a consequence of constitutive deletion of DOPr. Together, these findings indicate that the endogenous DOPr system is recruited in response to both repeated and chronic morphine administration and that this recruitment serves an essential function in the development of tolerance, behavioral sensitization, and the conditioning of opiate reward. Importantly, they demonstrate that DOPr has a distinct role in the development of each of these drug-induced adaptations. The anti-rewarding and tolerance-reducing properties of DOPr antagonists may offer new opportunities for the treatment and prevention of opioid dependence as well as for the development of effective analgesics with reduced abuse liability.

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

    Science.gov (United States)

    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.

  16. Intraoperative administration of tramadol for postoperative nurse-controlled analgesia resulted in earlier awakening and less sedation than morphine in children after cardiac surgery.

    Science.gov (United States)

    Chu, Ya-Chun; Lin, Su-Man; Hsieh, Ying-Chou; Chan, Kwok-Hon; Tsou, Mei-Yung

    2006-06-01

    In adults, intraoperative administration of tramadol could result in earlier recovery and less sedation than morphine. In this controlled, randomized, double-blind study, we investigated whether an intraoperative initial dose of tramadol could cause more rapid awakening from general anesthesia, less sedation, and earlier tracheal extubation than morphine in children during the immediate postoperative period. Forty children aged 1-6 yr, scheduled for atrial or ventricular septal defect repair and tracheal extubation in the pediatric intensive care unit, were randomly allocated to receive morphine, initial dose 0.2 mg/kg, or tramadol 2 mg/kg given at the end of sternal closure, followed by nurse-controlled analgesia (bolus 0.02 mg/kg of morphine and 0.2 mg/kg of tramadol) with background infusions (0.015 mg x kg(-1) x h(-1) for morphine and 0.15 mg x kg(-1) x h(-1) for tramadol). Postoperatively, children receiving tramadol had earlier awakening from general anesthesia (P = 0.02) and were less sedated at 1 and 2 h postoperatively (P = 0.03 and P = 0.01, respectively). Tracheal extubation was earlier in the tramadol group (P = 0.01). Lengths of pediatric intensive care unit stay did not differ between groups. Times to first trigger of nurse-controlled analgesia bolus and objective pain scores during the 48 h observation period were comparable between groups. The incidence of desaturation and emesis were similar between groups. The patients ate well and did not differ on Day 1 or Day 2.

  17. Effects of Administration of Morphine on Sign-tracking/Goal-tracking under Different Distances%吗啡对不同距离条件下大鼠信号追踪和目标追踪的影响

    Institute of Scientific and Technical Information of China (English)

    常逢锦; 李新旺; 崔睿思

    2015-01-01

    investigate the effects of administration of morphine on sign-tracking and goal-tracking when the spatial separation between the CS and a US food was 8、30 and 60 cm. Fifty-six male Sprague-Dawley rats participated in the approach conditioning experiment of different distances consisted of habituation, food receptacle training, acquisition, administration of morphine which was given daily injection of morphine (5mg/kg) or saline for 7 days, extinction phases and reversal learning. Two different material objects served as CS+ and CS?, and a 10-sec food as US while approach duration of the CS (sign-tracking) and US (goal-tracking) was measured. Each CS+ was always followed by food delivery any of theexperiment phases except the extinction phases, whereas the CS? was not.The results were as following: (1) Sign tracking of rats developed when the CS was 60 cm from the US. Increasing the spatial separation between the CS and US resulted in a decline in sign tracking and had no effect on goal tracking under non-drug conditions. (2) Acute administration of morphine (5.0 mg/kg) decreased measures of sign-tracking, from 8 to 60cm, while simultaneously increasing measures of goal-tracking when the CS was 8 and 60 cm from the source of the US. Repeated administration of morphine decreased measures of sign-tracking while simultaneously increasing measures of goal-tracking when the CS was 8 and 30 cm from the source of the US. In the extinction test, prior morphine exposure decreased sign-tracking when the CS was 8 and 60cm from the source of the US, and increased goal-tracking when the spatial separation between the CS and US was 60 cm. (3) In the discrimination reversal learning, rats pre-exposed to morphine showed less contact to new CS+ compared to saline controls from 8 to 60cm, showed worse discrimination and biased to old CS+ when the spatial separation was 30 and 60 cm. The results of this study suggested that distance had little effect on suppression of sign-tracking but had

  18. Morphine sensitization increases the extracellular level of glutamate in CA1 of rat hippocampus via μ-opioid receptor.

    Science.gov (United States)

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

    2011-04-25

    Repeated administration of abuse drugs such as morphine elicits a progressive enhancement of drug-induced behavioral responses, a phenomenon termed behavioral sensitization. These changes in behavior may reflect plastic changes requiring regulation of glutamatergic system in the brain. In this study, we investigated the effect of morphine sensitization on extracellular glutamate concentration in the hippocampus, a brain region rich in glutamatergic neurons. Sensitization was induced by subcutaneous (s.c.) injection of morphine, once daily for 3 days followed by 5 days free of the opioid treatment. The results showed that extracellular glutamate concentration in the CA1 was decreased following administration of morphine in non-sensitized rats. However, morphine-induced behavioral sensitization significantly increased the extracellular glutamate concentration in this area. The enhancement of glutamate in morphine sensitized rats was prevented by administration of naloxone 30 min before each of three daily doses of morphine. These results suggest an adaptation of the glutamatergic neuronal transmission in the hippocampus after morphine sensitization and it is postulated that opioid receptors may play an important role in this effect.

  19. Effects of glycine, beta-alanine and diazepam upon morphine-tolerant-dependent mice.

    Science.gov (United States)

    Contreras, E; Tamayo, L

    1980-05-01

    The effects in mice of glycine, beta-alanine and diazepam on the analgesic response to morphine, on the intensity of tolerance and on the physical dependence on the analgesic have been examined. The two amino acids increased the analgesic response to morphine in a dose-related manner. However, both compounds were ineffective in the analgesic test (hot plate) when administered without morphine. Diazepam was ineffective in the analgesic test and it did not alter morphine analgesia, except when administered in a high dose which decreased and analgesic response. Glycine, either in single or repeated doses, did not modify tolerance to morphine, whereas beta-alanine induced a dose-related partial antagonism, which promptly reached a plateau. Diazepam induced a small decrease in the intensity of tolerance to the analgesic. The abstinence syndrome to morphine, induced by naloxone administration to primed mice, was reduced by single doses of glycine or beta-alanine. Diazepam behaved as a weak inhibitor of the abstinence syndrome when administered at a high dose. The potentiation of morphine analgesia and the antagonism of the abstinence syndrome induced by the amino acids may be related to their hyperpolarizing action in the c.n. system. The effects of beta-alanine on morphine tolerance cannot be explained by the same mechanism.

  20. Effect of cyanocobalamin (vitamin B12) in the induction and expression of morphine tolerance and dependence in mice.

    Science.gov (United States)

    Ghazanfari, S; Imenshahidi, M; Etemad, L; Moshiri, M; Hosseinzadeh, H

    2014-03-01

    The antinociceptive effect of cyanocobalamin (Vit B12) has been reported in animal models and human studies. Our previous study showed the effect of Vit B12 on morphine tolerance. The dependence and tolerance were induced in male mice using subcutaneous morphine injections, 3 times a day (50, 50 and 75 mg/kg/day) for 3 days. Mice also received Vit B12 (100, 250 and 500 µg/kg), clonidine, memantine and saline intraperitoneally before morphine administration. On fourth day mice received only 7 mg /kg morphine just before tail-flick test. To determine the expression of morphine dependence and tolerance, all compounds were injected once intraperitoneally on the day of experiment. The tolerance was evaluated by the tail-flick test. The effect of Vit B12 and other agents on dependence were evaluated by counting the number of jumps (induced by naloxone 5 mg/kg). Co-administration of Vit B12 (100-500 µg/kg) and morphine in 3 days reduced the development of tolerance to morphine analgesic effect (8.2±0.5 and 7.83±0.5 s. vs. normal saline, 3.57±0.3 s). Repeated administration of Vit B12, also, diminished the reduced naloxane withdrawal signs of naloxone withdrawal test (100-500 µg/kg: 5±1.9 and 1.2±0.8 jumps vs. normal saline 72.6±12.2). However, Vit B12 had no effect on the expression of morphine tolerance and physical dependence. It is concluded that co-administration of Vit B12 and morphine could reduce tolerance to analgesic effect of morphine chronic administration and also reduce its withdrawal symptoms. © Georg Thieme Verlag KG Stuttgart · New York.

  1. Effect of Tetrandrine on Morphine Induced Hyperactivity and Reinforcement in Mice

    Institute of Scientific and Technical Information of China (English)

    朱毅; 薛春生; 周歧新

    2001-01-01

    To study the effect of tetrandrine on morphine induced hyperactivity and reinforcement in mice. Methods: After single administration of morphine and the motion activity was measured by ambulometer, conditioned place-preference paradigm was used to study the reinforcing effect of morphine, climbing behavior was used to evaluate the relation with Dopaminergic system and immediate early expression of c-fos gene in brain was shown by immunohistochemical method. Results: Single administration of morphine could induce hyperactivity, repeated treatment would produce a conditioned place-preference response, tetrandrine 30 or 60 mg/kg hypodermic injection could inhibit the morphine induced hyperactivity, 60 mg/kg could inhibit the conditioned place-preference response but no influence on climbing behavior in mice was found. Tetrandrine could inhibit the c-fos gene expression in nucleus accumbens, ventral tegmental and prefrontal cortex in place-preference model formed by morphine. Conclusion: Tetrandrine could inhibit the hyperactivity and conditioned place-preference response induced by morphine, it might relate to reduce the c-fos gene expression in special area of brain in mice.

  2. Effects of Daily Morphine Administration and Deprivation on Choice and Demand for Remifentanil and Cocaine in Rhesus Monkeys

    Science.gov (United States)

    Wade-Galuska, Tammy; Galuska, Chad M.; Winger, Gail

    2011-01-01

    Choice procedures have indicated that the relative reinforcing effectiveness of opioid drugs increases during opioid withdrawal. The demand curve, an absolute measure of reinforcer value, has not been applied to this question. The present study assessed whether mild morphine withdrawal would increase demand for or choice of remifentanil or…

  3. The relationship between pupil diameter and pain by the administration of morphine and antidepressant drugs in mice.

    Science.gov (United States)

    Onal, A; Tuğlular, I

    1999-07-01

    Because the pain sensation is subjective, it is difficult to evaluate the responses to analgesic drugs. Some analgesics that affect the central nervous system are known to change the pupil diameter. The pupil diameter is a more objective criterion that shows the drug effect. We studied the relation between the pupil diameter and analgesia responses to morphine and antidepressants by using the selective micro-receptor agonist morphine (2 and 4 mg/kg), the noradrenaline reuptake inhibitor desipramine (7.5 and 10 mg/kg), the mixed serotonergic and noradrenergic uptake inhibitor and cholinergic receptor antagonist amitriptyline (2.5 and 5 mg/kg), and the selective serotonin reuptake inhibitor sertraline (2.5 and 5 mg/kg) in mice. Both monocular microscopy to assess pupil measurement and the hot-plate test to assess nociceptive thresholds were used in the same animals. We found that morphine played an important role in both mydriasis and analgesia, whereas amitriptyline and desipramine had a greater effect on pupil response than on nociception. Sertraline produced antinociception without causing a change in pupil diameter. As a result, although the pupil response is an important criterion in evaluating the analgesic effect of morphine, it is not possible to put forward the same criterion for the antidepressant drugs. Because different neurotransmitters are involved in pupil and pain mechanisms of antidepressant drugs, it is difficult to evaluate the analgesic response with the pupil diameter.

  4. Pharmacokinetic evaluation of pamidronate after oral administration: a study on dose proportionality, absolute bioavailability, and effect of repeated administration

    DEFF Research Database (Denmark)

    Hyldstrup, Lars; Flesch, G; Hauffe, S A

    1993-01-01

    30 minutes at constant infusion rate. Repeated peroral doses (75 and 150 mg) were administered to 12 females (aged 51-70 years) for 10 consecutive days. Urinary excretion of pamidronate after peroral and i.v. administration was used for estimation of pamidronate absorption. Renal excretion...

  5. Repeated morphine pretreatment reduces glutamatergic synaptic potentiation in the nucleus accumbens induced by acute morphine exposure%慢性吗啡预处理减弱急性吗啡对伏隔核谷氨酸能突触传递的影响

    Institute of Scientific and Technical Information of China (English)

    吴晓杰; 张静; 魏春玲; 刘志强; 任维

    2012-01-01

    Repeated exposure to morphine leads to the addiction, which influences its clinical application seriously. The glutamatergic projection from prefrontal cortex (PFC) to the nucleus accumbens (Nac) plays an important role in rewarding effects. It is still unknown whether morphine exposure changes PFC-Nac synaptic transmission. To address this question, in vivo field excitatory post-synaptic potentials (fEPSPs) induced by electric stimulating PFC-Nac projection fibers were recorded to evaluate the effect of acute morphine exposure (10 mg/kg, s.c.) on glutamatergic synaptic transmission in Nac shell of repeated saline/morphine pretreated rats. It was showed that acute morphine exposure enhanced fEPSP amplitude and reduced paired-pulse ratio (PPR) in saline pretreated rats, which could be reversed by following naloxone injection (1 mg/kg, I.p.), an opiate receptor antagonist. However, repeated morphine pretreatment significantly inhibited both the enhancement of fEPSP amplitude and reduction of PPR induced by acute morphine exposure. Those results indicate that the initial morphine exposure enhances PFC-Nac synaptic transmission by pre-synaptic mechanisms, whereas morphine pretreatment occludes this effect.%吗啡长期作用后会产生成瘾(addiction),严重影响其临床应用.前额叶(prefrontal cortex,PFC)投射至伏隔核(nucleus accumbens,NAc)的谷氨酸能突触对奖赏效应有重要的调节作用,但该突触在吗啡成瘾中的具体作用尚不完全清楚.为探讨PFC至NAc的谷氨酸能突触在成瘾形成过程中的具体作用及其机制,本研究利用成年大鼠在体记录的方式,记录电刺激PFC至NAc谷氨酸能传入纤维引起的NAc壳区场兴奋性突触后电位(filed excitatory postsynaptic potential,fEPSP),观察慢性吗啡/盐水预处理后依次急性皮下注射吗啡及腹腔注射纳络酮对fEPSP幅值和配对脉冲比率(paired-pulse ratio,PPR)的影响.结果显示,与基础fEPSP相比,慢性盐水预处理组急

  6. An unusual case of homicide by use of repeated administration of organophosphate insecticides.

    Science.gov (United States)

    De Letter, E A; Cordonnier, J A C M; Piette, M H A

    2002-03-01

    We present an unusual murder case by use of repeated administration of organophosphate insecticides. A 49-year-old woman suffering from mental retardation, epileptic fits and acromegaly was poisoned by her husband. At first, her death was considered as a 'sudden and unexpected' natural death. Abdominal abscesses of pancreatic origin found at autopsy were compatible with repeated administration of pesticides with anticholinergic action. In her medical history at least one episode consistent with an organophosphate intoxication was retrieved. Thorough inquiry revealed that the victim had ingested phosphamidon and/or omethoate orally. Organophosphate intoxication should be considered when unexplained neurological symptoms are associated with pancreatic disturbances.

  7. Activation of P2X7 receptors in the midbrain periaqueductal gray of rats facilitates morphine tolerance.

    Science.gov (United States)

    Xiao, Zhi; Li, You-Yan; Sun, Meng-Jie

    2015-08-01

    Opiates such as morphine exhibit analgesic effect in various pain models, but repeated and chronic morphine administration may develop resistance to antinociception. The purinergic signaling system is involved in the mechanisms of pain modulation and morphine tolerance. This study aimed to determine whether the P2X7 receptor in the ventrolateral midbrain periaqueductal gray (vlPAG) is involved in morphine tolerance. Development of tolerance to the antinociceptive effect of morphine was induced in normal adult male Sprague-Dawley (SD) rats through subcutaneous injection of morphine (10mg/kg). The analgesic effect of morphine (5mg/kg, i.p.) was assessed by measuring mechanical withdrawal thresholds (MWTs) in rats with an electronic von Frey anesthesiometer. The expression levels and distribution of the P2X7 receptor in the vlPAG was evaluated through Western blot analysis and immunohistochemistry. The acute effects of intra-vlPAG injection of the selective P2X7 receptor agonist Bz-ATP, the selective P2X7 receptor antagonist A-740003, or antisense oligodeoxynucleotide (AS ODN) targeting the P2X7 receptor on morphine-treated rats were also observed. Results demonstrated that repeated morphine administration decreased the mechanical pain thresholds. By contrast, the expression of the P2X7 receptor protein was up-regulated in the vlPAG in morphine tolerant rats. The percent changes in MWT were markedly but only transiently attenuated by intra-vlPAG injection of Bz-ATP (9nmol/0.3μL) but elevated by A-740003 at doses of 10 and 100nmol/0.3μL. AS ODN (15nmol/0.3μL) against the P2X7 receptor reduced the development of chronic morphine tolerance in rats. These results suggest that the development of antinociceptive tolerance to morphine is partially mediated by activating the vlPAG P2X7 receptors. The present data also suggest that the P2X7 receptors may be a therapeutic target for improving the analgesic effect of morphine in treatments of pain when morphine tolerance

  8. Chronic morphine and tramadol re-exposure induced an anti-anxiety effect in prepubertal rats exposed neonatally to the same drugs.

    Science.gov (United States)

    Gholami, Morteza; Saboory, Ehsan; Khalkhali, Hamid Reza

    2014-10-01

    Anxiety disorders are among the most common mental disorders. Drugs that are often administered to manage medical problems cause rebound anxiety. The use of morphine and tramadol has increased in recent decades. In the present study, the effects of morphine and tramadol exposure during the neonatal and prepubertal periods on anxiety-like behaviours in prepubertal rats were investigated. Male neonate rats were injected subcutaneously with saline, morphine or tramadol (3-21 mg/kg) on a daily basis from postnatal Day (P) 8 to P14. On P22, rats were divided into seven groups (saline/saline, saline/tramadol, saline/morphine, tramadol/saline, tramadol/tramadol, morphine/saline and morphine/morphine) and were injected with saline, tramadol or morphine for seven consecutive days. All rats were tested in an elevated plus maze (EPM) on P24 (acute effects), P27 (chronic effects) and P29. Locomotor activity was increased by the second and third exposure to the EPM. Re-exposure to chronic morphine and tramadol resulted in increased locomotor activity, whereas acute and chronic administration of these drugs induced no notable difference. Anxiety decreased markedly after re-exposure to tramadol and this anxiolytic-like behaviour was more dominant in EPM re-exposure in rats that had received higher doses of tramadol. Re-exposure to tramadol elicited a stronger anxiolytic-like behaviour than re-exposure to morphine. It can be concluded that repeated morphine and tramadol administration during the neonatal period followed by re-exposure to these drugs at an immature stage produces considerable anxiolytic-like behaviour. Exposure to chronic morphine and tramadol during the neonatal period may affect the developing brain, which may induce long-term changes in the opioid response.

  9. Morphine-induced sensitization of locomotor activity in mice: effect of social isolation on plasma corticosterone levels.

    Science.gov (United States)

    Francès, H; Graulet, A; Debray, M; Coudereau, J P; Guéris, J; Bourre, J M

    2000-03-31

    This study examined the influence of social isolation on behavioural sensitization to the locomotor effect of morphine and the link between this behaviour and plasma corticosterone concentrations. Four weeks isolation induced an increase in the locomotor effect of morphine. In social and isolated mice, repeated administrations (6) of morphine (one injection every 3 or 4 days) followed by 3 h in an actimeter induced behavioural sensitization to the locomotor effect of morphine. No interaction was observed between social isolation and behavioural sensitization to morphine. Resocializing previously isolated mice for 3 weeks reduced the morphine-induced locomotor effect without altering the behavioural sensitization. Corticosterone plasma levels were more increased (416%) in mice isolated 5 weeks than in mice isolated for 2 weeks (243%) and they return to the control levels following 3 weeks of resocialization. Since there was no interaction between the increase in morphine locomotor effect induced by social isolation and the morphine-induced behavioural sensitization, it is suggested that each of these two events acts independently. Whether or not a common mechanism (plasma corticosterone levels?) partly underlies both effects, the result resembles a simple additive effect.

  10. 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.).

  11. Complement factor C5a and C5a receptor contribute to morphine tolerance and withdrawal-induced hyperalgesia in rats.

    Science.gov (United States)

    Li, Yan-Hua; Jin, Hua; Xu, Jing-Shu; Guo, Guang-Qiong; Chen, DA-Lin; Bo, Yun

    2012-10-01

    Morphine is a potent opioid analgesic. However, the repeated use of morphine causes tolerance and hyperalgesia. Neuroinflammation has been reported to be involved in morphine tolerance and withdrawal-induced hyperalgesia. The complement system is a crucial effector mechanism of immune responses. The present study investigated the roles of complement factor C5a and C5a receptor (C5aR) in the development of morphine tolerance and withdrawal-induced hyperalgesia. In the present study, the levels of C5a and C5aR were increased in the L5 lumbar spinal cords of morphine-tolerant rats. The administration of C5a promoted the development of hyperalgesia and the expression of spinal antinociceptive tolerance to intrathecal morphine in both mechanical and thermal test. However, these phenomena caused by morphine were significantly attenuated by the C5aR antagonist PMX53. These results suggest that complement activation within the spinal cord is involved in morphine tolerance and withdrawal-induced hyperalgesia. C5a and C5aR may serve as novel targets for the control of morphine tolerance and withdrawal-induced hyperalgesia.

  12. Video Teleconference Administration of the Repeatable Battery for the Assessment of Neuropsychological Status

    Science.gov (United States)

    Galusha-Glasscock, Jeanine M.; Horton, Daniel K.; Weiner, Myron F.; Cullum, C. Munro

    2016-01-01

    Teleneuropsychology applications are growing, but a limited number of assessment tools have been studied in this context. The present investigation was designed to determine the feasibility and reliability of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) administration by comparing video teleconference (VTC) with face-to-face (FF) test conditions. Eighteen adult subjects over age 55 with and without cognitive impairment were administered Forms A and B of the RBANS in VTC and FF settings in counterbalanced fashion. Similar RBANS scores were obtained in both test conditions, with generally high correlations between administration methods. Results support the feasibility and reliability of remote administration of the RBANS via VTC. PMID:26446834

  13. The effects of a 5-HT7 receptor agonist and antagonist on morphine withdrawal syndrome in mice.

    Science.gov (United States)

    Shahidi, Siamak; Hashemi-Firouzi, Nasrin

    2014-08-22

    Withdrawal from opioids leads to the expression of aversion behaviors. Previous studies have shown that the serotonergic system has an important role in morphine withdrawal syndrome. The 5-HT7 receptor is a recently discovered member of the 5-HT receptor family that has been shown to be involved in these behaviors. The aim of the present study was to test the role of the 5-HT7 receptor in withdrawal syndrome in morphine-dependent mice with AS19 and SB269970, a selective agonist and antagonist of this receptor, respectively. Dependence was induced by the repeated administration of morphine for five consecutive days. The morphine-dependent mice received AS19 (3, 5, or 10mg/kg, intraperitoneal) or SB269970 (1, 3, or 10mg/kg, intraperitoneal) 15 min prior to the precipitation of morphine withdrawal syndromes by naloxone (3mg/kg, subcutaneous). Withdrawal symptoms, including percent weight loss, jumping, teeth chattering, writhing, body and face grooming, sniffing, standing, and head and limb shaking, were recorded for 30 min after the naloxone injection. The morphine-dependent mice had significantly more withdrawal symptoms than naive control mice. The administration of AS19 reduced most of the morphine withdrawal symptoms. However, SB2699 increased some of the withdrawal symptoms, including teeth chattering, face grooming, jumping, and head and limb shaking. These findings suggest that the 5-HT7 receptor is involved in morphine withdrawal. Its activation decreased and its inactivation increased the morphine withdrawal syndrome. Further studies are recommended to better understand the role of the 5-HT7 receptor in morphine dependence and withdrawal.

  14. Repeated administration of histamine improves memory retrieval of inhibitory avoidance by lithium in mice.

    Science.gov (United States)

    Zarrindast, Mohammad Reza; Parsaei, Leila; Ahmadi, Shamseddin

    2008-01-01

    The influence of repeated administration of histamine on lithium-induced state dependency has been investigated. A single-trial step-down inhibitory avoidance task was used to assess memory in adult male NMRI mice. Intraperitoneal (i.p.) administration of lithium (10 mg/kg), immediately after training (post-training), impaired inhibitory avoidance memory on the test day. Pre-test administration of lithium reversed amnesia induced by the drug given after training, with the maximum response at a dose of 10 mg/kg. Repeated intracerebroventricular (i.c.v.) administration of histamine (20 microg/mouse) for 3 consecutive days followed by 5 days of no drug treatment improved memory retrieval of inhibitory avoidance by a pre-test lower dose (5 mg/kg i.p.) of lithium. In contrast, 3 days of i.c.v. injections of both the histamine H1 receptor antagonist pyrilamine (40 microg/mouse) and the histamine H2 receptor antagonist ranitidine (6.25 and 12.5 microg/mouse) prevented the improving effect of pre-test lithium (10 mg/kg i.p.) on memory retrieval. The results suggest that the repeated administration of histaminergic agents may induce a sensitization which affects the memory impairment induced by lithium.

  15. Electroencephalographic Changes Associated with Antinociceptive Actions of Lidocaine, Ketamine, Meloxicam, and Morphine Administration in Minimally Anaesthetized Dogs

    Directory of Open Access Journals (Sweden)

    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.

  16. Lipoxin A4 analog attenuates morphine antinociceptive tolerance, withdrawal-induced hyperalgesia, and glial reaction and cytokine expression in the spinal cord of rat.

    Science.gov (United States)

    Jin, H; Li, Y H; Xu, J S; Guo, G Q; Chen, D L; Bo, Y

    2012-04-19

    Spinal neuroinflammation has been shown to play an important role in the development of morphine tolerance and morphine withdrawal-induced hyperalgesia. Lipoxins are endogenous lipoxygenase-derived eicosanoids that can function as "braking signals" in inflammation. The present study investigated the effect of 5 (S), 6 (R)-lipoxin A4 methyl ester (LXA4ME), a stable synthetic analog of lipoxin A4, on the expression of antinociceptive tolerance and withdrawal-induced hyperalgesia in chronic morphine-treated rats. Chronic morphine administration through repeated subcutaneous injection induced the development of hyperalgesia and the expression of spinal antinociceptive tolerance to morphine. However, LXA4ME treatment significantly attenuated the development of hyperalgesia and the expression of spinal antinociceptive tolerance to intrathecal morphine in both mechanical and thermal test. Moreover, the administration of LXA4ME during the induction of morphine tolerance inhibited the activation of microglia and astrocytes; reduced the expression of proinflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α); upregulated the expression of anti-inflammatory cytokines IL-10 and transforming growth factor-β1 (TGF-β1); and inhibited nuclear factor-kappa B (NF-κB) activation at the L5 lumbar spinal cord. These results suggest that treatment of LXA(4)ME provides a potential preventative or therapeutic approach for morphine tolerance and associated abnormal pain sensitivity.

  17. Effect of tramadol on metamizol pharmacokinetics and pharmacodynamics after single and repeated administrations in arthritic rats.

    Science.gov (United States)

    Moreno-Rocha, Luis Alfonso; López-Muñoz, Francisco Javier; Medina-López, José Raúl; Domínguez-Ramírez, Adriana Miriam

    2016-11-01

    Combined administration of certain doses of opioid compounds with a non-steroidal anti-inflammatory drug can produce additive or supra-additive effects while reducing unwanted effects. We have recently reported that co-administration of metamizol with tramadol produces antinociceptive effect potentiation, after acute treatment. However, none information about the effect produced by the combination after chronic or repeated dose administration exists. The aims of this study were to investigate whether the antinociceptive synergism produced by the combination of metamizol and tramadol (177.8 + 17.8 mg/kg, s.c. respectively) is maintained after repeated treatment and whether the effects observed are primarily due to pharmacodynamic interactions or may be related to pharmacokinetics changes. Administration of metamizol plus tramadol acute treatment significantly enhanced the antinociceptive effect of the drugs given alone (P metamizol and tramadol was found under acute treatment (P > 0.05). The mechanism involved in the synergism of the antinociceptive effect observed with the combination of metamizol and tramadol in single dose cannot be attributed to a pharmacokinetic interaction, and other pharmacodynamic interactions have to be considered. On the other hand, when metamizol and tramadol were co-administered under repeated administrations, a pharmacokinetic interaction and tolerance development occurred. Differences found in metamizol active metabolites' pharmacokinetics (P < 0.05) were related to the development of tolerance produced by the combination after repeated doses. This work shows an additional preclinical support for the combination therapy. The clinical utility of this combination in a suitable dose range should be evaluated in future studies.

  18. Effect of tramadol on metamizol pharmacokinetics and pharmacodynamics after single and repeated administrations in arthritic rats

    Directory of Open Access Journals (Sweden)

    Luis Alfonso Moreno-Rocha

    2016-11-01

    Full Text Available Combined administration of certain doses of opioid compounds with a non-steroidal anti-inflammatory drug can produce additive or supra-additive effects while reducing unwanted effects. We have recently reported that co-administration of metamizol with tramadol produces antinociceptive effect potentiation, after acute treatment. However, none information about the effect produced by the combination after chronic or repeated dose administration exists. The aims of this study were to investigate whether the antinociceptive synergism produced by the combination of metamizol and tramadol (177.8 + 17.8 mg/kg, s.c. respectively is maintained after repeated treatment and whether the effects observed are primarily due to pharmacodynamic interactions or may be related to pharmacokinetics changes. Administration of metamizol plus tramadol acute treatment significantly enhanced the antinociceptive effect of the drugs given alone (P  0.05. The mechanism involved in the synergism of the antinociceptive effect observed with the combination of metamizol and tramadol in single dose cannot be attributed to a pharmacokinetic interaction, and other pharmacodynamic interactions have to be considered. On the other hand, when metamizol and tramadol were co-administered under repeated administrations, a pharmacokinetic interaction and tolerance development occurred. Differences found in metamizol active metabolites’ pharmacokinetics (P < 0.05 were related to the development of tolerance produced by the combination after repeated doses. This work shows an additional preclinical support for the combination therapy. The clinical utility of this combination in a suitable dose range should be evaluated in future studies.

  19. 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.

  20. Different effects of L-arginine on morphine tolerance in sham and ovariectomized female mice

    Institute of Scientific and Technical Information of China (English)

    Reza KARAMI; Mahmoud HOSSEINI; Fatimeh KHODABANDEHLOO; Leila KHATAMI; Zahra TAIARANI

    2011-01-01

    Objective: The roles of gonadal hormones and nitric oxide (NO) on the analgesic effects of morphine,tolerance to morphine,and their interactions have been widely investigated.In the present study,the effect of L-arginine (an NO precursor) on morphine tolerance in sham and ovariectomized (OVX) female mice was investigated.Methods: Forty mice were divided into sham and OVX groups.On the first day,a hot plate test ((55±0.2) ℃; cut-off 30 s)was carried out as a base record 15 min before injection of morphine (10 mg/kg,subcutaneously (s.c.)) and was repeated every 15 min after injection.The sham group was then divided into two subgroups: sham-toleranceL-arginine (Sham-ToI-LA) and sham-tolerance-saline (Sham-ToI-Sal) which received either L-arginine 50 mg/kg (intraperitoneally (i.p.)) or saline 10 mi/kg (i.p.),respectively,three times in a day for three consecutive days.Morphine tolerance was induced in animals by injecting 30 mg/kg morphine (s.c.) three times/day for three days.This treatment was also used for OVX subgroups.On the fifth day,the hot plate test was repeated.The analgesic effect of morphine was calculated as the maximal percent effect (MPE).The results were compared using repeated measure analysis of variance (ANOVA).Results: There was no significant difference in MPE between the OVX and sham groups.The MPEs in both the Sham-ToI-Sal and OVX-ToI-Sal groups were lower than those in both the sham and OVX groups (P<0.01).The MPE in the OVX-ToI-Sal group was greater than that in the Sham-ToI-Sal group (P<0.01).The MPE in the Sham-ToI-LA group was higher than that in the Sham-ToI-Sal group (P<0.01).However,there was no significant difference between the Sham-ToI-LA and sham groups or between the OVX-ToI-LA and OVX-ToI-Sal groups.Conclusions: The results of the present study showed that repeated administration of morphine causes tolerance to the analgesic effect of morphine.L-Arginine could prevent tolerance to morphine but its effect was different in

  1. Brexpiprazole Alters Monoaminergic Systems following Repeated Administration: an in Vivo Electrophysiological Study

    OpenAIRE

    Oosterhof, Chris A.; Mansari, Mostafa El; Bundgaard, Christoffer; Blier, Pierre

    2015-01-01

    Background: Brexpiprazole was recently approved as adjunctive therapy for depression and treatment of schizophrenia in adults. To complement results from a previous study in which its acute effects were characterized, the present study assessed the effect of repeated brexpiprazole administration on monoaminergic systems. Methods: Brexpiprazole (1mg/kg, subcutaneous) or vehicle was administered once daily for 2 and 14 days. Single-unit electrophysiological recordings from noradrenaline neurons...

  2. Elimination of progressive mammary cancer by repeated administrations of chimeric antigen receptor-modified T cells.

    Science.gov (United States)

    Globerson-Levin, Anat; Waks, Tova; Eshhar, Zelig

    2014-05-01

    Continuous oncogenic processes that generate cancer require an on-going treatment approach to eliminate the transformed cells, and prevent their further development. Here, we studied the ability of T cells expressing a chimeric antibody-based receptor (CAR) to offer a therapeutic benefit for breast cancer induced by erbB-2. We tested CAR-modified T cells (T-bodies) specific to erbB-2 for their antitumor potential in a mouse model overexpressing a human erbB-2 transgene that develops mammary tumors. Comparing the antitumor reactivity of CAR-modified T cells under various therapeutic settings, either prophylactic, prior to tumor development, or therapeutically. We found that repeated administration of CAR-modified T cells is required to eliminate spontaneously developing mammary cancer. Systemic, as well as intratumoral administered CAR-modified T cells accumulated at tumor sites and eventually eliminated the malignant cells. Interestingly, within a few weeks after a single CAR T cells' administration, and rejection of primary lesion, tumors usually relapsed both in treated mammary gland and at remote sites; however, repeated injections of CAR-modified T cells were able to control the secondary tumors. Since spontaneous tumors can arise repeatedly, especially in the case of syndromes characterized by specific susceptibility to cancer, multiple administrations of CAR-modified T cells can serve to control relapsing disease.

  3. SLEEP AND GABA LEVELS IN THE ORAL PART OF RAT PONTINE RETICULAR FORMATION ARE DECREASED BY LOCAL AND SYSTEMIC ADMINISTRATION OF MORPHINE

    OpenAIRE

    Watson, Christopher J.; Lydic, Ralph; Baghdoyan, Helen A.

    2006-01-01

    Morphine, a μ-opioid receptor agonist, is a commonly prescribed treatment for pain. Although highly efficacious, morphine has many unwanted side effects including disruption of sleep and obtundation of wakefulness. One mechanism by which morphine alters sleep and wakefulness may be by modulating GABAergic signaling in brain regions regulating arousal, including the oral pontine reticular formation (PnO). This study used in vivo microdialysis in unanesthetized Sprague-Dawley rat to test the hy...

  4. Pharmacokinetics of marbofloxacin after single intravenous and repeat oral administration to cats.

    Science.gov (United States)

    Albarellos, G A; Montoya, L; Landoni, M F

    2005-09-01

    The pharmacokinetic properties of marbofloxacin, a third generation fluoroquinolone, were investigated in six cats after single intravenous (IV) and repeat oral (PO) administration at a daily dose of 2 mg/kg. Marbofloxacin serum concentration was analysed by microbiological assay using Klebsiella pneumoniae ATCC 10031 as micro-organism test. Serum marbofloxacin disposition was best described by bicompartmental and mono-compartmental open models with first-order elimination after IV and oral dosing respectively. After IV administration, distribution was rapid (T(1/2(d)) 0.23+/-0.24 h) and wide, as reflected by the steady-state volume of distribution of 1.01+/-0.15 L/kg. Elimination from the body was slow with a body clearance of 0.09+/-0.02 L/h kg and a T(1/2) of 7.98+/-0.57 h. After repeat oral administration, absorption half-life was 0.86+/-1.59 h and T(max) of 1.94+/-2.11 h. Bioavailability was almost complete (99+/-29%) with a peak plasma concentration at the steady-state of 1.97+/-0.61 mug/mL. Drug accumulation was not significant after six oral administrations. Calculation of efficacy predictors showed that marbofloxacin has good therapeutic profile against Gram-negative and Gram-positive bacteria with a MIC(50) value <0.25 microg/mL.

  5. Effect of repeated oral administration on taurocholate on hepatic excretory function in the rat.

    Science.gov (United States)

    Watkins, J B; Klaassen, C D

    1981-07-01

    The effect of repeated administration of taurocholate on bile acid pool size, biliary composition and biliary excretory capacity for bile acids and two xenobiotics was determined. The bile acid pool was increased 50 to 60% by oral administration of sodium taurocholate (300--900 mg/kg, 10 ml/kg) every 12 hr for 2 days to male Sprague-Dawley rats. Bile flow, biliary excretion of bile acids, cholesterol and phospholipid and the concentrations of phospholipid and bile acids in bile were increased in rats treated with 750 mg of taurocholate per kg. No effect was observed on Na+,K+ or Cl- levels. The biliary transport maximum for taurocholate was increased by 30% in rats treated with 750 mg/kg. In contrast, the plasma disappearance and biliary excretion of phenol-3,6-dibromphthalein and ouabain were not affected by taurocholate administration.

  6. Midazolam exacerbates morphine tolerance and morphine-induced hyperactive behaviors in young rats with burn injury.

    Science.gov (United States)

    Song, Li; Wang, Shuxing; Zuo, Yunxia; Chen, Lucy; Martyn, Jeevendra A; Mao, Jianren

    2014-05-20

    Midazolam and morphine are often used in pediatric intensive care unit (ICU) for analgesia and sedation. However, how these two drugs interact behaviorally remains unclear. Here, we examined whether (1) co-administration of midazolam with morphine would exacerbate morphine tolerance and morphine-induced hyperactive behaviors, and (2) protein kinase C (PKC) would contribute to these behavioral changes. Male rats of 3-4 weeks old were exposed to a hindpaw burn injury. In Experiment 1, burn-injured young rats received once daily saline or morphine (10mg/kg, subcutaneous, s.c.), followed 30min later by either saline or midazolam (2mg/kg, intraperitoneal, i.p.), for 14 days beginning 3 days after burn injury. In Experiment 2, young rats with burn injury were administered with morphine (10mg/kg, s.c.), midazolam (2mg/kg, i.p.), and chelerythrine chloride (a non-specific PKC inhibitor, 10nmol, intrathecal) for 14 days. For both experiments, cumulative morphine anti-nociceptive dose-response (ED50) was tested and hyperactive behaviors such as jumping and scratching were recorded. Following 2 weeks of each treatment, ED50 dose was significantly increased in rats receiving morphine alone as compared with rats receiving saline or midazolam alone. The ED50 dose was further increased in rats receiving both morphine and midazolam. Co-administration of morphine and midazolam also exacerbated morphine-induced hyperactive behaviors. Expression of the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor and PKCγ in the spinal cord dorsal horn (immunohistochemistry; Western blot) was upregulated in burn-injured young rats receiving morphine alone or in combination with midazolam, and chelerythrine prevented the development of morphine tolerance. These results indicate that midazolam exacerbated morphine tolerance through a spinal NMDA/PKC-mediated mechanism.

  7. Midazolam Exacerbates Morphine Tolerance and Morphine-induced Hyperactive Behaviors in Young Rats with Burn Injury

    Science.gov (United States)

    Song, Li; Wang, Shuxing; Zuo, Yunxia; Chen, Lucy; Martyn, Jeevendra A.; Mao, Jianren

    2014-01-01

    Midazolam and morphine are often used in pediatric intensive care unit (ICU) for analgesia and sedation. However, how these two drugs interact behaviorally remains unclear. Here, we examined whether 1) co-administration of midazolam with morphine would exacerbate morphine tolerance and morphine-induced hyperactive behaviors, and 2) protein kinase C (PKC) would contribute to these behavioral changes. Male rats of 3 to 4 weeks old were exposed to a hindpaw burn injury. In Experiment 1, burn-injured young rats received once daily saline or morphine (10 mg/kg, subcutaneous, s.c.), followed 30 min later by either saline or midazolam (2 mg/kg, intraperitoneal, i.p.), for 14 days beginning 3 days after burn injury. In Experiment 2, young rats with burn injury were administered with morphine (10 mg/kg, s.c.), midazolam (2 mg/kg, i.p.), and chelerythrine chloride (a non-specific PKC inhibitor 10 nmol, intrathecal) for 14 days. For both experiments, cumulative morphine anti-nociceptive dose-response (ED50) was tested and hyperactive behaviors such as jumping and scratching were recorded. Following 2 weeks of each treatment, ED50 dose was significantly increased in rats receiving morphine alone as compared with rats receiving saline or midazolam alone. The ED50 dose was further increased in rats receiving both morphine and midazolam. Co-administration of morphine and midazolam also exacerbated morphine-induced hyperactive behaviors. Expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and PKCγ in the spinal cord dorsal horn (immunohistochemistry; Western blot) was upregulated in burn-injured young rats receiving morphine alone or in combination with midazolam, and chelerythrine prevented the development of morphine tolerance. These results indicate that midazolam exacerbated morphine tolerance through a spinal NMDA/PKC-mediated mechanism. PMID:24713351

  8. Varenicline impairs extinction and enhances reinstatement across repeated cycles of nicotine self-administration in rats.

    Science.gov (United States)

    Macnamara, Claire L; Holmes, Nathan M; Westbrook, R Fred; Clemens, Kelly J

    2016-06-01

    Varenicline is a partial nicotine receptor agonist widely prescribed as a smoking cessation medication. Repeated (or long-term) use of varenicline has been proposed as a treatment option for tobacco addiction. However the effect of repeated varenicline use on motivation for nicotine is unknown. Here the intravenous nicotine self-administration paradigm in rats was used to model the consequences of varenicline treatment across repeated cycles of administration, extinction and reinstatement. Rats acquired nicotine self-administration across 20 days before undergoing 6 days of extinction, where each extinction session was preceded by a single injection of varenicline or saline. This was followed by a single varenicline-free nicotine-primed reinstatement test. All rats then reacquired nicotine self-administration for 10 days followed by a second cycle of extinction. Across this period, rats either received a second cycle of varenicline (VAR-VAR) or saline (SAL-SAL), or the alternative treatment (SAL-VAR, VAR-SAL), followed by a final reinstatement test. Treatment with varenicline increased responding across the first cycle of extinction, but did not affect responding in the reinstatement test. Across the second cycle, varenicline again increased responding across extinction, and critically, rats treated with varenicline across cycle 1 and saline across cycle 2 (Group VAR-SAL) exhibited more reinstatement than rats in any other group. The effect of VAR on nicotine seeking was not due to its effects on locomotor activity. Instead, the results suggest that a history of VAR can increase vulnerability to reinstatement/relapse when its treatment is discontinued. The possible mechanisms of this increased vulnerability are discussed.

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

    Science.gov (United States)

    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.

  10. Regional cerebral glucose utilization during morphine withdrawal in the rat.

    OpenAIRE

    Wooten, G.F.; DiStefano, P.; Collins, R. C.

    1982-01-01

    Regional cerebral glucose utilization was studied by 2-deoxy[14C]glucose autoradiography in morphine-dependent rats and during naloxone-induced morphine withdrawal. In morphine-dependent rats, glucose utilization was increased compared with naive controls uniformly (23-54%) in hippocampus, dentate gyrus, and subiculum and reduced in frontal cortex, striatum, anterior ventral thalamus, and medial habenular nucleus. On precipitation of morphine withdrawal by subcutaneous administration of nalox...

  11. Effects of nicotine gum on repeated administration of the Stroop test.

    Science.gov (United States)

    Provost, S C; Woodward, R

    1991-01-01

    Using a double-blind procedure, 24 non-smoking subjects chewed either 2 mg nicorette gum or a placebo for 20 min, before completing a Stroop test on three occasions. Colour-word reading and simple colour naming times were consistent across repeats, and were unaffected by nicotine. However, the time taken to name the colour of incongruous colour word stimuli declined across trials. This increase in speed across repeats was significantly greater in those subjects who had received nicotine. These data are consistent with previous reports of a decreased Stroop effect following nicotine administration, but are not compatible with a simple model which assumes that nicotine alters the way in which information is filtered by selective attentional mechanisms. The present results can be explained by postulating that nicotine influences either the rate at which colour naming become more automatic, or changes the way in which resources are allocated to non-automatic processes.

  12. Repeated administration of imipramine modifies GABAergic transmission in rat frontal cortex.

    Science.gov (United States)

    Wabno, Joanna; Hess, Grzegorz

    2013-05-01

    Alterations in the functions of brain gamma-aminobutyric acid (GABA) inhibitory system and a distortion in the balance between excitatory and inhibitory synaptic transmission have been hypothesized to be possible causes of mood disorders. Experimental evidence points to modifications of GABAergic transmission as a result of prolonged treatment with antidepressant drugs, however, the influence of the tricyclic antidepressant imipramine on inhibitory synaptic transmission in the rat cerebral cortex has not yet been investigated. Therefore, in the present study the effects of single and repeated administration of imipramine were evaluated ex vivo in slices of the rat frontal cortex using electrophysiological approach. In slices prepared 2 days after the last drug administration from animals receiving imipramine for 14 days (dose 10 mg/kg p.o., twice daily) the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from layer II/III pyramidal neurons was decreased, while the mean amplitude of sIPSCs was increased. These effects were absent in slices obtained from rats which received imipramine once. Application of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN 082), a selective mGluR7 allosteric agonist, to the slice incubation medium resulted in a decrease in the mean frequency of sIPSCs in preparations obtained from repeated imipramine-treated animals, in contrast to slices originating from control rats where no AMN 082-induced effects were observed. Repeated imipramine treatment reduced protein density levels of the three tested GABAA receptor subunits: α 1, β 2 and γ 2. These data indicate that repeated treatment of normal rats with imipramine results in a modification of the release mechanism of GABA from presynaptic terminals and its modulation by mGluR7 receptors as well as in an alteration in GABAA receptor subunit protein levels in the rat cerebral cortex.

  13. Persistence and accumulation of micronucleated hepatocytes in liver of rats after repeated administration of diethylnitrosamine.

    Science.gov (United States)

    Narumi, Kazunori; Ashizawa, Koji; Fujiishi, Yohei; Tochinai, Ryota; Okada, Emiko; Tsuzuki, Yasuhiro; Tatemoto, Hideki; Hamada, Shuichi; Kaneko, Kimiyuki; Ohyama, Wakako

    2013-08-15

    A repeat-dose micronucleus assay in adult rat liver was recently developed [Mutat. Res. 747 (2012) 234-239]. This assay demonstrated a high detectability of hepatocarcinogens at relatively low doses, as indicated by dose-dependent micronucleus induction. Because the adult rat liver is known to have a long life-span, this desirable property of the assay will be an advantage in detecting micronucleated hepatocytes (MNHEPs) that have persisted for long periods in the liver following repeated dosing. However, no data directly supporting the underlying mechanisms have been published to date. In the present study, we verified the mechanisms by means of pulse-labeling of micronucleated hepatocytes with the thymidine analog 5-ethynyl-2'-deoxyuridine (EdU). The rodent hepatocarcinogen diethylnitrosamine (DEN) was repeatedly administered orally to male Crl:CD (SD) rats (6 weeks old) for up to 2 weeks, and EdU was injected intraperitoneally on days 1, 7, or 14. Hepatocytes were isolated by use of a non-perfusion technique at 24h, 1 week, or 2 weeks after EdU injection and analyzed for EdU incorporation and micronucleus formation. The results of our study confirmed that MNHEPs labeled with EdU on the first day of DEN administration persisted until 2 weeks post-administration in the rat livers. However, the frequency of MHNEPs among EdU-labeled hepatocytes decreased over time. In addition, the number of terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL)-positive cells in the liver tissue increased, suggesting selective removal of micronucleated cells. Theoretical calculation of the cumulative MNHEP frequency on each of the days on which DEN was administered, taking into account the rate of loss, came out closer to the actual value observed in the liver micronucleus test. Taken together, these results indicate that although micronucleated cells induced in rat livers by administration of the genotoxic hepatocarcinogen DEN undergo selective removal, they

  14. 侧脑室注射东莨菪碱对吗啡依赖大鼠戒断反应的抑制作用%Intracerebroventricular administration of scopolamine attenuates naloxone precipitated morphine abstinence syndrome

    Institute of Scientific and Technical Information of China (English)

    顾钧; 唐甩恩; 周文华; 杨国栋

    2001-01-01

    Aim To investigate the effect of cholinergic receptors in central nervous system on morphine dependent rats. Methods Male Sprague-Dawley rats weighing 200~250 g were rendered dependent on morphine by subcutaneous injection of morphine in increasing doses for 5 days. Prior to testing, rats received infusion of either a solution of drug (scopolamine, pirenzepine, methoctramine) or vehicle (normal saline) in lateral cerebral ventricle. Withdrawal behavior was monitored for 60 min after intraperitoneal administration of naloxone. Results The animal pretreatment with scopolamine (25,50 μg) or muscarinic subtype antagonists (20 μg pirenzepine, 25 μg methoctramine) could significantly attenuate naloxone precipitated morphine abstinence syndrome. Central administration of scopolamine could reduce reaction of morphine withdrawal in a dose-dependent manner. Conclusion The central cholinergic receptors may be play an important role in the process of morphine withdrawal. Both M1 and M2 receptors may contribute to the development of morphine dependence and tolerance.%目的 观察非选择性毒蕈碱(M)受体拮抗剂东莨菪碱、选择性M1受体拮抗剂哌拉唑嗪以及选择性M2受体拮抗剂美索四氨对吗啡戒断反应的影响.方法采用吗啡依赖大鼠模型侧脑室注射上述药物,并用腹腔注射纳洛酮诱发戒断反应,记录 60 min 内戒断症状.结果侧脑室注射东莨菪碱(25,50 μg)、哌拉唑嗪(20 μg)和美索四氨(25 μg)可明显抑制由纳洛酮诱发戒断反应,东莨菪碱减轻吗啡戒断症状呈明显量效关系.结论侧脑室注射东莨菪碱能减轻吗啡戒断反应,提示中枢胆碱能神经毒蕈碱(M)受体在吗啡依赖和耐受过程中起重要作用.

  15. Antinociceptive effects of tramadol in co-administration with metamizol after single and repeated administrations in rats.

    Science.gov (United States)

    Moreno-Rocha, Luis Alfonso; Domínguez-Ramírez, Adriana Miriam; Cortés-Arroyo, Alma Rosa; Bravo, Guadalupe; López-Muñoz, Francisco Javier

    2012-11-01

    Combinations of two analgesic drugs of the same or different class are widely used in clinical therapy to enhance its antinociceptive effects and reduce the side effects. In order to evaluate a possible antinociceptive synergistic interaction of metamizol s.c., a nonsteroidal antiinflammatory drug (NSAID), and tramadol s.c., an atypical opioid (opioid receptor agonist), were administered alone or in combination. In the present study, the antinociceptive efficacy and the possible development of pharmacological tolerance produced by the combination tramadol plus metamizol during a 4-day treatment in rats using the plantar test was evaluated. Male Wistar rats were s.c. injected with tramadol (17.8 mg/kg), metamizol (177.8 mg/kg) or the combination tramadol plus metamizol three times a day for 4 days. Both metamizol and tramadol produced antinociceptive effects with a low rate trend towards tolerance development at the end of the treatment. The antinociceptive efficacy of tramadol and metamizol co-administration gradually decreased after the second injection. These data suggest that when the combination is given in a unique administration it results in an important potentiation of their individual antinociceptive effects. But, the repeated coadministration of tramadol plus metamizol results in a development of tolerance.

  16. Alteration in metabolism and toxicity of acetaminophen upon repeated administration in rats.

    Science.gov (United States)

    Kim, Sun J; Lee, Min Y; Kwon, Do Y; Kim, Sung Y; Kim, Young C

    2009-10-01

    Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system.

  17. Latent inhibition is disrupted by acute and repeated administration of corticosterone.

    Science.gov (United States)

    Shalev, U.; Feldon, J.; Weiner, I.

    1998-12-01

    Latent inhibition (LI), namely, a retardation in conditioning to a stimulus, as a consequence of its prior non- reinforced pre-exposure, is disrupted in amphetamine-treated rats and humans and in some subsets of schizophrenic patients. One factor that has been repeatedly implicated in precipitating and/or exacerbating psychotic episodes is stress. Since a principal biological response to stress is the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, leading, as its end product, to the secretion of corticosterone, the present experiments tested whether increase in corticosterone levels following exogenous corticosterone administration would disrupt LI. Both repeated (Experiment 1) and acute (Experiment 2) administration of corticosterone led to LI disruption, providing evidence for the involvement of the HPA axis alterations in LI and further supporting the viability of disrupted LI as an animal model of psychosis. Both regimens also increased amphetamine-induced activity. We suggest that disrupted LI may reflect a cognitive mechanism whereby prolonged periods of increased corticosterone levels can lead to 'sensory flooding' characteristic of psychosis.

  18. Repeated Administration of Bone Marrow-Derived Cells Prevents Disease Progression in Experimental Silicosis

    Directory of Open Access Journals (Sweden)

    Miquéias Lopes-Pacheco

    2013-12-01

    Full Text Available Background/Aims: Bone marrow-derived cells (BMDCs reduced mechanical and histologic changes in the lung in a murine model of silicosis, but these beneficial effects did not persist in the course of lung injury. We hypothesized that repeated administration of BMDCs may decrease lung inflammation and remodeling thus preventing disease progression. Methods: One hundred and two C57BL/6 mice were randomly divided into SIL (silica, 20 mg intratracheally [IT] and control (C groups (saline, IT. C and SIL groups were further randomized to receive BMDCs (2×106 cells or saline IT 15 and 30 days after the start of the protocol. Results: By day 60, BMDCs had decreased the fractional area of granuloma and the number of polymorphonuclear cells, macrophages (total and M1 phenotype, apoptotic cells, the level of transforming growth factor (TGF-β‚ and types I and III collagen fiber content in the granuloma. In the alveolar septa, BMDCs reduced the amount of collagen and elastic fibers, TGF-β, and the number of M1 and apoptotic cells. Furthermore, interleukin (IL-1β, IL-1R1, caspase-3 mRNA levels decreased and the level of IL-1RN mRNA increased. Lung mechanics improved after BMDC therapy. The presence of male donor cells in lung tissue was not observed using detection of Y chromosome DNA. Conclusion: repeated administration of BMDCs reduced inflammation, fibrogenesis, and elastogenesis, thus improving lung mechanics through the release of paracrine factors.

  19. Prior experience of morphine application alters the c-fos response to MDMA ('ecstasy') and cocaine in the rat striatum.

    Science.gov (United States)

    Erdtmann-Vourliotis, M; Mayer, P; Riechert, U; Höllt, V

    2000-04-14

    Repeated morphine application usually leads to the development of tolerance but under certain circumstances sensitization may arise simultaneously. This phenomenon becomes obvious in behavioral tests as increasing locomotor activity and increasing drug self-administration during a course of chronic morphine application. It was suggested recently that sensitization could contribute to addiction. The molecular mechanisms of sensitization may include the long lasting increase in neuronal responsiveness to morphine which was observed in defined brain areas after repeated morphine injections. In this work, we studied whether morphine-sensitized Wistar rats also display an enhanced neuronal activity in response to other drugs of abuse (so called co-sensitization). The substances to be tested were injected as single doses 4 weeks after completion of a 10-day morphine pretreatment. MDMA (3, 4-methylenedioxymethamphetamine, 6 mg/kg) as a single test dose yielded a c-fos response in a wide range of brain areas. In the caudate putamen, the expression pattern of c-fos was clearly altered if the rats had received repeated morphine application previously. In this case, the MDMA-induced c-fos expression was markedly confined to the centromedial, mesolimbic aspect of the striatum whereas it had a diffuse appearance in rats not exposed to the opiate earlier. Cocaine application (50 mg/kg) elicited an intense c-fos expression in the medial striatum if the animals were morphine-pretreated; it was virtually absent in drug-naive rats after the same cocaine dose. Ten mg/kg cocaine had a similar but weaker effect. No difference in the c-fos expression pattern between morphine and saline pretreated animals was observed in the case of a THC (Delta(9)-tetrahydrocannabinol, 25 mg/kg) or an LSD (lysergic acid diethylamide, 1 mg/kg) test application. These findings imply that morphine sensitizes the brain towards other addicting drugs. In consequence, morphine sensitization obviously does not

  20. Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models.

    Science.gov (United States)

    Bourin, M; Hascoet, M; Mansouri, B; Colombel, M C; Bradwejn, J

    1992-01-01

    The behavioral and clinical profiles of various benzodiazepines after acute and chronic treatment are not well defined and may differ. The aim of this study was to evaluate the behavioral profiles of alprazolam, bromazepam, diazepam and lorazepam in mice after single and repeated (every half-life for seven half-lives) administrations using a stimulation-sedation test (actimeter), a myorelaxation test (rotarod), and an anxiolysis test ("four plates"). A dose range from 0.03 to 4 mg/kg was used. A single administration of alprazolam showed stimulating and anxiolytic effects which diminished after repeated administration. Lorezapam's sedative effect diminished but its anxiolytic effect increased upon repeated administration. Except for lorazepam, the myorelaxing effect of all four drugs increased after repeated treatment. These results suggest that the behavioral profile of benzodiazepines may not be identical during acute and chronic treatment. These differences may be present in clinical treatment and warrant investigation in humans. PMID:1637802

  1. Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models.

    Science.gov (United States)

    Bourin, M; Hascoet, M; Mansouri, B; Colombel, M C; Bradwejn, J

    1992-06-01

    The behavioral and clinical profiles of various benzodiazepines after acute and chronic treatment are not well defined and may differ. The aim of this study was to evaluate the behavioral profiles of alprazolam, bromazepam, diazepam and lorazepam in mice after single and repeated (every half-life for seven half-lives) administrations using a stimulation-sedation test (actimeter), a myorelaxation test (rotarod), and an anxiolysis test ("four plates"). A dose range from 0.03 to 4 mg/kg was used. A single administration of alprazolam showed stimulating and anxiolytic effects which diminished after repeated administration. Lorezapam's sedative effect diminished but its anxiolytic effect increased upon repeated administration. Except for lorazepam, the myorelaxing effect of all four drugs increased after repeated treatment. These results suggest that the behavioral profile of benzodiazepines may not be identical during acute and chronic treatment. These differences may be present in clinical treatment and warrant investigation in humans.

  2. Pharmacokinetics and tissue disposition of meloxicam in beef calves after repeated oral administration.

    Science.gov (United States)

    Coetzee, J F; Mosher, R A; Griffith, G R; Gehring, R; Anderson, D E; KuKanich, B; Miesner, M

    2015-12-01

    The objective of this study was to investigate the pharmacokinetics and tissue disposition of meloxicam after repeated oral administration in calves. Thirteen male British × Continental beef calves aged 4 to 6 months and weighing 297-392 kg received 0.5 mg/kg meloxicam per os once daily for 4 days. Plasma meloxicam concentrations were determined in 8 calves over 6 days after first treatment. Calves were randomly assigned to be euthanized at 5, 10, 15 (n = 3/timepoint), and 19 days (n = 4) after final administration. Meloxicam concentrations were determined in plasma (LOQ= 0.025 μg/mL) and muscle, liver, kidney, and fat samples (LOQ = 2 ng/g) after extraction using validated LC-MS-MS methods. The mean (± SD) Cmax , Cmin , and Caverage plasma meloxicam concentrations were 4.52 ± 0.87 μg/mL, 2.95 ± 0.77 μg/mL, and 3.84 ± 0.81 μg/mL, respectively. Mean (± SD) tissue meloxicam concentrations were highest in liver (226.67 ± 118.16 ng/g) and kidney samples (52.73 ± 39.01 ng/g) at 5 days after final treatment. Meloxicam concentrations were below the LOQ in all tissues at 15 days after treatment. These findings suggest that tissue from meloxicam-treated calves will have low residue concentrations by 21 days after repeated oral administration.

  3. Complex motivated behaviors for natural rewards following a binge-like regimen of morphine administration: mixed phenotypes of anhedonia and craving after short-term withdrawal

    Directory of Open Access Journals (Sweden)

    Yunjing eBai

    2014-02-01

    Full Text Available The anhedonia-like behaviors following about one-week withdrawal from morphine were examined in the present study. Male rats were pretreated with either a binge-like morphine paradigm or daily saline injection for 5 days. Three types of natural reward were used, food reward (2.5%, 4%, 15%, 30%, 40% and 60% sucrose solutions, social reward (male rat and sexual reward (estrous female rat. For each type of natural stimulus, consummatory behavior and motivational behaviors under varied testing conditions were investigated. The results showed that the morphine-treated rats significantly reduced their consumption of 2.5% sucrose solution during the 1-hour consumption testing and their operant responding for 15%, 30% and 40% sucrose solutions under a fixed ratio 1 (FR1 schedule. However, performance under a progressive ratio (PR schedule increased in morphine-treated rats reinforced with 60% sucrose solution, but not in those reinforced with sucrose concentrations lower than 60%. Pretreatment with morphine significantly decreased the male rats’ ejaculation frequency during the 1-hour copulation testing, and impaired the maintenance of appetitive motivations to sexual and social stimuli under a free-approach condition. Moreover, the morphine-treated rats demonstrated a diminished motivation to approach social stimulus in the effort-based appetitive behavior test but showed a remarkable increase in motivation to approach sexual stimulus in the risky appetitive behavior test. These results demonstrated some complex motivated behaviors following about one week of morphine withdrawal: (1 The anhedonia-like behavior was consistently found in animals withdrawn from morphine. However, for a given reward, there was often a dissociation of the consummatory behaviors from the motivational behaviors, and whether the consummatory or the motivational anhedonia-like behaviors could be discovered heavily depended on the type and magnitude of the reward and the type

  4. 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...... 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...

  5. Effects of morphine in the isolated mouse urinary bladder.

    Science.gov (United States)

    Acevedo, C G; Tamayo, L; Contreras, E

    1986-01-01

    Acute morphine increased the responses to acetylcholine of the isolated mouse urinary bladder. A chronic morphine treatment did not change the responses of the urinary bladder to acetylcholine or ATP. The acute administration of morphine did not modify the contractile response to ATP in the urinary bladders from untreated or chronically morphine treated mice. Methadone and ketocyclazocine decreased the responses to the electrical stimulation of the urinary bladder. These depressant effects were not modified by naloxone. The results suggest the nonexistence of opiate receptors in the mouse urinary bladder and the lack of direct effects of morphine on the neuroeffector junction.

  6. Evaluation of safety profile of black shilajit after 91 days repeated administration in rats

    Institute of Scientific and Technical Information of China (English)

    Velmurugan C; Vivek B; Wilson E; Bharathi T; Sundaram T

    2012-01-01

    Objective: To evaluate the safety of shilajit by 91 days repeated administration in different dose levels in rats. Methods: In this study the albino rats were divided into four groups. Group I received vehicle and group II, III and IV received 500, 2500 and 5000 mg/kg of shilajit, respectively. Finally animals were sacrificed and subjected to histopathology and iron was estimated by flame atomic absorption spectroscopy and graphite furnace. Results: The result showed that there were no significant changes in iron level of treated groups when compared with control except liver (5000 mg/kg) and histological slides of all organs revealed normal except negligible changes in liver and intestine with the highest dose of shilajit. The weight of all organs was normal when compared with control. Conclusions: The result suggests that black shilajit, an Ayurvedic formulation, is safe for long term use as a dietary supplement for a number of disorders like iron deficiency anaemia.

  7. Anxiolytic profile of fluoxetine as monitored following repeated administration in animal rat model of chronic mild stress

    Directory of Open Access Journals (Sweden)

    Muhammad Farhan

    2016-09-01

    Full Text Available Background: Fluoxetine, a selective serotonin re-uptake inhibitor (SSRI, has been proposed to be more effective as an antidepressive drug as compared to other SSRIs. After chronic SSRI administration, the increase in synaptic levels of 5-HT leads to desensitization of somatodentritic 5-HT autoreceptors in the raphe nuclei. Chronic stress may alter behavioral, neurochemical and physiological responses to drug challenges and novel stressors. Methods: Twenty four male rats were used in this study. Animals of CMS group were exposed to CMS. Animals of stressed and unstressed group were administrated with fluoxetine at dose of 1.0 mg/kg s well as 5.0 mg/kg repeatedly for 07 days 1 h before exposed to CMS. The objective of the present study was to evaluate that repeated treatment with fluoxetine could attenuate CMS-induced behavioral deficits. Results: Treatment with fluoxetine attenuated CMS-induced behavioral deficits. Fluoxetine administration induced hypophagia in unstressed as well as CMS rats. Acute and repeated administration of fluoxetine increased motor activity in familiar environment but only repeated administration increased exploratory activity in open field. Anxiolytic effects of fluoxetine were greater in unstressed rats. These anxiolytic effects were produced as result of repeated administration not on acute administration of fluoxetine at 1.0 mg/kg as well as 5.0 mg/kg. Conclusion: The present study demonstrated that CMS exposure resulted into behavioral deficits and produced depressive-like symptoms. Fluoxetine, an SSRI, administration attenuated behavioral deficits induced by CMS. Anxiolytic effects of repeated fluoxetine administration were greater in unstressed than CMS animals.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    2009-01-01

    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. PMID:19930722

  10. Effects of denervation on the sensitizing effect to noradrenaline induced by morphine in the vas deferens of mice treated chronically with morphine.

    Science.gov (United States)

    Contreras, E; Tamayo, L; Gaete, S; Juica, S

    1982-08-01

    The acute administration of morphine to the isolated vas deferens from mice chronically exposed to this analgesic, induced a facilitatory effect on the responses of the muscle to exogenous noradrenaline. It has been suggested that this sensitizing property of morphine might reflect a dependence-like state of the vas deferens. In the present paper, the capability of met- and leu-enkephalin to substitute for morphine was studied, as well as the influence of innervation on the apparent dependence state. The contractile responses to noradrenaline and to acetylcholine were increased after the administration of morphine to the bath containing a denervated vas deferences, prepared from chronically morphinized mice. Morphine administration facilitated noradrenaline- but not acetylcholine-induced contractile effects in vas deferens isolated from mice which had been chronically treated with either morphine or morphine plus guanethidine. The presence of met- or leu-enkephalin in the isolated vas deferens from chronically morphinized mice (either intact, denervated or treated with guanethidine) failed to sensitize contractile responses to noradrenaline or acetylcholine. It is concluded that (a) the sensitizing effect induced by morphine in the vas deferens from mice chronically treated with morphine is specific for the adrenergic neurotransmitter; (b) the effect of morphine is not mimicked by opiate peptides; and (c) denervation of the vas deferens of mice treated chronically with morphine does not suppress the noradrenaline-sensitizing property of morphine.

  11. The inhibition of cocaine-induced locomotor activity by CART 55-102 is lost after repeated cocaine administration.

    Science.gov (United States)

    Job, Martin O; Shen, Li L; Kuhar, Michael J

    2013-08-29

    CART peptide is known for having an inhibitory effect on cocaine- and dopamine-mediated actions after acute administration of cocaine and dopamine. In this regard, it is postulated to be a homeostatic, regulatory factor on dopaminergic activity in the nucleus accumbens (NAc). However, there is no data on the effect of CART peptide after chronic administration of cocaine, and this study addresses this. It was found that CART peptide blunted cocaine-induced locomotion (LMA) after acute administration of cocaine, as expected, but it did not affect cocaine-mediated LMA after chronic administration of cocaine. The loss of CART peptide's inhibitory effect did not return for up to 9 weeks after stopping the repeated cocaine administration. It may not be surprising that homeostatic regulatory mechanisms in the NAc are lost after repeated cocaine administration, and that this may be a mechanism in the development of addiction.

  12. Penetration of prulifloxacin into gynaecological tissues after single and repeated oral administrations.

    Science.gov (United States)

    Gorlero, Franco; Lorenzi, Paola; Rosignoli, Maria Teresa; Picollo, Rossella; Ruggieri, Alessandro; Barattè, Simona; Dionisio, Paolo

    2007-01-01

    This study aimed to evaluate the penetration into gynaecological tissues of ulifloxacin, the active metabolite of prulifloxacin, a once-daily fluoroquinolone administered once or in repeated doses. This was an open-label, randomised study that included 20 consenting female inpatients (age range 40-65 years) requiring total simple hysterectomy as a result of benign disease. Three groups of patients were enrolled: group A (four patients whose gynaecological tissue samples were used to set up the bioanalytical method); group B (eight patients treated 3 hours before surgery with one 600 mg tablet of prulifloxacin); group C (eight patients treated with prulifloxacin 600 mg once daily for 3 days and undergoing surgery 3 hours after the last dose). Patients to be treated with prulifloxacin were randomly allocated to group B or C. During surgery, samples of blood were collected jointly with healthy tissue removed from the endometrium, proximal fallopian tube, vaginal posterior fornix and portio vaginalis. Ulifloxacin concentrations in plasma and gynaecological tissues were determined by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method. An intrastudy assessment of the bioanalytical method performance was also conducted for plasma and tissues using calibration and quality control data (spiked samples). Ulifloxacin mean concentrations were always higher in group C than in group B patients, both in plasma (0.76 vs 0.53 microg/mL) and in gynaecological tissues, namely fallopian tube (1.38 vs 0.81 microg/g), posterior fornix (1.48 vs 1.05 microg/g), portio vaginalis (1.46 vs 1.45 microg/g) and endometrium (2.20 vs 1.39 microg/g), as expected after repeated drug administrations. Tissue concentrations observed after repeated administrations were generally higher than the ulifloxacin minimum inhibitory concentrations for pathogens more frequently involved in gynaecological bacterial infections. The mean tissue/plasma ratios ranged between 1.5 and

  13. Thalidomide Promotes Morphine Efficacy and Prevents Morphine-Induced Tolerance in Rats with Diabetic Neuropathy.

    Science.gov (United States)

    Zhao, Jianhui; Wang, Hong; Song, Tieying; Yang, Yunliang; Gu, Kunfeng; Ma, Pengyu; Zhang, Zaiwang; Shen, Limin; Liu, Jiabao; Wang, Wenli

    2016-12-01

    Opioid analgesics have less efficacy in diabetic neuropathy treatment, and tolerance often occurs after chronic usage. Given that thalidomide can potentiate the morphine efficacy in diabetic neuropathy treatment, we investigated the effects of intrathecal administrations of thalidomide on morphine tolerance during the treatment of diabetic neuropathy. We found that intrathecal administrations of thalidomide (25 mg/kg/ml) potentiated the analgesic effects of morphine on mechanical hyperalgesia and prevented the development of morphine tolerance. While this treatment regimen did not alter the protein levels of μ-opioid receptor (MOR) in the spinal cord of diabetic rats, chronic morphine treatment robustly increased MOR binding density in the synaptic plasma membranes fraction, but decreased it in the microsomal fraction. Furthermore, thalidomide was able to reverse the distribution of MOR altered by chronic morphine treatment. Finally, STZ-induced diabetes promoted PKC activation and enhanced TNFα level in the spinal cord, which were attenuated by intrathecal administrations of thalidomide. Taken together, these results suggested that thalidomide may potentiate morphine efficacy on diabetic neuropathy and prevent the development of morphine tolerance by suppressing PKC activation and TNFα level in the spinal cord.

  14. Distribution and excretion of arsenic in cynomolgus monkey following repeated administration of diphenylarsinic acid

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, Yayoi [National Institute for Environmental Studies, Environmental Health Sciences Division, Tsukuba, Ibaraki (Japan); Negishi, Takayuki [Aoyama Gakuin University, Department of Chemistry and Biological Science, Tokyo (Japan); Mizumura, Ayano; Watanabe, Takayuki [Chiba University, Graduate School of Pharmaceutical Sciences, Chiba (Japan); Hirano, Seishiro [Chiba University, Graduate School of Pharmaceutical Sciences, Chiba (Japan); National Institute for Environmental Studies, Research Center for Environmental Risk, Tsukuba, Ibaraki (Japan)

    2008-08-15

    Diphenylarsinic acid (DPAA), a possible product of degradation of arsenic-containing chemical weapons, was detected in well water in Kamisu City, Ibaraki Prefecture, Japan, in 2003. Although some individuals in this area have been affected by drinking DPAA-containing water, toxicological findings on DPAA are limited. To elucidate the mechanism of its toxicity, it is necessary to determine the metabolic behavior of DPAA in the body. In this study, pregnant cynomolgus monkeys at the 50th day of pregnancy were used. The monkeys were treated daily with 1.0 mg DPAA/kg body weight using a nasogastric tube, and the distribution and excretion of arsenic were examined after the repeated administration and 198-237 days after the last administration of DPAA. Fecal excretion was higher than urinary excretion (ca. 3:2 ratio), and arsenic accumulated in the hair and erythrocytes. Distribution of DAPP to plasma and hemolyzed erythrocytes was also examined by high-performance liquid chromatography-inductively coupled argon plasma mass spectrometry (HPLC-ICP MS). Two peaks were found in the elution profile of arsenic, due to free and probably protein-bound DPAA. The protein-bound arsenic compounds were presumably trivalent diphenylarsenic compounds, since free DPAA was recovered after treatment of heat-denatured samples with hydrogen peroxide. (orig.)

  15. [Repeated perioperative administration of fructose and sorbitol in a female patient with hereditary fructose intolerance [HFI)].

    Science.gov (United States)

    Sachs, M; Asskali, F; Förster, H; Encke, A

    1993-03-01

    The present paper reports on an adult female patient whose hereditary fructose intolerance (HFI) was at first not diagnosed and who, within the space of 2 years after repeated elective surgery and the perioperative administration of fructose and sorbitol, developed "hepatic and renal failure of unclear origin." At a later stage we were able to establish the diagnosis of HFI by means of a fructose tolerance test in both she and her brother, for whom intolerance to fruit and desserts had been known since early childhood. In addition, literature references to fatalities following the parenteral application of fructose and sorbitol were analyzed. During the course of fructose infusion in both the patient and her brother with HFI, the following metabolic changes were noted: hypoglycemia, elevated rise in the blood fructose concentration, hyperlactacidemia, elevated rise in the blood fructose concentration, hyperlactacidemia, and hyperammonemia. These metabolic changes proved to be reversible after discontinuing the fructose infusion. Analysis of the literature on the fatalities following parenteral fructose administration established that fruit and dessert intolerance was known for all collated patients with HFI, and that, clearly, no regular metabolic tests had been conducted.

  16. Intrathecal PLC(β3) oligodeoxynucleotides antisense potentiates acute morphine efficacy and attenuates chronic morphine tolerance.

    Science.gov (United States)

    Quanhong, Zhou; Ying, Xue; Moxi, Chen; Tao, Xu; Jing, Wang; Xin, Zhang; Li, Wang; Derong, Cui; Xiaoli, Zhang; Wei, Jiang

    2012-09-07

    Morphine is a mainstay for chronic pain treatment, but its efficacy has been hampered by physical tolerance. The underlying mechanism for chronic morphine induced tolerance is complicated and not well understood. PLC(β3) is regarded as an important factor in the morphine tolerance signal pathway. In this study, we determined intrathecal (i.t.) administration of an antisense oligodeoxynucleotide (ODN) of PLC(β3) could quicken the on-set antinociceptive efficacy of acute morphine treatment and prolong the maximum effect up to 4h. The antisense could also attenuate the development of morphine-induced tolerance and left shift the ED50 after 7 day of coadministration with morphine. These results probably were contributed by the PLC(β3) antisense ODN as they successfully knocked down protein expression levels and reduced activity of PLC(β3) in spinal cord in rats. The mismatch group had no such effects. The results confirmed the important involvement of PLC(β3) in both acute morphine efficacy and chronic morphine tolerance at spinal level in rats. This study may provide an idea for producing a novel adjuvant for morphine treatment.

  17. Repeated otilonium bromide administration prevents neurotransmitter changes in colon of rats underwent to wrap restraint stress.

    Science.gov (United States)

    Traini, Chiara; Evangelista, Stefano; Girod, Vincent; Faussone-Pellegrini, Maria Simonetta; Vannucchi, Maria Giuliana

    2017-04-01

    Otilonium bromide (OB) is a spasmolytic drug successfully used for the treatment of irritable bowel syndrome (IBS). Its efficacy has been attributed to the block of L- and T-type Ca(2+) channels and muscarinic and tachykinin receptors in the smooth muscle. Furthermore, in healthy rats, repeated OB administration modified neurotransmitter expression and function suggesting other mechanisms of action. On this basis, we investigated whether repeated OB treatment prevented the functional and neurochemical changes observed in the colon of rats underwent to wrap restrain stress (WRS) a psychosocial stressor considered suitable to reproduce the main IBS signs and symptoms. In control, WRS and OB/WRS rats functional parameters were measured in vivo and morphological investigations were done ex vivo in the colon. The results showed that OB counteracts most of the neurotransmitters changes caused by WRS. In particular, the drug prevents the decrease in SP-, NK1r-, nNOS-, VIP-, and S100β-immunoreactivity (IR) and the increase in CGRP-, and CRF1r-IR. On the contrary, OB does not affect the increase in CRF2r-IR neurons observed in WRS rats and does not interfere with the mild mucosal inflammation due to WRS. Finally, OB per se increases the Mr2 expression in the muscle wall and decreases the number of the myenteric ChAT-IR neurons. Functional findings show a significantly reduction in the number of spontaneous abdominal contraction in OB treated rats. The ability of OB to block L-type Ca(2+) channels, also expressed by enteric neurons, might represent a possible mechanism through which OB exerts its actions. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  18. Morphine: Myths and Reality

    Science.gov (United States)

    ... and Families Take the Quiz Morphine: Myths and Reality February, 2013 The mere mention of “Morphine” can ... due to misinformation and lack of training. The reality is that Morphine (and other opiates that work ...

  19. A dual action of valproic acid upon morphine analgesia and morphine withdrawal.

    Science.gov (United States)

    Tamayo, L; Contreras, E

    1983-01-01

    Effects of valproic acid administration on morphine analgesia and on morphine tolerance and dependence were investigated in mice. Valproate increased the reaction time to thermal stimulation in naive animals. This effect was additive with morphine when valproate was administered shortly before the analgesic. However, an antagonism was observed if a 4-hour period elapsed between valproate and morphine administration. When administered to mice receiving a sustained release preparation of morphine, valproate antagonized the development of tolerance to morphine. Valproate elicited a dual action on the abstinence signs observed after naloxone administration in morphine-treated mice. The effect consisted in a reduction of abstinence behavior if the anticonvulsant was administered a few minutes before naloxone; the same treatment increased the severity of the abstinence behavior when valproate was injected 1 h before the precipitating dose of naloxone. In this latter schedule, concomitant administration of gamma-vinyl-GABA failed to reduce the severity of the convulsions observed during the abstinence syndrome. These results suggest that valproate is metabolized to a compound responsible for decreased analgesia and intensified withdrawal signs.

  20. Pharmacokinetics of marbofloxacin in lactating cows after repeated intramuscular administrations and pharmacodynamics against mastitis isolated strains.

    Science.gov (United States)

    Schneider, M; Vallé, M; Woehrlé, F; Boisramé, B

    2004-01-01

    The plasma and milk pharmacokinetics of marbofloxacin, a fluoroquinolone antibacterial compound, were evaluated in dairy cows, as well as its pharmacodynamic characteristics against mastitis-isolated pathogens. Marbofloxacin was given intramuscularly as a 10% aqueous solution to dairy cows either at a single dose or at repeated doses of 2 mg/kg once daily for 3 d. Blood and milk samples were collected for the determination of the concentration of marbofloxacin and of its putative metabolites: N-desmethyl-marbofloxacin and N-oxide-marbofloxacin. Bacterial field isolates were from milk samples collected from dairy cows suspected of having an intramammary infection. After identification, the minimal inhibitory concentration (MIC) was determined against the isolated strains. The maximal marbofloxacin concentration (Cmax) observed in milk after the first administration was 1.024 microg/mL, and the area under the curve during the first dosing interval was 6.513 microg/h per milliliter. After the third administration, these parameters were slightly increased (about 20% at most). Both metabolites were detected in the milk, but their concentrations were below the limit of quantification. The MIC against 90% of the population (MIC90) of Escherichia coli was 0.016 microg/mL, and it was 0.229 microg/mL against Staphylococcus aureus. The following surrogate clinical outcome markers were obtained against E. coli strains: a Cmax/MIC ratio of 67 and an area under the curve/MIC ratio of 407 h. Hence, a possible efficacy of marbofloxacin in the treatment of E. coli-induced mastitis could be expected as the endpoints of 10 and 250 h, respectively, are reached.

  1. Calcium channel antagonists increase morphine-induced analgesia and antagonize morphine tolerance.

    Science.gov (United States)

    Contreras, E; Tamayo, L; Amigo, M

    1988-04-13

    The influence of calcium channel blockers on morphine-induced analgesia and on tolerance to the chronic administration of the opiate was investigated in mice. The effects of a test dose of morphine were significantly increased by the administration of diltiazem, flunarizine, nicardipine and verapamil. In contrast, nifedipine induced an antagonistic effect. The calcium channel antagonists did not change the reaction time to thermal stimulation in mice (hot plate test). The administration of nifedipine, flunarizine and verapamil reduced the intensity of the tolerance induced by a single dose of morphine administered in a slow release preparation. Diltiazem induced a non-significant decrease of the process. The present results are in accordance with the known interaction of acute and chronic morphine administration with the intracellular calcium concentration in neurones of the central nervous system.

  2. Morphine Sulphate Toxicity on Liver Function Tests in Fructose-Induced Insulin Resistant Male Rats

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Shahraki

    2014-02-01

    Full Text Available Background: Since liver is a gland which has an important role in drug metabolism, the present study was conducted to evaluate the effect of a single dose and repeated administration of morphine on LFT, blood sugar and fasting insulin resistance index in fructose- fed male rats. Materials and Methods: The experiment was performed on 36 Wistar-Albino male rats, which were divided into a control (A and three tests groups (B, C and D. The control group consumed tap water, but the test groups consumed fructose-enriched water (10%, w/v and received null, single, and repeated doses of morphine, respectively. At the end, animals were anesthetized and blood samples were collected. Liver enzymes, insulin and insulin resistance were measured. Data were analyzed by SPSS-11, using ANOVA and Tukey tests as post hoc test. Results were expressed as mean±SD and Statistical differences were recognized significant by p<0.05. Results: The results showed that all test groups were insulin resistant; alanine aminotransferase (ALT and asparatate aminotransferase (AST activity values in group D significantly increased compared to other groups while its plasma glucose and insulin values showed a significant decrease in comparison to other test groups. Conclusion: It seems that repeated morphine administration can affect liver function test (LFT and fasting Insulin resistance index (FIRI in fructose- fed male rats.

  3. Mice with neuropathic pain exhibit morphine tolerance due to a decrease in the morphine concentration in the brain.

    Science.gov (United States)

    Ochiai, Wataru; Kaneta, Mitsumasa; Nagae, Marina; Yuzuhara, Ami; Li, Xin; Suzuki, Haruka; Hanagata, Mika; Kitaoka, Satoshi; Suto, Wataru; Kusunoki, Yoshiki; Kon, Risako; Miyashita, Kazuhiko; Masukawa, Daiki; Ikarashi, Nobutomo; Narita, Minoru; Suzuki, Tsutomu; Sugiyama, Kiyoshi

    2016-09-20

    The chronic administration of morphine to patients with neuropathic pain results in the development of a gradual tolerance to morphine. Although the detailed mechanism of this effect has not yet been elucidated, one of the known causes is a decrease in μ-opioid receptor function with regard to the active metabolite of morphine, M-6-G(morphine-6-glucuronide), in the ventrotegmental area of the midbrain. In this study, the relationship between the concentration of morphine in the brain and its analgesic effect was examined after the administration of morphine in the presence of neuropathic pain. Morphine was orally administered to mice with neuropathic pain, and the relationship between morphine's analgesic effect and its concentration in the brain was analysed. In addition, the expression levels of the conjugation enzyme, UGT2B (uridine diphosphate glucuronosyltransferase), which has morphine as its substrate, and P-gp, which is a transporter involved in morphine excretion, were examined. In mice with neuropathic pain, the concentration of morphine in the brain was significantly decreased, and a correlation was found between this decrease and the decrease in the analgesic effect. It was considered possible that this decrease in the brain morphine concentration may be due to an increase in the expression level of P-gp in the small intestine and to an increase in the expression level and binding activity of UGT2B in the liver. The results of this study suggest the possibility that a sufficient analgesic effect may not be obtained when morphine is administered in the presence of neuropathic pain due to a decrease in the total amount of morphine and M-6-G that reach the brain. Copyright © 2016. Published by Elsevier B.V.

  4. Implication of DOP2 but not DOP1 in development of morphine analgesic tolerance in a rat model of chronic inflammatory pain

    Science.gov (United States)

    Beaudry, H.; Gendron, L.; Morón, Jose A.

    2014-01-01

    Opioids are well known for their robust analgesic effects. Chronic activation of mu opioid receptors (MOPs) is however accompanied by various unwanted effects such as analgesic tolerance. Among other mechanisms, interactions between MOP and delta opioid receptor (DOP) are thought to play an important role in morphine-induced behavioral adaptations. Interestingly, certain conditions such as inflammation enhance the function of the DOP through a MOP-dependent mechanism. Here, we investigated the role of DOP during the development of morphine-tolerance in an animal model of chronic inflammatory pain. Using behavioral approaches we first established that repeated systemic morphine treatment induces morphine analgesic tolerance in rats coping with chronic inflammatory pain. We then observed that blockade of DOP with subcutaneous naltrindole (NTI), a selective DOP antagonist, significantly attenuates the development of morphine tolerance in a dose-dependent manner. We confirmed that this effect was DOP-mediated by showing that an acute injection of NTI had no effect on morphine-induced analgesia in naïve animals. Previous pharmacological characterizations revealed the existence of DOP1 and DOP2 subtypes. As opposed to NTI, 7-benzylidenenaltrexone (BNTX) and naltriben (NTB) were reported to be selective DOP1 and DOP2 antagonists, respectively. Interestingly, NTB but not BNTX was able to attenuate the development of morphine analgesic tolerance in inflamed rats. Altogether, our results suggest that targeting of DOP2 with antagonists provides a valuable strategy to attenuate the analgesic tolerance that develops after repeated morphine administration in the setting of chronic inflammatory pain. PMID:25639561

  5. AMN082, a metabotropic glutamate receptor 7 allosteric agonist, attenuates locomotor sensitization and cross-sensitization induced by cocaine and morphine in mice.

    Science.gov (United States)

    Jenda, M; Gawel, K; Marszalek, M; Komsta, L; Kotlinska, J H

    2015-03-03

    Previous studies have indicated that metabotropic glutamate receptors 7 (mGluR7s) are involved in drug addiction. However, the role of these receptors in drug-induced behavioral sensitization is unknown. The aim of the present study was to determine whether systemic injection of AMN082, a selective mGluR7 allosteric agonist, reduces the cocaine- and morphine-induced hyperactivity and the development and expression of locomotor sensitization, and also affects the reciprocal cross-sensitization to the stimulant effect of cocaine and morphine in mice. AMN082 (1.25-10.0 mg/kg, i.p.) did not have an impact on locomotion of naive mice and did not affect the acute cocaine- or morphine-induced hyperactivity, except the dose of 10 mg/kg that suppressed the locomotor effect of both drugs. Repeated exposure to cocaine or morphine (10 mg/kg, 5× every 3 days) gradually increased locomotion during induction of sensitization and after 4 (cocaine) or 7 day (morphine) withdrawal phase when challenged with cocaine (10 mg/kg, i.p.) or morphine (10 mg/kg, i.p.) on day 17 or 20, respectively. Pretreatment of animals with the lower doses of AMN082 (1.25-5.0 mg/kg, i.p.), 30 min before every cocaine or morphine injection during repeated drug administration or before cocaine or morphine challenge, dose-dependently attenuated the development, as well as the expression of cocaine or morphine locomotor sensitization. AMN082 also inhibited the reciprocal cross-sensitization between these drugs. Prior to administration of MMPIP (10 mg/kg, i.p.), a selective mGluR7 antagonist reversed the inhibitory effect of AMN082 on the development or expression of cocaine or morphine sensitization. These data indicate that AMN082 attenuated the development and expression of cocaine and morphine sensitization, and the reciprocal cross-sensitization via a mechanism that involves mGluR7s. Thus, AMN082 might have therapeutic implications not only in the treatment of cocaine or opioid addiction but also in the

  6. Orexin A-mediated AKT signaling in the dentate gyrus contributes to the acquisition, expression and reinstatement of morphine-induced conditioned place preference.

    Science.gov (United States)

    Guo, Sui-Jun; Cui, Yu; Huang, Zhen-Zhen; Liu, Huan; Zhang, Xue-Qin; Jiang, Jin-Xiang; Xin, Wen-Jun

    2016-05-01

    Accumulating evidence indicates that the hippocampal dentate gyrus (DG), a critical brain region contributing to learning and memory, is involved in the addiction and relapse to abused drugs. Emerging studies also suggest the role of orexin signaling in the rewarding behavior induced by repeated exposure to opiates. In the present study, we investigated the dynamic adaptation of orexin signaling in the DG and its functional significance in the acquisition, expression, maintenance of and relapse to rewarding behavior induced by morphine. Repeated place conditioning with morphine significantly increased the orexin A content released from the lateral hypothalamic area projecting neurons into the DG. Local infusions of orexin A into the DG sensitized the acquisition of and relapse to the conditioned place preference induced by morphine. The application of the orexin receptor type 1 (OXR1) antagonist SB334867 significantly abolished the acquisition, expression and maintenance of the conditioned place preference induced by repeated exposure to morphine. Furthermore, the significant increase of the phosphorylation of AKT in the DG was associated with preference for the morphine-paired chamber in rats, which was reversed by the local administration of an OXR1 antagonist. Thus, these findings suggested that the dynamic upregulation of orexin A signaling, via the AKT pathway in the DG, may promote the acquisition and maintenance of opioid-induced craving behaviors and may increase sensitivity to the rewarding effect of subsequent opioids.

  7. Modulation of morphine-induced antinociception by ibogaine and noribogaine.

    Science.gov (United States)

    Bagal, A A; Hough, L B; Nalwalk, J W; Glick, S D

    1996-11-25

    The potential modulation of morphine antinociception by the putative anti-addictive agent ibogaine and its active metabolite (noribogaine) was investigated in rats with the radiant heat tail-flick test. Ibogaine pretreatment (40 mg/kg, i.p., 19 h) significantly decreased morphine (4 mg/kg, s.c.) antinociception, with no effects in the absence of morphine. However, co-administration of ibogaine (1-40 mg/kg, i.p.) and morphine (4 mg/kg, s.c.) exhibited a dose-dependent enhancement of morphine antinociception. Co-administration of noribogaine (40 mg/kg, i.p.) and morphine also resulted in an increase in morphine antinociception, while noribogaine pretreatment (19 h) had no effect on morphine antinociception. The results show that ibogaine acutely potentiates morphine antinociception and that noribogaine could be the active metabolite responsible for this effect. However, the inhibitory effects of a 19 h ibogaine pretreatment, which resemble ibogaine-induced inhibition of morphine's stimulant properties, cannot be accounted for by noribogaine.

  8. Morphine sulphation in children.

    OpenAIRE

    Choonara, I.; Ekbom, Y; Lindström, B; Rane, A.

    1990-01-01

    The metabolism of morphine was studied in nine children and seven preterm neonates receiving a continuous infusion of morphine. All the neonates and three children had detectable concentrations of morphine-3-sulphate (M3S) in urine. None of the neonates or the children had detectable concentrations of morphine-6-sulphate (M6S) in urine. None of the children had detectable concentrations of M3S in plasma. The M3S/morphine ratios were significantly higher in neonates than children (P less than ...

  9. Human gliomas contain morphine

    DEFF Research Database (Denmark)

    Olsen, Peter; Rasmussen, Mads; Zhu, Wei

    2005-01-01

    morphine via high pressure liquid chromatography (HPLC). The HPLC peak corresponding to an authentic morphine standard had its morphine level determined via radioimmune assay. The identity of this material was established by Q-TOF-MS analysis. RESULTS: Each glioma exhibited an endogenous morphine presence....... Tumor extractions demonstrated a molecular mass of 286.14 da, identical to authentic morphine. Subsequent fragmentation analysis of this molecule revealed fragment masses of 129.01 da, 183.09 da and 201.07 da, corresponding to authentic morphine fragments. This material was not found in any......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...

  10. Repeated oral administration of chitosan/DNA nanoparticles delivers functional FVIII with the absence of antibodies in hemophilia A mice.

    Science.gov (United States)

    Dhadwar, S S; Kiernan, J; Wen, J; Hortelano, G

    2010-12-01

    Current treatment of hemophilia A is expensive and involves regular infusions of factor (F)VIII concentrates. The supply of functional FVIII is further compromised by the generation of neutralizing antibodies. Thus, the development of an alternative safe, cost effective, non-invasive treatment that circumvents immune response induction is desirable. To evaluate the feasibility of oral administration of chitosan nanoparticles containing FVIII DNA to provide sustainable FVIII activity in hemophilia A mice. Nanoparticles were characterized for morphology, DNA protection and transfection efficiency. Oral administration of nanoparticles containing canine FVIII in C57Bl/6 FVIII(-/-) hemophilia A mice was evaluated for biodistribution, plasma FVIII activity and phenotypic correction. Sustainable FVIII expression was elucidated after repeated nanoparticle administration. Immune responses to repeated oral nanoparticle administration were also investigated. Chitosan nanoparticles had a particle size range of 200-400 nm and protected DNA from endonuclease and pH degradation. In addition, nanoparticles transfected HEK 293 cells resulted in expression of eGFP, luciferase and FVIII. Hemophilia A mice that ingested chitosan nanoparticles demonstrated transient canine FVIII expression reaching > 100 mU 1 day after treatment, together with partial phenotypic correction. The delivered FVIII plasmid DNA was detected in the intestine and, to a lesser extent, in the liver. Importantly, repeated weekly administrations restored FVIII activity. Furthermore, inhibitors and non-neutralizing FVIII antibodies were not detectable. Repeat oral administration of FVIII DNA formulated in chitosan nanoparticles resulted in sustained FVIII activity in hemophilic mice, and thus may provide a non-invasive alternative treatment for hemophilia A. © 2010 International Society on Thrombosis and Haemostasis.

  11. Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration.

    Science.gov (United States)

    Kenward, Hannah; Pelligand, Ludovic; Elliott, Jonathan

    2014-08-01

    Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.

  12. Effects of ketamine and midazolam on morphine induced dependence and tolerance in mice

    OpenAIRE

    Bohlul Habibi Asl Kambiz Hassanzadeh

    2004-01-01

    The aim of this study was to investigate the effects of ketamine and midazolam on prevention of the development of morphine tolerance and dependence in mice. Different groups of mice received morphine (50 mg/kg, sc), morphine (50 mg/kg, sc) + ketamine (25,50,75 mg/kg, ip), morphine (50 mg/kg, sc) + midazolam (0.5,1,2 mg/kg, ip) , morphine (50 mg/kg , sc) + ketamine (50 mg/kg, ip) + midazolam (1 mg/kg, ip) once a day for four days. Tolerance was assessed by administration of morphine (9 mg/kg,...

  13. Morphine metabolism in human skin microsomes.

    Science.gov (United States)

    Heilmann, S; Küchler, S; Schäfer-Korting, M

    2012-01-01

    For patients with severe skin wounds, topically applied morphine is an option to induce efficient analgesia due to the presence of opioid receptors in the skin. However, for topical administration it is important to know whether the substance is biotransformed in the skin as this can eventually reduce the concentration of the active agent considerably. We use skin microsomes to elucidate the impact of skin metabolism on the activity of topically applied morphine. We are able to demonstrate that morphine is only glucuronidated in traces, indicating that the biotransformation in the skin can be neglected when morphine is applied topically. Hence, there is no need to take biotransformation into account when setting up the treatment regimen.

  14. Intrahippocampal administration of D2 but not D1 dopamine receptor antagonist suppresses the expression of conditioned place preference induced by morphine in the ventral tegmental area.

    Science.gov (United States)

    Haghparast, Abbas; Esmaeili, Mohammad-Hossein; Taslimi, Zahra; Kermani, Mojtaba; Yazdi-Ravandi, Saeid; Alizadeh, Amir-Mohammad

    2013-04-29

    The ventral tegmental area (VTA) as a major source of dopamine neurons projecting to cortical and limbic regions has a crucial role in reward and addiction. The current study assessed the role of D1 and D2 receptors within the dorsal hippocampus (CA1) in the expression of conditioned place preference (CPP) by intra-VTA morphine in the rats. In the present study, 160 adult male albino Wistar rats weighing 220-290g were bilaterally implanted by two cannulae into the CA1 and VTA. The CPP paradigm was done and animal displacement, conditioning score and locomotor activity were recorded. For blocking the dopamine D1/D2 receptors in the dorsal hippocampus, SCH23390 (0.02, 0.05, 0.2 and 0.5μg per side) or sulpiride (0.25, 0.75, 1.5 and 3μg per side) were microinjected into the CA1, just 5min before the CPP test on the post-conditioning day. All animals received intra-VTA morphine (1μg per side) during 3-days conditioning phase. Our results showed that sulpiride (1.5 and 3μg) but not SCH23390 in the dorsal hippocampus significantly decreased the expression of CPP induced by intra-VTA morphine (phippocampus have a key role in the expression of CPP induced by morphine at the level of the VTA and there is a relationship between dopaminergic D2 receptors and opioidergic systems in these areas in reward circuit.

  15. Vértigo con nistagmo vertical por administración de morfina intratecal y reversión con naloxona Vertigo and vertical nystagmus associated with intrathecal morphine administration and resolution by naloxone

    Directory of Open Access Journals (Sweden)

    Jorge De All

    2011-10-01

    Full Text Available La anestesia regional combinada es utilizada frecuentemente como herramienta para el tratamiento del dolor postoperatorio. Los efectos secundarios de los opioides utilizados por esta vía son similares a los que se presentan luego de la administración sistémica. La aparición de vértigo con nistagmo vertical es un efecto adverso muy pocas veces descripto con el uso de morfina por vía intratecal, epidural o endovenosa. Comunicamos el caso de un paciente que presentó esta complicación en el postoperatorio de una nefrectomía parcial, luego de la administración de morfina intratecal, con resolución completa mediante el uso de naloxona endovenosa.Combined regional anesthesia is frequently used as a tool for management of postoperative pain. The profile of side effects of the opioids used via this route is similar to those occurring after systemic administration. The onset of vertigo with vertical nystagmus is an adverse effect rarely described after the use of intrathecal, epidural or intravenous morphine. We report the case of a patient who presented this complication in the postoperative period of a partial nephrectomy, after the administration of intrathecal morphine, with complete resolution by intravenous naloxone.

  16. Evidence that behavioral phenotypes of morphine in β-arr2-/- mice are due to the unmasking of JNK signaling.

    Science.gov (United States)

    Mittal, Nitish; Tan, Miao; Egbuta, Onyemachi; Desai, Nina; Crawford, Cynthia; Xie, Cui-Wei; Evans, Christopher; Walwyn, Wendy

    2012-07-01

    The altered behavioral effects of morphine, but not most other mu agonists, in mice lacking β-arrestin 2, suggest that this scaffolding protein regulates the signaling cascade of this commonly used analgesic. One of the cascades that could be regulated by β-arrestin 2 is cJun-N-terminal kinase (JNK), which binds with β-arrestin 2 and modulates the analgesic effects of morphine. Using neurons lacking β-arrestin 2 (β-arr2-/-) to examine this interaction, we found that β-arr2-/- neurons show altered intracellular distribution of JNK and cJun, and that morphine, but not fentanyl, increased the nuclear localization of the phosphorylated, therefore activated, form of cJun, a JNK target in dorsal root ganglia neurons. This suggests that deleting β-arrestin 2 affects the JNK cascade. We therefore examined whether some of the behavioral phenotypes of mice lacking β-arrestin 2 could be a result of altered JNK signaling. Indeed, two different JNK inhibitors reversed the enhanced analgesic effect of morphine, a known phenotype of β-arr2-/- mice, to +/+ levels. Both the reduced locomotor effect of morphine and the psychomotor sensitization to repeated morphine administration in β-arr2-/- mice were also returned to +/+ levels by inhibiting JNK. In contrast, the behavioral effects of fentanyl were neither genotype-dependent nor affected by JNK inhibition. Furthermore, a PKC inhibitor had a similar effect as inhibiting JNK in reducing the enhanced analgesic effect of morphine in β-arr2-/- mice to +/+ levels. In summary, removing β-arrestin 2 reveals mu receptor activation of the JNK cascade in a ligand-specific manner explaining several behavioral phenotypes of β-arr2-/- mice.

  17. Pleiotrophin modulates morphine withdrawal but has no effects on morphine-conditioned place preference.

    Science.gov (United States)

    Gramage, Esther; Vicente-Rodríguez, Marta; Herradón, Gonzalo

    2015-09-14

    Pleiotrophin (PTN) is a neurotrophic factor with important functions in addiction and neurodegenerative disorders. Morphine administration induces an increase in the expression of PTN and Midkine (MK), the only other member of this family of cytokines, in brain areas related with the addictive effects of drug of abuse, like the Ventral Tegmental Area or the hippocampus. In spite of previous studies showing that PTN modulates amphetamine and ethanol rewarding effects, and that PTN is involved in morphine-induced analgesia, it was still unknown if the rewarding effects of morphine may be regulated by endogenous PTN. Thus, we aim to study the role of PTN in the reward and physical dependence induced by morphine. We used the Conditioned Place Preference (CPP) paradigm in PTN genetically deficient (PTN-/-) and wild type (WT) mice to assess the rewarding effects of morphine in absence of endogenous PTN. Second, to study if PTN may be involved in morphine physical dependence, naloxone-precipitated withdrawal syndrome was induced in PTN-/- and WT morphine dependent mice. Although the increase in the time spent in the morphine-paired compartment after conditioning tended to be more pronounced in PTN-/- mice, statistical significance was not achieved. The data suggest that PTN does not exert an important role in morphine reward. However, our results clearly indicate that PTN-/- mice develop a more severe withdrawal syndrome than WT mice, characterized as a significant increase in the time standing and in the total incidences of forepaw licking, forepaw tremors, wet dog shake and writhing. The data presented here suggest that PTN is a novel genetic factor that plays a role in morphine withdrawal syndrome.

  18. 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...... higher plasma concentrations after colostomy application than after rectal administration. It is concluded that administration of morphine suppositories in a colostomy cannot be recommended....

  19. RELATIONSHIP BETWEEN ANALGESIA AND EXTRACELLULAR MORPHINE IN BRAIN AND SPINAL-CORD IN AWAKE RATS

    NARCIS (Netherlands)

    MATES, FF; ROLLEMA, H; TAIWO, YO; LEVINE, JD; BASBAUM, AI

    1995-01-01

    Extracellular concentrations of morphine from the dorsal spinal cord, the periaqueductal gray (FAG) including the dorsal raphe, and the lateral hypothalamus were measured by microdialysis in awake rats after intraperitoneal (i.p.) administration of 2.5, 5.0 and 10 mg/kg morphine. Morphine concentrat

  20. 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 indication for morphine use is primarily pain, but also a combined analgesic and sedative effect may be the rationale behind morphine administration. Paediatric morphine regimens have been reported for children with postoperative pain, pain related to cancer, sickle cell crisis pain, burns...

  1. 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...

  2. Impact of tramadol and morphine abuse on the activities of acetylcholine esterase, Na+/K+-ATPase and related parameters in cerebral cortices of male adult rats.

    Science.gov (United States)

    El-Hamid Mohamed Elwy, Abd; Tabl, Ghada

    2017-03-01

    To determine the effect of the most commonly abused drugs (tramadol and morphine), on acetylcholine esterase (AChE), Na(+)/K(+)-ATPase activities and related parameters, Na(+) and K(+) as biomarkers of neurotoxicity. Tramadol - as a weak μ opioid receptor agonist- and morphine - as opiate analgesic drugs, were chosen for the present study. Four series of experimental animals were conducted for either tramadol or morphine: control series; repeated single equal doses (therapeutic dose) series; cumulative increasing doses series and delay (withdrawal) series (96 hours withdrawal period after last administration), at time period intervals 7, 14 and 21 days. Acetylcholine esterase (AChE), Na(+)/K(+)-ATPase activities and related parameters, Na(+) and K(+) were measured in cerebral cortices of experimental rats. Acetylcholine esterase (AChE) activity in the brain cerebral cortex increased after the administration of therapeutic repeated doses of either tramadol (20 mg/kg b.w.) or morphine (4 mg/kg b.w.) in different groups. The daily intraperitoneal injection of cumulative increasing dose levels of either tramadol 20, 40 and 80 mg/kg or morphine 4, 8 and 12 mg/kg revealed a significant increase in the mean of acetylcholine esterase activities. The withdrawal groups of either tramadol or morphine showed significant decreases in their levels. Na(+)/K(+) ATPase activity in the brain cerebral cortex of either repeated therapeutic doses of tramadol (20 mg/kg) or morphine repeated therapeutic doses (4 mg/kg) for 21 consecutive days at different intervals 7, 14 and 21 days, induced a significant decrease in the levels of Na(+)/K(+)-ATPase in all groups. Withdrawal groups showed a significant decrease in Na(+)/K(+)-ATPase level. Furthermore, the daily intraperitoneal injection of cumulative increasing dose levels of either tramadol (20, 40 and 80 mg/kg b.w.) or morphine (4, 8 and 12 mg/kg b.w.) induced significant decreases in Na(+)/K(+)-ATPase levels in all studied groups

  3. Short-term repeated corticosterone administration enhances glutamatergic but not GABAergic transmission in the rat motor cortex.

    Science.gov (United States)

    Kula, Joanna; Blasiak, Anna; Czerw, Anna; Tylko, Grzegorz; Sowa, Joanna; Hess, Grzegorz

    2016-04-01

    It has been demonstrated that stress impairs performance of skilled reaching and walking tasks in rats due to the action of glucocorticoids involved in the stress response. Skilled reaching and walking are controlled by the primary motor cortex (M1); however, it is not known whether stress-related impairments in skilled motor tasks are related to functional and/or structural alterations within the M1. We studied the effects of single and repeated injections of corticosterone (twice daily for 7 days) on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) recorded from layer II/III pyramidal neurons in ex vivo slices of the M1, prepared 2 days after the last administration of the hormone. We also measured the density of dendritic spines on pyramidal cells and the protein levels of selected subunits of AMPA, NMDA, and GABAA receptors after repeated corticosterone administration. Repeatedly administered corticosterone induced an increase in the frequency but not in the amplitude of sEPSCs, while a single administration had no effect on the recorded excitatory currents. The frequency and amplitude of sIPSCs as well as the excitability of pyramidal cells were changed neither after single nor after repeated corticosterone administration. Treatment with corticosterone for 7 days did not modify the density of dendritic spines on pyramidal neurons. Corticosterone influenced neither the protein levels of GluA1, GluA2, GluN1, GluN2A, and GluN2B subunits of glutamate receptors nor those of α1, β2, and γ2 subunits of the GABAA receptor. The increase in sEPSCs frequency induced by repeated corticosterone administration faded out within 7 days. These data indicate that prolonged administration of exogenous corticosterone selectively and reversibly enhances glutamatergic, but not GABAergic transmission in the rat motor cortex. Our results suggest that corticosterone treatment results in an enhancement of spontaneous glutamate release from presynaptic

  4. Pharmacokinetics of Repeated Melatonin Drug Administrations Prior to and After Surgery

    DEFF Research Database (Denmark)

    Harpsøe, Nathja Groth; Andersen, Lars Peter Kloster; Mielke, Louise Vennegaard

    2016-01-01

    treatment protocol was standardized between patients. During the study, each patient received two separate oral administrations of melatonin 10 mg. Melatonin was administered 60 min before surgery, and at 9:00 p.m. the evening after surgery. The pharmacokinetic variables absorption half-life (t ½ absorption...... not differ between the study phases (p > 0.05). CONCLUSIONS: These preliminary results indicate that postoperative melatonin dose should be augmented compared with preoperative administration if corresponding melatonin plasma levels are intended. Furthermore, postoperative administration times should...... be advanced compared with preoperative administration....

  5. Influence of pre-exposure to morphine on cannabinoid-induced impairment of spatial memory in male rats.

    Science.gov (United States)

    Farahmandfar, Maryam; Kadivar, Mehdi; Naghdi, Nasser; Choopani, Samira; Zarrindast, Mohammad-Reza

    2013-11-01

    In the present study, we investigated the effects of repeated morphine pre-treatment on impairment of spatial memory acquisition induced by intra dorsal hippocampus (intra-CA1) administration of the non-selective cannabinoid CB1/CB2 receptor agonist, WIN55,212-2 in adult male rats. 2-day version of Morris water maze task has been used for the assessment of spatial memory. On the training day, rats were trained by a single training session of eight trials and 24 h later a probe trial test consist of 60s free swim period without a platform and the visible test was administered. Animals received pre-treatment subcutaneous (s.c.) injections of morphine, once daily for three days followed by five days drug-free treatment before training trials. The results indicated that bilateral pre-training intra-CA1 infusions of WIN55,212-2 (0.25 and 0.5 μg/rat) impaired acquisition of spatial memory on the training and test day. The amnesic effect of WIN55, 212-2 (0.5 μg/rat) was prevented in rats previously injected with morphine (20 mg/kg/day × 3 days, s.c.). Improvement in spatial memory acquisition in morphine-pretreated rats was inhibited by once daily administration of naloxone (1 and 2 mg/kg, s.c.) 15 min prior to injection of morphine for three days. The results suggest that sub-chronic morphine treatment may produced sensitization to cannabinoids, which in turn reversed the impairment of spatial memory acquisition induced by WIN55,212-2 and mu- opioid receptors may play an important role in this effect.

  6. Dysregulation of dopaminergic regulatory mechanisms in the mesolimbic pathway induced by morphine and morphine withdrawal.

    Science.gov (United States)

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

    2015-07-01

    Dopamine (DA) is thought to represent a teaching signal and has been implicated in the induction of addictive behaviours. Previously, it has been proposed that the transcription factors Nurr1 and Pitx3, which are critical for transcription of a set of genes involved in DA metabolism in the mesolimbic pathway, are associated with addiction pathology. The aim of our study was to investigate abnormalities in the mesolimbic pathway associated with morphine dependence and withdrawal. Using quantitative real-time PCR, immunofluorescence, HPLC and Western blotting, here we studied the effects of single morphine administration, morphine dependence and morphine withdrawal on Nurr1 and Pitx3 expression as well as on the DA marker tyrosine hydroxylase (TH) and the turnover of DA in the ventral tegmental area (VTA) and/or nucleus accumbens. We showed that the three experimental conditions caused induction of Nurr1 and Pitx3 in the VTA, which correlated with changes in TH expression during chronic morphine administration. Present data also confirmed the colocalization of Nurr1 and Pitx3 with TH-positive neurons in the posterior VTA. Furthermore, during morphine dependence, Nurr1 was detected in the nucleus compartment of VTA TH-positive neurons, whereas Pitx3 was strongly detected in the nucleus of TH-positive neurons after single morphine administration and during morphine withdrawal. The number of TH neurons, number of Nurr1 or Pitx3-positive cells, and the number of TH neurons expressing Nurr1 or Pitx3 were not modified in the subpopulations of DA neurons. Present data provide novel insight into the potential correlation between Nurr1 and Pitx3 and DA neurons plasticity during opiate addiction in the mesolimbic pathway.

  7. Oral suspensions of morphine hydrochloride for controlled release: rheological properties and drug release.

    Science.gov (United States)

    Morales, M E; López, G; Gallardo, V; Ruiz, M A

    2011-04-04

    Recent developments in pharmaceutical technology have facilitated the design and production of modified release formulas for drugs whose physical, chemical or biological properties impede release and thus might compromise their efficacy or safety. One such drug is morphine, whose short half-life requires repeated doses at short intervals. The use of biocompatible polymers such as ethylcellulose has made it possible to develop microencapsulated formulations which facilitate liquid, sustained-release pharmaceutical formulas for oral administration. We developed a stable final formulation of morphine with an acceptable release profile by comparing the rheological properties and stability of formulations with different thickeners (xanthan gum, Carbopol, and carboxymethylcellulose with microcrystalline cellulose) at different concentrations from 0.25% to 1.0%. Release assays in a Franz-type cell were done to determine the most suitable release profile for the formulation.

  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...... found evidence for a contributory effect of M6G to the overall effects observed after morphine administration. Several studies have demonstrated that administration of M6G is accompanied by fewer and a milder degree of opioid-like side effects than observed after morphine administration, but most...... that M6G may be a more potent analgesic than morphine. Results from human studies regarding the analgesic effect of M6G are not unanimous. The potency ratio between systemic M6G and morphine in humans has not been settled, but is probably lower than previously assumed. Hitherto, only a few studies have...

  9. The delayed lung responses to single and repeated intratracheal administration of pure cobalt and hard metal powder in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Lasfargues, G.; Lardot, C.; Lauwerys, R.; Lison, D. [Catholic Univ. of Louvain (Belgium)] [and others

    1995-05-01

    Epidemiological and clinical studies suggest that inhalation of cobalt metal dust (Co) mixed with tungsten carbide particles (WC), but not of cobalt dust alone, may cause interstitial pulmonary lesions (hard metal disease). In previous studies in the rat, we have demonstrated the greater acute pulmonary toxicity of a WC-Co mixture was greater compared to Co or WC alone. The present study compares the delayed lung response after intratracheal administration of Co or WC-Co particles. The responses were also compared with those obtained after treatment with arsenic trioxide and crystalline silica used as reference materials producing an acute toxic insult and progressive fibrogenic response, respectively. Cellular and biochemical parameters were measured in bronchoalveolar lavage fluid following single and repeated intratracheal instillations. The results indicate the delayed lung response observed after WC-Co is different from that after cobalt metal alone. A single intratracheal dose of WC-Co (1, 5, or 10 mg/100 g body wt) induced an acute alveolitis which persisted for at least 1 month. Four months after a single instillation of WC-Co, no clear histological lung fibrosis could however be evidenced, indicating a reversibility of the lesions. The effects of cobalt (0.06, 0.3, or 0.6 mg/100 g body wt) were very modest, if any. Following repeated intratracheal instillations, increased lung hydroxyproline content and histopathological evidence of interstitial fibrosis were observed after WC-Co (4x1 mg/100 g body wt), but not after administration of each component separately, i.e., Co (4x0.06 mg/100 g body wt) or WC (4x1 mg/100 g body wt). The mechanism of the fibrotic reaction induced by WC-Co seems different from the progressive inflammatory reaction induced by crystalline silica. We suggest that it might result from a scarring reaction elicited by repeated acute insults as observed after repeated administration of arsenic trioxide. 34 refs., 10 figs., 3 tabs.

  10. Repeated Administration of Mercury Intensifies Brain Damage in Multiple Sclerosis through Mitochondrial Dysfunction

    Science.gov (United States)

    Kahrizi, Farzad; Salimi, Ahmad; Noorbakhsh, Farshid; Faizi, Mehrdad; Mehri, Freshteh; Naserzadeh, Parvaneh; Naderi, Nima; Pourahmad, Jalal

    2016-01-01

    In this study we investigated the additive effect of mercury on the brain mitochondrial dysfunction in experimental autoimmune encephalomyelitis (EAE) model. Experimental animals (female C57BL/6 mice) are divided into four groups (n = 8); control, Hg, EAE, EAE with Hg. EAE model of MS induced by injecting myelin oligodendrocyte glycoprotein (MOG). Neurobehavioral alterations are recorded and then mice were sacrificed at day 28 and brain mitochondria were isolated and mitochondrial toxicity parameters including mitochondrial swelling, reactive oxygen species (ROS) formation, collapse of mitochondrial membrane potential (MMP) and cytochrome c release were measured. Our results showed that repeated treatment of mercury following induction of EAE in mice significantly increased the neurobehavioral scores, as well as mitochondrial toxicity through ROS formation, mitochondrial swelling, collapse of MMP and cytochrome c release. Our findings proved that repeated exposure with mercury accelerates progression of MS through mitochondrial damage related to oxidative stress and finally apoptosis.

  11. Evaluation of statistical tools used in short-term repeated dose administration toxicity studies with rodents.

    Science.gov (United States)

    Kobayashi, Katsumi; Pillai, K Sadasivan; Sakuratani, Yuki; Abe, Takemaru; Kamata, Eiichi; Hayashi, Makoto

    2008-02-01

    In order to know the different statistical tools used to analyze the data obtained from twenty-eight-day repeated dose oral toxicity studies with rodents and the impact of these statistical tools on interpretation of data obtained from the studies, study reports of 122 numbers of twenty-eight-day repeated dose oral toxicity studies conducted in rats were examined. It was found that both complex and easy routes of decision trees were followed for the analysis of the quantitative data. These tools include Scheffe's test, non-parametric type Dunnett's and Scheffe's tests with very low power. Few studies used the non-parametric Dunnett type test and Mann-Whitney's U test. Though Chi-square and Fisher's tests are widely used for analysis of qualitative data, their sensitivity to detect a treatment-related effect is questionable. Mann-Whitney's U test has better sensitivity to analyze qualitative data than the chi-square and Fisher's tests. We propose Dunnett's test for analysis of quantitative data obtained from twenty-eight-day repeated dose oral toxicity tests and for qualitative data, Mann-Whitney's U test. For both tests, one-sided test with p=0.05 may be applied.

  12. Two different methods for repeated intrathecal administration in rats%大鼠鞘内反复给药两种方法的比较

    Institute of Scientific and Technical Information of China (English)

    任占杰; 于志军; 张增臻; 张成明; 张广学

    2009-01-01

    Objective To compare the feasibility of direct spinal puncture and reserving micro-catheter in spinal space during repeated intrathecal administration. Methods Forty Sprague-Dawley rats were randomly divided into 2 groups:direct spinal puncture (group puncture) and reserving micro-catheter in spinal space group (group reserve). The duration of operation were recorded. 5 days after operation, rata in both groups were intrathecally administerde morphine(10 μg/10μl) for 7 days and thermal withdrawal latency(TWL) were assessed. Results The operation in group reserve took shorter time than the group puncture, but micro-catheter were pulled out in 5 rats in group reserve. There is no difference of TWL between two groups. Conclusion Both methods are suitable for repeated intrathecal administration.%目的 比较大鼠蛛网膜下腔长期置管和反复蛛网膜下腔穿刺两种给药方法的难易程度及反复给药的可行性.方法 40只清洁级SD大鼠以随机数字表法分为置管组和穿刺组各20只.置管组通过蛛网膜下腔长期置管给药,穿刺组反复行蛛网膜下腔穿刺给药.记录每次进行操作所用的时间.2组均从实验第5天开始鞘内注射吗啡10 μg/1μl,连续给药7 d,用热辐射法测定大鼠热缩足潜伏期(TWL).对2组实验时间和TWL进行比较分析.结果 置管组操作时间较穿刺组短,差异有统计学意义(P<0.01).置管组5只大鼠导管脱出.鞘内给药后,置管组和穿刺组TWL测定值均较基础值增加,差异有统计学意义(P<0.01).2组间TWL测定值差异无统计学意义.结论 蛛网膜下腔长期置管和反复蛛网膜下腔穿刺均可作为鞘内多次给药方法,但在选择时应该考虑到操作难易程度、给药方式、反复给药并发症等因素的影响.

  13. Effect of pre- and post-operative phenylbutazone and morphine administration on the breathing response to skin incision, recovery quality, behavior and cardiorespiratory variables in horses undergoing fetlock arthroscopy. A pilot study.

    Directory of Open Access Journals (Sweden)

    Clara eConde-Ruiz

    2015-11-01

    Full Text Available This prospective blinded randomized study aimed to determine whether the timing of morphine and phenylbutazone administration affects the breathing response to skin incision, recovery quality, behavior and cardiorespiratory variables in horses undergoing fetlock arthroscopy.Ten Standardbred horses were premedicated with acepromazine (0.04 mg kg-1 IM and romifidine (0.04 mg kg-1 IV. Anesthesia was induced with diazepam (0.05 mg kg-1 and ketamine (2.2 mg kg-1 IV at T0. Horses in group PRE (n = 5 received morphine (0.1 mg kg-1 and phenylbutazone (2.2 mg kg-1 IV after induction and an equivalent amount of saline after surgery. Horses in group POST (n = 5 received the inversed treatment. Anesthesia was maintained with isoflurane 2% in 100% oxygen. Hypotension (mean arterial pressure < 60 mmHg was treated with dobutamine. All horses breathed spontaneously. Dobutamine requirements, respiratory rate (fR, heart rate (HR, mean arterial blood pressure, end tidal CO2, inspired (i and expired (e tidal and minute volume (VT and V̇E, inspiratory time (IT and the inspiratory gas flow (VTi/IT were measured every five minutes. Data were averaged during four 15 minutes periods before (P1, P2 and after the incision (P3, P4. Serial blood-gas analyses were also performed. Recoveries were unassisted, video-recorded and scored by three anesthetists blinded to the treatment. The post-operative behavior of the horses (25 demeanors, HR and fR were recorded at three time points before induction (T0-24h, T0-12h, and T0-2h and six time points after recovery (TR (TR+2, 4, 6, 12, 24, 48 h.Data were compared between groups using a Wilcoxon test and within groups using a Friedman test or a Kruskal-Wallis signed rank test when applicable.Tidal volumes (VTe and VTi were higher in PRE than in POST during all the considered periods but the difference between groups was only significant during P2 (VTe in ml kg-1 in PRE: 13 [9, 15], in POST: 9 [8,9], p = 0.01. None of the other

  14. Repeated Intrathecal Triamcinolone Acetonide Administration in Progressive Multiple Sclerosis: A Review

    Directory of Open Access Journals (Sweden)

    Mazen Abu-Mugheisib

    2011-01-01

    Full Text Available At the present time, anti-inflammatory, immunomodulatory, or immunosuppressive treatments of multiple sclerosis (MS are mainly effective in the early phases of the disease but are of less advantage in progressive phases. Current therapeutic strategies of both primary and secondary progressive MS are rare. One alternative may be intrathecal application of triamcinolone acetonide (TCA. Number of papers deal with advantages and disadvantages of intrathecal administration in MS. Former trials lacked detailed selection of MS patients, with small sample sizes, low steroid dosages, and only a small number of intrathecal administration of short acting steroids. The present paper summarizes recent trials performed following a different treatment regime. They were conducted in patients with progressive MS suffering mainly from spinal symptoms and documented a significant improvement of EDSS and walking distance (WD. Intrathecal TCA administration is a proposal to take into account as one therapy option in patients with a progressive clinical course and predominantly spinal symptoms.

  15. Morphine in the treatment of acute pulmonary oedema--Why?

    Science.gov (United States)

    Ellingsrud, C; Agewall, S

    2016-01-01

    Morphine has for a long time, been used in patients with acute pulmonary oedema due to its anticipated anxiolytic and vasodilatory properties, however a discussion about the benefits and risks has been raised recently. A literature search in Medline and Embase using the keywords "pulmonary oedema" OR "lung oedema" OR "acute heart failure" AND "morphine" was performed. A certain vasodilation has been described after morphine administration, but the evidence for this mechanism is relatively poor and morphine-induced anxiolysis may possibly be the most important factor of morphine in pulmonary oedema and therefore some authors have suggested benzodiazepines as an alternative treatment. Respiratory depression seems to be a less relevant clinical problem according to the literature, whereas vomiting is common, which may cause aspiration. In the largest outcome study, based on the ADHERE registry, morphine given in acute decompensated heart failure was an independent predictor of increased hospital mortality, with an odds ratio of 4.8 (95% CI: 4.52-5.18, pmorphine administration and mortality, which was lost after adjusting for confounding factors. Morphine is still used for pulmonary oedema in spite of poor scientific background data. A randomised, controlled study is necessary in order to determine the effect--and especially the risk--when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided.

  16. Gadolinium deposition within the dentate nucleus and globus pallidus after repeated administrations of gadolinium-based contrast agents - current status

    Energy Technology Data Exchange (ETDEWEB)

    Stojanov, Dragan [University of Nis, Faculty of Medicine, Nis (Serbia); Center for Radiology, Nis (Serbia); Aracki-Trenkic, Aleksandra [Center for Radiology, Nis (Serbia); Benedeto-Stojanov, Daniela [University of Nis, Faculty of Medicine, Nis (Serbia)

    2016-05-15

    Gadolinium-based contrast agents (GBCAs) have been used clinically since 1988 for contrast-enhanced magnetic resonance imaging (CE-MRI). Generally, GBCAs are considered to have an excellent safety profile. However, GBCA administration has been associated with increased occurrence of nephrogenic systemic fibrosis (NSF) in patients with severely compromised renal function, and several studies have shown evidence of gadolinium deposition in specific brain structures, the globus pallidus and dentate nucleus, in patients with normal renal function. Gadolinium deposition in the brain following repeated CE-MRI scans has been demonstrated in patients using T1-weighted unenhanced MRI and inductively coupled plasma mass spectroscopy. Additionally, rodent studies with controlled GBCA administration also resulted in neural gadolinium deposits. Repeated GBCA use is associated with gadolinium deposition in the brain. This is especially true with the use of less-stable, linear GBCAs. In spite of increasing evidence of gadolinium deposits in the brains of patients after multiple GBCA administrations, the clinical significance of these deposits continues to be unclear. Here, we discuss the current state of scientific evidence surrounding gadolinium deposition in the brain following GBCA use, and the potential clinical significance of gadolinium deposition. There is considerable need for further research, both to understand the mechanism by which gadolinium deposition in the brain occurs and how it affects the patients in which it occurs. (orig.)

  17. Decreased AMPA GluR2, but not GluR3, mRNA expression in rat amygdala and dorsal hippocampus following morphine-induced behavioural sensitization.

    Science.gov (United States)

    Sepehrizadeh, Zargham; Bahrololoumi Shapourabadi, Mina; Ahmadi, Shamseddin; Hashemi Bozchlou, Saeed; Zarrindast, Mohammad-Reza; Sahebgharani, Mousa

    2008-11-01

    1. Repeated administration of psychostimulants and micro-opioid receptor agonists elicits a progressive enhancement of drug-induced behavioural responses, a phenomenon termed behavioural sensitization. These changes in behaviour may reflect plastic changes requiring regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor function. 2. In the present study, rats were treated for 7 days with saline or morphine (10 mg/kg). After a washout period of either 24 h or 7 days, locomotion, oral stereotypy and state-dependent memory in a passive avoidance test were measured in the presence or absence of 6-cyano-7-nitroquinoxaline-2,3-dione disodium salt (CNQX; 3 mg/kg), an AMPA receptor antagonist. In order to evaluate the mechanism underlying the behavioural responses, quantitative real-time reverse transcription-polymerase chain reaction was used to evaluate mRNA expression of the AMPA receptor subunits GluR2 and GluR3 in the striatum, prefrontal cortex, hippocampus, hypothalamus and amygdala of animals treated repeatedly with morphine. 3. The results indicate that repeated morphine treatment followed by 7 days (but not 24 h) washout produces behavioural sensitization, as determined by locomotion, oral stereotypy and state-dependent memory. Blockade of AMPA receptors with CNQX on the test day did not alter these behavioural responses. In addition, repeated morphine treatment followed by 7 days (but not 24 h) washout decreased GluR2 mRNA expression in both the amygdala (by 50%) and hippocampus (by 35%). Repeated morphine treatment did not alter GluR3 mRNA expression in any brain area assessed. 4. These data imply that AMPA receptors are involved in the development (but not expression) phase of behavioural sensitization. The decreases in GluR2 mRNA expression in the amygdala and hippocampus may result in the formation of calcium-permeable AMPA receptors, which are believed to play an important role in behavioural sensitization.

  18. The influence of repeated administration of poloxamer 407 on serum lipoproteins and protease activity in mouse liver and heart.

    Science.gov (United States)

    Korolenko, Tatyana A; Tuzikov, Fedor V; Johnston, Thomas P; Tuzikova, Natalia A; Kisarova, Yana A; Zhanaeva, Svetlana Ya; Alexeenko, Tatyana V; Zhukova, Natalia A; Brak, Ivan V; Spiridonov, Victor K; Filjushina, Elena E; Cherkanova, Marina S; Monoszon, Anna A

    2012-11-01

    The effects of repeated administration of poloxamer 407 (P-407) on lipoprotein-cholesterol (LP-C) and lipoprotein-triglyceride (LP-TG) fractions and subfractions, as well as the effect on liver and heart proteases, were studied. Repeated administration of P-407 to male CBA mice resulted in a model of atherosclerosis with increased diastolic blood pressure; there was a drastic increase in total serum cholesterol and especially TG. A novel small-angle X-ray scattering method for the determination of the fractional and subfractional composition of LP-C and LP-TG was used. In chronically P-407-treated mice, P-407 significantly increased atherogenic low-density lipoprotein C (LDL-C) fractions, as well as intermediate-density lipoprotein C (IDL-C), and LDL₁₋₃-C subfractions, and very-low-density lipoprotein-C (VLDL-C) fractions, as well as VLDL₁₋₂-C and VLDL₃₋₅-C subfractions), to a lesser extent, the total anti-atherogenic high-density lipoprotein C (HDL-C) fraction, as well as HDL₂-C and HDL₃-C subfractions. Additionally, we demonstrated an increase in the serum chitotriosidase activity, without significant changes in serum matrix metalloprotease (MMP) activity. Morphological changes observed in P-407-treated mice included atherosclerosis in the heart and storage syndrome in the liver macrophages. P-407 significantly increased the activity of cysteine, aspartate proteases, and MMPs in the heart, and only the activity of cathepsin B and MMPs in the liver of mice. Thus, repeated administration of P-407 to mice induced atherosclerosis secondary to sustained dyslipidemia and formation of foamy macrophages in liver, and also modulated the activity of heart and liver proteases.

  19. Efficiency of postoperative pain management after gynecologic oncological surgeries with the use of morphine + acetaminophen + ketoprofen versus morphine + metamizol + ketoprofen.

    Science.gov (United States)

    Samulak, D; Michalska, M; Gaca, M; Wilczak, M; Mojs, E; Chuchracki, M

    2011-01-01

    Surgical treatment used in gynecological oncology involves acute postoperative pain which requires efficient treatment. This study covered a group of 128 patients who were randomly divided into two groups. In the postoperative period patients in group I were administered morphine subcutaneously, acetaminophen intravenously and naproxen per rectum. The pain intensity level was checked by means of the pain intensity numeric rating scale (NRS). In the instances of pain rated at 5 or more, patients were additionally administered ketoprofen intravenously. Patients in group II were administered morphine, naproxen, and metamizole instead of acetaminophen and ketoprofen additionally. In group I after the administration of morphine and acetaminophen 22 patients (34.37%) needed additional doses of ketoprofen. In group II 33 women (51.56%) required ketoprofen after the administration of morphine and metamizole (N1 = 22 vs N2 = 33, p metamizol with morphine (without ketoprofen) gave worse analgesic results than acetaminophen with morphine, but the combination of morphine, acetaminophen and ketoprofen or morphine, metamizol and ketoprofen gave satisfactory analgesic results.

  20. Postoperative analgesia with epidural opioids after cesarean section: Comparison of sufentanil, morphine and sufentanil-morphine combination

    Directory of Open Access Journals (Sweden)

    Kalpana S Vora

    2012-01-01

    Conclusion: Epidural administration of a combination of sufentanil and morphine offered the advantage of faster onset of action and longer duration of analgesia as compared to the two drugs administered alone.

  1. The effects of repeated intravenous iohexol administration on renal function in healthy beagles – a preliminary report

    Directory of Open Access Journals (Sweden)

    Kirberger Robert M

    2012-08-01

    Full Text Available Abstract Background Contrast induced nephrotoxicity (CIN is a well described syndrome in humans undergoing contrast medium examinations. To date CIN has received minimal attention in the veterinary literature despite increasing use of contrast medium examinations in computed tomographic studies. Methods This prospective study evaluated the effect of 1290 mg/kg iohexol given intravenously to 5 normal beagle dogs in a divided dose at an interval of 6–8 weeks. Renal function was evaluated by means of scintigraphically determined glomerular filtration rate (GFR and a variety of laboratory assays. Results Only GFR showed a significant decrease (17% after the second injection but not to a clinically or pathologically significant level. Conclusions No clinically significant effect of repeated contrast medium administration was determined in this limited study. However in dogs with reduced renal function the risk of CIN is likely to increase dramatically post contrast administration.

  2. Repeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertility

    Science.gov (United States)

    Bai, Yuhong; Zhang, Yi; Zhang, Jingping; Mu, Qingxin; Zhang, Weidong; Butch, Elizabeth R.; Snyder, Scott E.; Yan, Bing

    2010-09-01

    Soluble carbon nanotubes show promise as materials for in vivo delivery and imaging applications. Several reports have described the in vivo toxicity of carbon nanotubes, but their effects on male reproduction have not been examined. Here, we show that repeated intravenous injections of water-soluble multiwalled carbon nanotubes into male mice can cause reversible testis damage without affecting fertility. Nanotubes accumulated in the testes, generated oxidative stress and decreased the thickness of the seminiferous epithelium in the testis at day 15, but the damage was repaired at 60 and 90 days. The quantity, quality and integrity of the sperm and the levels of three major sex hormones were not significantly affected throughout the 90-day period. The fertility of treated male mice was unaffected; the pregnancy rate and delivery success of female mice that mated with the treated male mice did not differ from those that mated with untreated male mice.

  3. Repeated oral administration of capsaicin increases anxiety-like behaviours with prolonged stress-response in rats

    Indian Academy of Sciences (India)

    Y-J Choi; J Y Kim; S B Yoo; J-H Lee; J W Jahng

    2013-09-01

    This study was conducted to examine the psycho-emotional effects of repeated oral exposure to capsaicin, the principal active component of chili peppers. Each rat received 1 mL of 0.02% capsaicin into its oral cavity daily, and was subjected to behavioural tests following 10 daily administrations of capsaicin. Stereotypy counts and rostral grooming were significantly increased, and caudal grooming decreased, in capsaicin-treated rats during the ambulatory activity test. In elevated plus maze test, not only the time spent in open arms but also the percent arm entry into open arms was reduced in capsaicin-treated rats compared with control rats. In forced swim test, although swimming duration was decreased, struggling increased in the capsaicin group, immobility duration did not differ between the groups. Repeated oral capsaicin did not affect the basal levels of plasma corticosterone; however, the stress-induced elevation of plasma corticosterone was prolonged in capsaicin treated rats. Oral capsaicin exposure significantly increased c-Fos expression not only in the nucleus tractus of solitarius but also in the paraventricular nucleus. Results suggest that repeated oral exposure to capsaicin increases anxiety-like behaviours in rats, and dysfunction of the hypothalamic-pituitary-adrenal axis may play a role in its pathophysiology.

  4. 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.

  5. Effect of Repeated Administration of hCG on Ovarian Response in PMSG-superovulated Ouled Djellal Ewes (Algeria

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    Lamraoui, R.

    2014-01-01

    Full Text Available The objective of this study was to evaluate the effect of repeated administration of hCG on ovarian response in PMSG-superovulated ewes. Intravaginal pessaries containing 40 mg fluorogestone acetate (FGA were inserted in all ewes (n=9 and remained in situ for 14 days. Two days prior to pessary removal, all ewes were treated with 1000 IU of PMSG. On the day of sponge removal (day 0, the females were randomly assigned to 2 treatments. The first group (n=3 did not receive any hCG, while the second group (n=6 treated inter-muscular with hCG (500 IU during days 0-2. On day 8, laparotomy was performed to assess numbers of corpora lutea (CL and anovulatory follicles (AF. Blood samples were collected for analysis of serum progesterone (P4 using radioimmunoassay (RIA method. The results obtained for first and second group was in number of CL (6.33±1.15 and 10.50±5.54, number of AF (2 ±3.46 and 4.16±5.70, then the levels of P4 (5.75± 4.45 and 13.22±6.80 ng/ml, respectively. These results indicate that the repeated administration of hCG post-sponge removal increases number of CL and improves luteal function in ewes after PMSG-superovulatory treatment.

  6. The chronic treatment in vivo of salicylate or morphine alters excitatory effects of subsequent salicylate or morphine tests in vitro in hippocampus area CA1.

    Science.gov (United States)

    Sadegh, Mehdi; Fathollahi, Yaghoub; Semnanian, Saeed

    2013-12-05

    The current practical tests were designed to study in vitro interactions in the field potential between salicylate and morphine analgesics in the hippocampus area CA1 taken from morphine-(7 days) or salicylate (6 days)-treated rats. For this, morphine or salicylate was applied in vitro to the hippocampal slices derived from chronically drug-treated or saline-injected rats and drug-induced changes in evoked field potentials of area CA1 were evaluated. Chronic treatment in vivo of morphine or salicylate had no impact on baseline field EPSP and population spikes (PS) but a leftward shift in fEPSP/PS (E/S) curves and an increase in paired pulse ratio at 10 ms IPI were seen. Acute in vitro salicylate produced a durable PS potentiation in morphine-treated group, whereas an increase in PS of all groups was observed after long-term exposure to in vitro salicylate. Acute in vitro morphine caused a stable PS potentiation in control and salicylate treated groups, but not in morphine treated group. A potentiated fEPSP and a greater PS potentiation in salicylate treated group were observed after long-term exposure to in vitro morphine. It is concluded that the chronic treatment in vivo of salicylate or morphine incites lasting changes in the CA1 circuitry, which alters excitatory effects of subsequent salicylate or morphine tests in vitro in a way that an increase in reactivity or tolerance to the acute salicylate or morphine administration was observed.

  7. Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

    Science.gov (United States)

    Mittal, Nitish; Tan, Miao; Egbuta, Onyemachi; Desai, Nina; Crawford, Cynthia; Xie, Cui-Wei; Evans, Christopher; Walwyn, Wendy

    2012-01-01

    The altered behavioral effects of morphine, but not most other mu agonists, in mice lacking β-arrestin 2, suggest that this scaffolding protein regulates the signaling cascade of this commonly used analgesic. One of the cascades that could be regulated by β-arrestin 2 is cJun-N-terminal kinase (JNK), which binds with β-arrestin 2 and modulates the analgesic effects of morphine. Using neurons lacking β-arrestin 2 (β-arr2−/−) to examine this interaction, we found that β-arr2−/− neurons show altered intracellular distribution of JNK and cJun, and that morphine, but not fentanyl, increased the nuclear localization of the phosphorylated, therefore activated, form of cJun, a JNK target in dorsal root ganglia neurons. This suggests that deleting β-arrestin 2 affects the JNK cascade. We therefore examined whether some of the behavioral phenotypes of mice lacking β-arrestin 2 could be a result of altered JNK signaling. Indeed, two different JNK inhibitors reversed the enhanced analgesic effect of morphine, a known phenotype of β-arr2−/− mice, to +/+ levels. Both the reduced locomotor effect of morphine and the psychomotor sensitization to repeated morphine administration in β-arr2−/− mice were also returned to +/+ levels by inhibiting JNK. In contrast, the behavioral effects of fentanyl were neither genotype-dependent nor affected by JNK inhibition. Furthermore, a PKC inhibitor had a similar effect as inhibiting JNK in reducing the enhanced analgesic effect of morphine in β-arr2−/− mice to +/+ levels. In summary, removing β-arrestin 2 reveals mu receptor activation of the JNK cascade in a ligand-specific manner explaining several behavioral phenotypes of β-arr2−/− mice. PMID:22491351

  8. 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 postop......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...

  9. Pain management in emergency department: intravenous morphine vs. intravenous acetaminophen

    Directory of Open Access Journals (Sweden)

    Morteza Talebi Doluee

    2015-01-01

    Full Text Available Pain is the most common complaint in emergency department and there are several methods for its control. Among them, pharmaceutical methods are the most effective. Although intravenous morphine has been the most common choice for several years, it has some adverse effects. There are many researches about intravenous acetaminophen as an analgesic agent and it appears that it has good analgesic effects for various types of pain. We searched some electronic resources for clinical trials comparing analgesic effects of intravenous acetaminophen vs. intravenous morphine for acute pain treatment in emergency setting.In two clinical trials, the analgesic effect of intravenous acetaminophen has been compared with intravenous morphine for renal colic. The results revealed no significant difference between analgesic effects of two medications. Another clinical trial revealed that intravenous acetaminophen has acceptable analgesic effects on the post-cesarean section pain when combined with other analgesic medications. One study revealed that administration of intravenous acetaminophen compared to placebo before hysterectomy decreased consumption of morphine via patient-controlled analgesia pump and decreased the side effects. Similarly, another study revealed that the infusion of intravenous acetaminophen vs. placebo after orthopedic surgery decreased the consumption of morphine after the surgery. A clinical trial revealed intravenous acetaminophen provided a level of analgesia comparable to intravenous morphine in isolated limb trauma, while causing less side effects than morphine.It appears that intravenous acetaminophen has good analgesic effects for visceral, traumatic and postoperative pains compare with intravenous morphine.

  10. Liquid chromatographic determination and depletion profile of oxytetracycline in milk after repeated intramuscular administration in sheep.

    Science.gov (United States)

    Fletouris, Dimitrios J; Papapanagiotou, Elias P; Nakos, Dimitrios S

    2008-12-01

    A simple, rapid and specific ion-pair liquid chromatographic method for the routine determination of the marker residue of oxytetracycline in sheep milk, at levels as low as 20 microg/kg, has been developed. Milk samples were acidified and extracted with acetonitrile. The extracts were purified by treatment with ammonium sulphate and concentrated into diluted phosphoric acid. Separation was carried out isocratically on a Nucleosil C(18) column using a mobile phase that contained both positively and negatively charged pairing ions. The in-house validated method gave overall recoveries and overall relative standard deviations better than 86% and 4.6%, respectively. The method was successfully applied to study the depletion of oxytetracycline in sheep milk and to estimate the withdrawal period after intramuscular administration of a commercial oxytetracycline formulation.

  11. Behavioral and neurochemical effects of repeated MDMA administration during late adolescence in the rat.

    Science.gov (United States)

    Cox, Brittney M; Shah, Mrudang M; Cichon, Teri; Tancer, Manuel E; Galloway, Matthew P; Thomas, David M; Perrine, Shane A

    2014-01-01

    Adolescents and young adults disproportionately abuse 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy'); however, since most MDMA research has concentrated on adults, the effects of MDMA on the developing brain remain obscure. Therefore, we evaluated place conditioning to MDMA (or saline) during late adolescence and assessed anxiety-like behavior and monoamine levels during abstinence. Rats were conditioned to associate 5 or 10mg/kg MDMA or saline with contextual cues over 4 twice-daily sessions. Five days after conditioning, anxiety-like behavior was examined with the open field test and brain tissue was collected to assess serotonin (5-hydroxytryptamine, 5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal raphe, amygdala, and hippocampus by high-pressure liquid chromatography (HPLC). In a separate group of rats, anxiety-like and avoidant behaviors were measured using the light-dark box test under similar experimental conditions. MDMA conditioning caused a place aversion at 10, but not at 5, mg/kg, as well as increased anxiety-like behavior in the open field and avoidant behavior in light-dark box test at the same dose. Additionally, 10mg/kg MDMA decreased 5-HT in the dorsal raphe, increased 5-HT and 5-HIAA in the amygdala, and did not alter levels in the hippocampus. Overall, we show that repeated high (10mg/kg), but not low (5mg/kg), dose MDMA during late adolescence in rats increases anxiety-like and avoidant behaviors, accompanied by region-specific alterations in 5-HT levels during abstinence. These results suggest that MDMA causes a region-specific dysregulation of the serotonin system during adolescence that may contribute to maladaptive behavior.

  12. Assessment of morphine-induced hyperalgesia and analgesic tolerance in mice using thermal and mechanical nociceptive modalities.

    Science.gov (United States)

    Elhabazi, Khadija; Ayachi, Safia; Ilien, Brigitte; Simonin, Frédéric

    2014-07-29

    Opioid-induced hyperalgesia and tolerance severely impact the clinical efficacy of opiates as pain relievers in animals and humans. The molecular mechanisms underlying both phenomena are not well understood and their elucidation should benefit from the study of animal models and from the design of appropriate experimental protocols. We describe here a methodological approach for inducing, recording and quantifying morphine-induced hyperalgesia as well as for evidencing analgesic tolerance, using the tail-immersion and tail pressure tests in wild-type mice. As shown in the video, the protocol is divided into five sequential steps. Handling and habituation phases allow a safe determination of the basal nociceptive response of the animals. Chronic morphine administration induces significant hyperalgesia as shown by an increase in both thermal and mechanical sensitivity, whereas the comparison of analgesia time-courses after acute or repeated morphine treatment clearly indicates the development of tolerance manifested by a decline in analgesic response amplitude. This protocol may be similarly adapted to genetically modified mice in order to evaluate the role of individual genes in the modulation of nociception and morphine analgesia. It also provides a model system to investigate the effectiveness of potential therapeutic agents to improve opiate analgesic efficacy.

  13. Effects of ketamine and magnesium on morphine induced tolerance and dependence in mice

    Directory of Open Access Journals (Sweden)

    Bohlul Habibi Asl

    2005-05-01

    Full Text Available The goal of this study was to evaluate the effects of ketamine and magnesium on prevention of development of morphine tolerance and dependence in mice. In this study different groups of mice received morphine (50 mg/kg, sc + (saline 10ml/kg, morphine (50 mg/kg, sc + ketamine (25,50 or 75mg/kg, ip, morphine (50 mg/kg, sc + magnesium (10,20 or 40 mg/kg, ip, morphine (50 mg/kg, sc +ketamine (25 mg/kg, ip + magnesium (10 mg/kg, ip] once a day for four days. Tolerance was assessed by administration of morphine (9 mg/kg, ip and using hot plate test on fifth day. Withdrawal symptoms were assessed by administration of naloxone (4 mg/kg, ip two hours after co-administration of morphine with either ketamine or magnesium. It was found that pretreatment with ketamine or magnesium decreased the degree of tolerance and dependence. Additionally, co-administration of ketamine and magnesium before morphine administration decreased the tolerance and dependence significantly. From these results it may be concluded that administration of ketamine or magnesium alone or together could prevent the development of tolerance and dependence to the analgesic effects of morphine. These effects may be related to the N-Methyl-DAspartate (NMDA receptor antagonist behavior of ketamine and the ability of magnesium to block the Ca channel of NMDA receptors.

  14. Repeated Oral Administration of Oleanolic Acid Produces Cholestatic Liver Injury in Mice

    Directory of Open Access Journals (Sweden)

    Yasha Xu

    2013-03-01

    Full Text Available Oleanolic acid (OA is a triterpenoid and a fantastic molecule with many beneficial effects. However, high-doses and long-term use can produce adverse effects. This study aimed to characterize the hepatotoxic potential of OA. Mice were given OA at doses of 100–3,000 µmol/kg (45–1,350 mg/kg, po for 10 days, and the hepatotoxicity was determined by serum biochemistry, histopathology, and toxicity-related gene expression via real-time RT-PCR. Animal body weight loss was evident at OA doses of 1,000 µmol/kg and above. Serum alanine aminotransferase activities were increased in a dose-dependent manner, indicative of hepatotoxicity. Serum total bilirubin concentrations were increased, indicative of cholestasis. OA administration produced dose-dependent pathological lesions to the liver, including inflammation, hepatocellular apoptosis, necrosis, and feathery degeneration indicative of cholestasis. These lesions were evident at OA doses of 500 µmol/kg and above. Real-time RT-PCR revealed that OA produced dose-dependent increases in acute phase proteins (MT-1, Ho-1, Nrf2 and Nqo1, decreases in bile acid synthesis genes (Cyp7a1 and Cyp8b1, and decreases in liver bile acid transporters (Ntcp, Bsep, Oatp1a1, Oatp1b2, and Ostβ. Thus, the clinical use of OA and OA-type triterpenoids should balance the beneficial effects and toxicity potentials.

  15. Matricaria chamomilla extract inhibits both development of morphine dependence and expression of abstinence syndrome in rats.

    Science.gov (United States)

    Gomaa, Adel; Hashem, Tahia; Mohamed, Mahmoud; Ashry, Esraa

    2003-05-01

    The effect of Matricaria chamomilla (M. chamomilla) on the development of morphine dependence and expression of abstinence was investigated in rats. The frequencies of withdrawal behavioral signs (paw tremor, rearing, teeth chattering, body shakes, ptosis, diarrhea, and urination) and weight loss induced by naloxone challenge were demonstrated in morphine-dependent rats receiving M. chamomilla extract or saline. The withdrawal behavioral manifestations and weight loss were inhibited significantly by chronic co-administration of M. chamomilla extract with morphine. Administration of a single dose of M. chamomilla before the naloxone challenge in morphine-dependent animals abolished the withdrawal behavioral manifestations. The dramatic increase of plasma cAMP induced by naloxone-precipitated abstinence was prevented by chronic co-administration of M. chamomilla extract with morphine. These results suggest that M. chamomilla extract inhibits the development of morphine dependence and expression of abstinence syndrome.

  16. Tolerance in the anxiolytic profile following repeated administration of diazepam but not buspirone is associated with a decrease in the responsiveness of postsynaptic 5-HT-1A receptors.

    Science.gov (United States)

    Khan, Asma; Haleem, D J

    2007-12-01

    To understand the role of serotonin (5-hydroxytryptamine; 5-HT)-1A receptors in the treatment of anxiety and the development of tolerance to benzodiazepines the present study was designed to monitor the responsiveness of postsynaptic 5-HT-1A receptors following repeated administration of diazepam and buspirone. Results show that tolerance in the anxiolytic profile is produced following repeated administration (2 weeks) of diazepam (2 mg/kg) but not buspirone (0.5 mg/kg). The behavioral effects of 8-OH-DPAT at a dose of 0.25 mg/kg were monitored 3 days after repeated administration of saline or buspirone or diazepam. The results show that 8-OH-DPAT elicited forepaw treading was smaller in repeated diazepam but not repeated buspirone injected rats, while hyperlocomotive effects of 8-OH-DPAT were smaller in both repeated buspirone and repeated diazepam injected rats. The results suggest that postsynaptic 5-HT-1A receptor-dependent responses were attenuated following long-term administration of diazepam but not buspirone. Role of 5-HT-1A receptors in the development of tolerance to the anxiolytic effects of diazepam but not buspirone is discussed.

  17. Population pharmacokinetic modelling of morphine, gabapentin and their combination in the rat

    DEFF Research Database (Denmark)

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Gabel-Jensen, Charlotte

    2016-01-01

    Purpose The combination of morphine and gabapentin seems promising for the treatment of postoperative and neuropathic pain. Despite the well characterised pharmacodynamic interaction, little is known about possible pharmacokinetic interactions. The aim of this study was to evaluate whether co......-administration of the two drugs leads to modifications of their pharmacokinetic profiles. Methods The pharmacokinetics of morphine, morphine-3-glucuronide and gabapentin were characterised in rats following subcutaneous injections of morphine, gabapentin or their combination. Non-linear mixed effects modelling was applied...... and gabapentin bioavailability. Enterohepatic circulation of morphine-3-glucuronide was modelled using an oscillatory model. The combination did not lead to pharmacokinetic interactions for morphine or gabapentin but resulted in an estimated ~33% diminished morphine-3-glucuronide formation. Conclusions...

  18. Intrathecal cdk5 inhibitor, roscovitine,attenuates morphine antinociceptive tolerance in rats

    Institute of Scientific and Technical Information of China (English)

    Cheng-haung WANG; Tsung-hsing LEE; Yi-jung TSAI; Jong-kang LIU; Yann-jang CHEN; Lin-cheng YANG; Cheng-yuan LU

    2004-01-01

    AIM: To investigate the effect of cyclin-dependent kinase 5 (Cdk5) inhibitor roscovitine on the morphine antinociceptive tolerance development in rats. METHODS: Tail-flick test as pain threshold measurement and intrathecal injection techniques were used. RESULTS: Intrathecal roscovitine infusion alone produced an antinociceptive effect. Tolerance was induced by continuous intrathecal infusion of morphine 5 μg/h for 5 d. Coadministration of intrathecal roscovitine 1 μg/h for 5 d enhanced the morphine antinociceptive effect in tolerant rats.It also caused a shift in the morphine antinociceptive doseCresponse curve to the left when co-administered with morphine during tolerance induction, and caused a 67 % reduction in the increase in the ED50 of morphine (dose producing 50 % of the maximum response). CONCLUSION: Cdk5 modulation is involved in the antinociceptive tolerance of morphine. Intrathecal roscovitine administration could attenuate this tolerance development.

  19. Microinjection of the vehicle dimethyl sulfoxide (DMSO) into the periaqueductal gray modulates morphine antinociception.

    Science.gov (United States)

    Fossum, Erin N; Lisowski, Mark J; Macey, Tara A; Ingram, Susan L; Morgan, Michael M

    2008-04-14

    Dimethyl sulfoxide (DMSO) is commonly used as a solvent for water-insoluble drugs. Given that DMSO has varying cellular and behavioral effects ranging from increased membrane permeability to toxicity, microinjection of DMSO as a vehicle could confound the effects of other drugs. For example, DMSO is often used as a vehicle for studies examining the neurochemical mechanisms underlying morphine antinociception. Given that the ventrolateral periaqueductal gray (vlPAG) plays a major role in morphine antinociception and tolerance, the effects of DMSO on morphine antinociception mediated by the vlPAG needs to be evaluated. The present experiment tested whether co-administration of DMSO (0, 0.2, 2, or 20%) would alter the antinociceptive effect of microinjecting morphine into the vlPAG. DMSO had no effect on nociception when microinjected into the vlPAG alone, but 2% DMSO enhanced morphine potency when co-administered with morphine. In contrast, twice daily microinjections of DMSO (5 or 20%) for two days reduced the potency of subsequent microinjections of morphine into the vlPAG--an effect that persisted for at least one week. A similar rightward shift in the morphine dose-response curve was caused by morphine tolerance. Co-administration of morphine and DMSO during the pretreatment did not cause a greater shift in the morphine dose-response curve compared to morphine pretreated alone. In conclusion, DMSO can alter morphine antinociception following both acute (enhancement) and chronic (inhibition) administration depending on the concentration. These data reinforce the need to be cautious when using DMSO as a vehicle for drug administration.

  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. Repeated methamphetamine administration differentially alters fos expression in caudate-putamen patch and matrix compartments and nucleus accumbens.

    Directory of Open Access Journals (Sweden)

    Jakub P Jedynak

    Full Text Available BACKGROUND: The repeated administration of psychostimulant drugs produces a persistent and long-lasting increase ("sensitization" in their psychomotor effects, which is thought to be due to changes in the neural circuitry that mediate these behaviors. One index of neuronal activation used to identify brain regions altered by repeated exposure to drugs involves their ability to induce immediate early genes, such as c-fos. Numerous reports have demonstrated that past drug experience alters the ability of drugs to induce c-fos in the striatum, but very few have examined Fos protein expression in the two major compartments in the striatum--the so-called patch/striosome and matrix. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we used immunohistochemistry to investigate the effects of pretreatment with methamphetamine on the ability of a subsequent methamphetamine challenge to induce Fos protein expression in the patch and matrix compartments of the dorsolateral and dorsomedial caudate-putamen and in the ventral striatum (nucleus accumbens. Animals pretreated with methamphetamine developed robust psychomotor sensitization. A methamphetamine challenge increased the number of Fos-positive cells in all areas of the dorsal and ventral striatum. However, methamphetamine challenge induced Fos expression in more cells in the patch than in the matrix compartment in the dorsolateral and dorsomedial caudate-putamen. Furthermore, past experience with methamphetamine increased the number of methamphetamine-induced Fos positive cells in the patch compartment of the dorsal caudate putamen, but not in the matrix or in the core or shell of the nucleus accumbens. CONCLUSIONS/SIGNIFICANCE: These data suggest that drug-induced alterations in the patch compartment of the dorsal caudate-putamen may preferentially contribute to some of the enduring changes in brain activity and behavior produced by repeated treatment with methamphetamine.

  2. Effects of ketamine and midazolam on morphine induced dependence and tolerance in mice

    Directory of Open Access Journals (Sweden)

    Bohlul Habibi Asl Kambiz Hassanzadeh

    2004-08-01

    Full Text Available The aim of this study was to investigate the effects of ketamine and midazolam on prevention of the development of morphine tolerance and dependence in mice. Different groups of mice received morphine (50 mg/kg, sc, morphine (50 mg/kg, sc + ketamine (25,50,75 mg/kg, ip, morphine (50 mg/kg, sc + midazolam (0.5,1,2 mg/kg, ip , morphine (50 mg/kg , sc + ketamine (50 mg/kg, ip + midazolam (1 mg/kg, ip once a day for four days. Tolerance was assessed by administration of morphine (9 mg/kg, ip on fifth day. Withdrawal symptoms were assessed by administration of naloxane (4 mg/kg, ip two hours after co-administration of morphine with either ketamine or midazolam. It was found that pretreatment with ketamine or midazolam decreased the degree of tolerance and withdrawal symptoms. Additionally co-administration of ketamine and midazolam before morphine therapy decreased the tolerance and dependence significantly. From these results it may concluded that administration of ketamine and midazolam alone or in combination could prevent the development of tolerance and dependence to morphine. These effects can be related to the N-Methyl-D-Aspartate (NMDA receptor antagonist behavior of ketamine and GABA-receptor agonist behavior of midazolam.

  3. In vitro morphine metabolism by rat microglia.

    Science.gov (United States)

    Togna, Anna Rita; Antonilli, Letizia; Dovizio, Melania; Salemme, Adele; De Carolis, Lorenza; Togna, Giuseppina I; Patrignani, Paola; Nencini, Paolo

    2013-12-01

    Morphine is mainly transformed to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in the liver. Glucuronidation is also performed by rat brain homogenates and UDP-glucuronosyltransferases (UGTs) are present in the brain. Here we investigated the possibility that microglia transforms morphine into its metabolites M3G and M6G. Primary cultures of neonatal rat microglia were incubated for different intervals of time in basal conditions or with different concentrations of morphine. The following measures were performed on these cultures and/or in the medium: (i) morphine as well as M3G and M6G concentrations; (ii) levels of mRNA coding for UGT1A1, UGT1A6, UGT1A7, and UGT2B1 as well as their protein levels; (iii) released prostaglandin (PG)E2 and nitrite concentrations. Results show that in basal conditions morphine and M3G are produced by microglia; accordingly, these cells expressed UGT1A1, UGT1A6 and UGT1A7, but not UGT2B1. When cultures were exposed to different concentrations of exogenous morphine, M6G was also synthesized. This shift in the glucuronidation was associated with variations in the expression of UGT isozymes. In particular, UGT1A7 expression was rapidly upregulated and this event was translated into enhanced protein levels of UGT1A7; lesser effects were exerted on UGT1A1 and UGT1A6. Upon prolonged exposure to morphine, microglial cell UGT expression returned to baseline conditions or even to reduced levels of expression. Morphine exposure did not affect the synthesis of both PGE2 and nitrites, ruling out a generalized priming of microglia by morphine. In conclusion, this study suggests that morphine glucuronides found in the cerebrospinal liquor upon peripheral morphine administration may at least in part be brain-born, reconciling the conceptual gap between the high hydrophilic features of morphine glucuronides and their presence beyond the blood-brain barrier.

  4. Morphine enhances purine nucleotide catabolism in rive and in vitro

    Institute of Scientific and Technical Information of China (English)

    Chang LIU; Jian-kai LIU; Mu-jie KAN; Lin GAO; Hai-ying FU; Hang ZHOU; Min HONG

    2007-01-01

    Aim: To investigate the effect and mechanism of morphine on purine nucleotide catabolism. Methods: The rat model of morphine dependence and withdrawal and rat C6 glioma cells in culture were used. Concentrations of uric acid in the plasma were measured by the uricase-rap method, adenosine deaminase (ADA) and xan- thine oxidase (XO) in the plasma and tissues were measured by the ADA and XO test kit. RT-PCR and RT-PCR-Southern blotting were used to examine the relative amount of ADA and XO gene transcripts in tissues and C6 cells. Results: (i) the concentration of plasma uric acid in the morphine-administered group was signifi-cantly higher (P<0.05) than the control group; (ii) during morphine administration and withdrawal periods, the ADA and XO concentrations in the plasma increased significantly (P<0.05); (iii) the amount of ADA and XO in the parietal lobe, liver, small intestine, and skeletal muscles of the morphine-administered groups increased, while the level of ADA and XO in those tissues of the withdrawal groups decreased; (iv) the transcripts of the ADA and XO genes in the parietal lobe, liver, small intestine, and skeletal muscles were higher in the morphine-administered group. The expression of the ADA and XO genes in those tissues returned to the control level during morphine withdrawal, with the exception of the skeletal muscles; and (v) the upregulation of the expression of the ADA and XO genes induced by morphine treatment could be reversed by naloxone. Conclusion: The effects of morphine on purine nucleotide metabolism might be an important, new biochemical pharmacological mechanism of morphine action.

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

    Institute of Scientific and Technical Information of China (English)

    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

  6. Role of dorsal hippocampal orexin-1 receptors in memory restoration induced by morphine sensitization phenomenon.

    Science.gov (United States)

    Alijanpour, S; Tirgar, F; Zarrindast, M-R

    2016-01-15

    The present study was examined the blockade of CA1 orexin-1 receptors (OX1Rs) of the dorsal hippocampus in the induction or expression phase on morphine sensitization-induced memory restoration using the Morris water maze (MWM) apparatus. Results showed that pre-training administration of morphine (5mg/kg, s.c.) increases escape latency and traveled distance, while does not alter swimming speed. This supports the impairing effect of morphine on the spatial memory acquisition in male adult rats. Also, in the retrieval session (probe trial) this treatment decreased the time spent in the target quadrant. Moreover, morphine-induced sensitization (15 or 20mg/kg, s.c.; once daily for 3days and followed by 5days no drug treatment) restored the memory acquisition/retrieval deficit which had been induced by pre-training administration of morphine (5mg/kg, s.c.). Intra-CA1 microinjection of subthreshold doses of SB-334867 (OX1Rs antagonist; 10, 20 and 40nmol/rat), 5min before morphine (20mg/kg/day×3days, s.c.; induction phase for morphine sensitization) did not alter restoration of memory acquisition/retrieval produced by the morphine sensitization phenomenon. In contrast, microinjection of subthreshold doses of SB-334867 (10, 20 and 40nmol/rat) into the CA1 region in the training session, 5min prior to morphine (5mg/kg, s.c.; expression phase for morphine sensitization) blocked the spatial memory acquisition/retrieval in morphine-sensitized rats. In conclusion, these findings show that morphine sensitization reverses morphine-induced amnesia. Furthermore, the blockade of CA1 OX1Rs in the expression phase, but not in the induction phase, disrupts memory restoration induced by morphine sensitization.

  7. Impact of chronic morphine on delta opioid receptor-expressing neurons in the mouse hippocampus.

    Science.gov (United States)

    Erbs, E; Faget, L; Ceredig, R A; Matifas, A; Vonesch, J-L; Kieffer, B L; Massotte, D

    2016-01-28

    Delta opioid (DOP) receptors participate to the control of chronic pain and emotional responses. Recent data also identified their implication in spatial memory and drug-context associations pointing to a critical role of hippocampal delta receptors. To better appreciate the impact of repeated drug exposure on their modulatory activity, we used fluorescent knock-in mice that express a functional delta receptor fused at its carboxy-terminus with the green fluorescent protein in place of the native receptor. We then tested the impact of chronic morphine treatment on the density and distribution of delta receptor-expressing cells in the hippocampus. A decrease in delta receptor-positive cell density was observed in the CA1, CA3 and dentate gyrus without alteration of the distribution across the different GABAergic populations that mainly express delta receptors. This effect partly persisted after four weeks of morphine abstinence. In addition, we observed increased DOP receptor expression at the cell surface compared to saline-treated animals. In the hippocampus, chronic morphine administration thus induces DOP receptor cellular redistribution and durably decreases delta receptor-expressing cell density. Such modifications are likely to alter hippocampal physiology, and to contribute to long-term cognitive deficits.

  8. Region-specific induction of deltaFosB by repeated administration of typical versus atypical antipsychotic drugs.

    Science.gov (United States)

    Atkins, J B; Chlan-Fourney, J; Nye, H E; Hiroi, N; Carlezon, W A; Nestler, E J

    1999-08-01

    Whereas acute administration of many types of stimuli induces c-Fos and related proteins in brain, recent work has shown that chronic perturbations cause the region-specific accumulation of novel Fos-like proteins of 35-37 kD. These proteins, termed chronic FRAs (Fos-related antigens), have recently been shown to be isoforms of DeltaFosB, which accumulate in brain due to their enhanced stability. In the present study, we sought to extend earlier findings that documented the effects of acute administration of antipsychotic drugs (APDs) on induction of Fos-like proteins by investigating the ability of typical and aytpical APDs, after chronic administration, to induce these DeltaFosB isoforms in several brain regions implicated in the clinical actions of these agents. By Western blotting we found that chronic administration of the typical APD, haloperidol, dramatically induces DeltaFosB in caudate-putamen (CP), a brain region associated with the extrapyramidal side effects of this drug. A smaller induction was seen in the nucleus accumbens (NAc) and prefrontal cortex (PFC), brain regions associated with the antipsychotic effects of the drug. In contrast, chronic administration of the prototype atypical APD clozapine failed to significantly increase levels of DeltaFosB in any of the three brain regions, and even tended to reduce DeltaFosB levels in the NAc. Two putative atypical APDs, risperidone and olanzapine, produced small but still significant increases in the levels of DeltaFosB in CP, but not NAc or PFC. Studies with selective receptor antagonists suggested that induction of DeltaFosB in CP and NAc is most dependent on antagonism of D2-D3 dopamine receptors, with antagonism of D1-like receptors most involved in the PFC. Immunohistochemical analysis confirmed the greater induction of DeltaFosB in CP by typical versus atypical APDs, with no significant induction seen in PFC with either class of APD. Together, these findings demonstrate that repeated administration

  9. Permanent relief from intermittent cold stress-induced fibromyalgia-like abnormal pain by repeated intrathecal administration of antidepressants

    Directory of Open Access Journals (Sweden)

    Mukae Takehiro

    2011-09-01

    Full Text Available Abstract Background Fibromyalgia (FM is characterized by chronic widespread pain, which is often refractory to conventional painkillers. Numerous clinical studies have demonstrated that antidepressants are effective in treating FM pain. We previously established a mouse model of FM-like pain, induced by intermittent cold stress (ICS. Results In this study, we find that ICS exposure causes a transient increase in plasma corticosterone concentration, but not in anxiety or depression-like behaviors. A single intrathecal injection of an antidepressant, such as milnacipran, amitriptyline, mianserin or paroxetine, had an acute analgesic effect on ICS-induced thermal hyperalgesia at post-stress day 1 in a dose-dependent manner. In addition, repeated daily antidepressant treatments during post-stress days 1-5 gradually reversed the reduction in thermal pain threshold, and this recovery was maintained for at least 7 days after the final treatment. In addition, relief from mechanical allodynia, induced by ICS exposure, was also observed at day 9 after the cessation of antidepressant treatment. In contrast, the intravenous administration of these antidepressants at conventional doses failed to provide relief. Conclusions These results suggest that the repetitive intrathecal administration of antidepressants permanently cures ICS-induced FM pain in mice.

  10. Regulation of dopaminergic markers expression in response to acute and chronic morphine and to morphine withdrawal.

    Science.gov (United States)

    García-Pérez, Daniel; Núñez, Cristina; Laorden, M Luisa; Milanés, M Victoria

    2016-03-01

    Dopamine (DA) is thought to represent a teaching signal and has been implicated in the induction of addictive behaviours. Dysfunction of DA homeostasis leading to high or low DA levels is causally linked to addiction. Previously, it has been proposed that the transcription factors Nurr1 and Pitx3, which are critical for transcription of a set of genes involved in DA metabolism in the mesolimbic pathway, are associated with addiction pathology. Using quantitative real-time polymerase chain reaction, immunofluorescence and Western blotting, we studied the effects of single morphine administration, morphine dependence and withdrawal on the DA markers DA transporters (DAT), vesicular monoamine transporters (VMAT2) and DA 2 receptor subtype (DRD2), DA 1 receptor subtype as well as tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and/or nucleus accumbens (NAc). In addition, Nurr1 and Pitx3 expression was also measured. Present data showed a high degree of colocalization of Nurr1 and Pitx3 with TH(+) neurons in the VTA. We found that the increased Nurr1 and/or Pitx3 levels during morphine dependence and in morphine-withdrawn rats were associated to an increase of DAT, VMAT2 and DRD2. Altogether, present data indicate that morphine dependence and withdrawal induced consistent alterations of most of the DA markers, which was correlated with transcription factors involved in the maintenance of DA neurons in drug-reward pathways, suggesting that Nurr1 and Pitx3 regulation might be associated with controlling adaptation to chronic morphine and to morphine withdrawal-induced alterations of DA neurons activity in the mesolimbic pathway.

  11. Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice.

    Science.gov (United States)

    Schiavon, Angélica Pupin; Bonato, Jéssica Mendes; Milani, Humberto; Guimarães, Francisco Silveira; Weffort de Oliveira, Rúbia Maria

    2016-01-04

    Therapeutic effects of antidepressants and atypical antipsychotics may arise partially from their ability to stimulate neurogenesis. Cannabidiol (CBD), a phytocannabinoid present in Cannabis sativa, presents anxiolytic- and antipsychotic-like effects in preclinical and clinical settings. Anxiolytic-like effects of repeated CBD were shown in chronically stressed animals and these effects were parallel with increased hippocampal neurogenesis. However, antidepressant-like effects of repeated CBD administration in non-stressed animals have been scarcely reported. Here we investigated the behavioral consequences of single or repeated CBD administration in non-stressed animals. We also determined the effects of CBD on cell proliferation and neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ). Single CBD 3mg/kg administration resulted in anxiolytic-like effect in mice submitted to the elevated plus maze (EPM). In the tail suspension test (TST), single or repeated CBD administration reduced immobility time, an effect that was comparable to those of imipramine (20 mg/kg). Moreover, repeated CBD administration at a lower dose (3 mg/kg) increased cell proliferation and neurogenesis, as seen by an increased number of Ki-67-, BrdU- and doublecortin (DCX)-positive cells in both in DG and SVZ. Despite its antidepressant-like effects in the TST, repeated CBD administration at a higher dose (30 mg/kg) decreased cell proliferation and neurogenesis in the hippocampal DG and SVZ. Our findings show a dissociation between behavioral and proliferative effects of repeated CBD and suggest that the antidepressant-like effects of CBD may occur independently of adult neurogenesis in non-stressed Swiss mice.

  12. Relief of abdominal pain by morphine without altering physical signs in acute appendicitis

    Institute of Scientific and Technical Information of China (English)

    YUAN Yong; CHEN Jia-yong; GUO Hao; ZHANG Yi; LIANG Dao-ming; ZHOU Dong; ZHAO Hui; LIN Feng

    2010-01-01

    Background Abdominal pain is a common symptom among patients with acute appendicitis, yet these patients havelong been denied relief from suffering because of widespread misconceptions associated with the use of opioids. Wedetermined whether morphine hydrochloride masked the physical signs in adults with acute appendicitis and assessedthe efficacy of morphine in relieving abdominal pain.Methods A prospective, double-blind, placebo controlled, clinical trial was conducted with 106 adult patients between16 and 70 years old with acute appendicitis. Patients were randomly divided into a morphine group (n=54) or a normalsaline group (n=52). All patients presented with acute abdominal pain with onset within 3 days. The morphine groupreceived hypodermic injection of morphine (0.15 mg/kg; maximum 20 mg) and the control group members were given anequivalent volume of normal saline solution. The clinical symptoms, physical signs, and patients' cooperation duringphysical examination were assessed before and after 30 minutes of morphine or normal saline administration.Results Abdominal pain was significantly relieved and the patients' cooperation was improved in the morphine groupafter 30 minutes treatment compared with the control group and before morphine administration (P0.05).Conclusions Morphine relieved abdominal pain and improved the patients' cooperation for treatment and care.Furthermore, the morphine did not mask the physical signs of acute appendicitis.

  13. Clonidine attenuates morphine withdrawal and subsequent drug sensitization in rhesus monkeys1

    Institute of Scientific and Technical Information of China (English)

    Su-qing CHEN; Hai-feng ZHAI; Yan-ying CUI; Jie SHI; Bernard LE FOLL; Lin LU

    2007-01-01

    Aim: Clonidine is an α2 adrenoceptor agonist that is frequently used to reduce withdrawal symptoms during opioid detoxification in humans. The long-term effects of clonidine on withdrawal symptoms and its effects on subsequent drug exposure have not been thoroughly documented. The aim of the study was to determine if clonidine administered during morphine withdrawal in rhesus mon-keys produces long-lasting effects on withdrawal symptoms and alters the effects of subsequently taken drugs of abuse. Methods: Adult male rhesus monkeys were treated with increasing doses of morphine for 90 d to induce opiate (narcotic)dependence. The immediate and long-lasting effects of 1 week's administration of clonidine were measured via the recording of morphine withdrawal signs and the subsequent effects of challenge injections of morphine or cocaine. Results:Monkeys chronically treated with morphine displayed withdrawal signs that lasted 2 weeks after cessation of morphine administration and displayed sensitized re-sponses to subsequent morphine and cocaine injections. Clonidine significantly reduced certain morphine withdrawal signs and overall withdrawal score, but these effects did not persist upon cessation of clonidine treatment. Sensitization to the effects of morphine and cocaine were significantly reduced in monkeys previ-ously treated with clonidine. Conclusion: Our results suggest that in addition to its short-term alleviating effect on morphine withdrawal signs, clonidine may re-duce subsequent effects of drugs of abuse after prolonged abstinence.

  14. Effects of berberine on acquisition and reinstatement of morphine-induced conditioned place preference in mice

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    Faezeh Vahdati Hassani

    2016-03-01

    Full Text Available Objective: It has been shown that berberine, a major component of Berberis vulgaris extract, modulates the activity of several neurotransmitter systems including dopamine (Da and N-methyl-D-aspartate (NMDA contributing to rewarding and reinforcing effects of morphine. Drug craving and relapsing even after a long time of abstinence therapy are the most important problems of addiction. In the present study, we investigated the alleviating effects of berberine on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP in mice. Materials and Methods: In male NMRI mice, the acquisition of CPP was established by 40 mg/kg of morphine sulphate injection and extinguished after the extinction training and reinstated by a 10 mg/kg injection of morphine.  The effects of different doses of berberine (5, 10, and 20 mg/kg on the acquisition and reinstatement induced by morphine were evaluated in a conditioned place preference test. Results: The results showed that intraperitoneal administration of berberine (5, 10, and 20 mg/kg did not induce conditioned appetitive or aversive effects. Injection of berberine (10 and 20 mg/kg 2 h before the morphine administration reduced acquisition of morphine-induced CPP. In addition, same doses of berberine significantly prevented the reinstatement of morphine-induced CPP. Conclusion: These results suggest that berberine can reduce the acquisition and reinstatement of morphine-induced conditioned place preference and may be useful in treatment of morphine addiction.

  15. Effect of Bacopasides on acquisition and expression of morphine tolerance.

    Science.gov (United States)

    Rauf, Khalid; Subhan, Fazal; Abbas, Muzaffar; Badshah, Amir; Ullah, Ihsan; Ullah, Sami

    2011-07-15

    Opioids are extensively used for the management of both chronic malignant and non malignant pains. One major serious limitation associated with chronic use of opioids is the development of tolerance to its analgesic effect. The effect of Bacopa monnieri, a renowned ayurvedic medicine for acquisition and expression of morphine tolerance in mice, was investigated. Bacopa monnieri, n-Butanol fraction was analyzed on High performance liquid chromatography (HPLC), for Bacopaside A major components i.e. Bacoside A(3), Bacopaside ll and Bacosaponin C. Antinociceptive effect of n-Butanol extract of Bacopa monnieri (n Bt-ext BM) (5, 10 and 15 mg/kg) was assessed on hot plate. Effect of different doses of n Bt-ext BM on morphine antinociception was also assessed. n Bt-ext BM was also screened for development of tolerance to antinociceptive effect of Bacopa monnieri by administering 15 mg/kg n Bt-ext BM for seven days. Tolerance to morphine analgesia was induced in mice by administering intraperitoneally (I.P.) 20 mg/kg morphine twice daily for five days. Acute and Chronic administration of 5, 10 and 15 mg/kg n Bt-ext BM significantly reduced both expression and development of tolerance to morphine analgesia in mice. Additionally, Bacopa monnieri was found to enhance antinociceptive effect of morphine in intolerant animals. However, no tolerance to Bacopa monnieri antinociceptive effect was observed in seven days treatment schedule. These findings indicate effectiveness of Bacopa monnieri for management of morphine tolerance.

  16. Interaction between halothane and morphine on isolated heart muscle.

    Science.gov (United States)

    Laorden, M L; Hernandez, J; Carceles, M D; Miralles, F S; Puig, M M

    1990-01-17

    The present study describes the effects of halothane on morphine activity in the isolated left atria of the rat. Concentration-response curves were obtained for the negative inotropic effects of morphine on electrically stimulated left atria. Morphine significantly decreased the contractile force, with an inhibitory concentration 16 (IC16) of 3.130.698 +/- 22.5 X 10(-9) M. The opiate agonist was more potent in reserpinized rats, causing a consistent negative inotropic action over a wide range (10(-8)-10(-4) M) or morphine concentrations. The IC16 of morphine was significantly (P less than 0.001) decreased in the presence of 1.5% v/v halothane. The administration of L-naloxone (3 X 10(-7)-10(-6) M) but not D-naloxone (10(-6) M) antagonized the inhibitory effects of morphine in the presence of halothane. These results demonstrate that halothane increases the potency of morphine on the isolated left atria and suggest that this effect is mediated by opioid receptors.

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

    OpenAIRE

    Zdenka Drastichova; Jitka Skrabalova; Petr Jedelsky; Jan Neckar; Frantisek Kolar; Jiri Novotny

    2012-01-01

    Morphine belongs among the most commonly used opioids in medical practice due to its strong analgesic effects. However, sustained administration of morphine leads to the development of tolerance and dependence and may cause long-lasting alterations in nervous tissue. Although proteomic approaches enabled to reveal changes in multiple gene expression in the brain as a consequence of morphine treatment, there is lack of information about the effect of this drug on heart tissue. Here we studied ...

  18. Early Effects of Single and Low-Frequency Repeated Administration of Teriparatide, hPTH(1-34), on Bone Formation and Resorption in Ovariectomized Rats.

    Science.gov (United States)

    Isogai, Yukihiro; Takao-Kawabata, Ryoko; Takakura, Aya; Sugimoto, Emika; Nakazono, Osamu; Ikegaki, Ichiro; Kuriyama, Hiroshi; Ishizuya, Toshinori

    2015-10-01

    Intermittent repeated administration of teriparatide (TPTD) has potent anabolic effects on bones in vivo. However, TPTD has both anabolic and catabolic effects on osteoblasts in vitro, and the mechanisms underlying its promotion of bone formation are unclear. This study aimed to elucidate the time-dependent changes in bone formation and resorption by examining changes in bone turnover markers and bone tissue over time after TPTD administration with low frequency in ovariectomized rats. The amount of serum osteocalcin, a bone formation marker, was transiently reduced after single TPTD administration, but increased thereafter, remaining increased for several days. In contrast, the amount of excreted urinary C-telopeptide, a bone resorption marker, increased transiently after single TPTD administration, and subsequently returned to control levels on the day after administration. Tissue histomorphometric analyses conducted 8 h after administration showed no changes in bone formation or bone resorption parameters. However, at 48 h, the bone formation parameters OS/BS and Ob.S/BS were increased, while the bone resorption parameter ES/BS was decreased. After repeated TPTD administration for 4 weeks, OS/BS, Ob.S/BS, and MS/BS increased, while Oc.S/BS decreased. Serum osteocalcin at 4 weeks after repeated administration was significantly correlated with OS/BS and Ob.S/BS. These present findings indicate that TPTD has dual, time-dependent effects on bone resorption and bone formation. Immediately after single administration, there was transient promotion of bone resorption and suppression of bone formation. However, sustained stimulation of bone formation occurred thereafter. Furthermore, these data suggest that this sustained bone formation led to anabolic effects with repeated TPTD administration.

  19. AMPAkines and morphine provide complementary analgesia.

    Science.gov (United States)

    Sun, Yongjun; Liu, Kevin; Martinez, Erik; Dale, Jahrane; Huang, Dong; Wang, Jing

    2017-09-15

    Glutamate signaling in the central nervous system is known to play a key role in pain regulation. AMPAkines can enhance glutamate signaling through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. previous studies have shown that AMPAkines are effective analgesic agents, and their site of action is likely in the brain. It is not known, however, if AMPAkines can provide complementary analgesia in combination with opioids, the most commonly used analgesics. Here, we show that the co-administration of an AMPAkine with morphine can provide additional analgesia, both in naïve rats and in rats that experience postoperative pain. Furthermore, we show that this AMPAkine can be administered directly into the prefrontal cortex to provide analgesia, and that prefrontal AMPAkine infusion, similar to systemic administration, can provide added pain relief to complement morphine analgesia. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  20. Use of polyglycerol (PG), instead of polyethylene glycol (PEG), prevents induction of the accelerated blood clearance phenomenon against long-circulating liposomes upon repeated administration.

    Science.gov (United States)

    Abu Lila, Amr S; Nawata, Kosuke; Shimizu, Taro; Ishida, Tatsuhiro; Kiwada, Hiroshi

    2013-11-01

    The accelerated blood clearance (ABC) phenomenon accounts for the rapid systemic clearance of PEGylated nanocarriers upon repeated administrations. IgM production against the polyethylene glycol (PEG) coating in PEGylated liposomes is now known to be responsible for such unexpected pharmacokinetical alterations. The ABC phenomenon poses a remarkable clinical challenge by reducing the therapeutic efficacy of encapsulated drugs and causing harmful effects due to the altered tissue distribution pattern of the drugs. In this study, we investigated the in vivo performance of liposomes modified with polyglycerol (PG) upon repeated injection, and the in vivo therapeutic efficacy of such liposomes when they encapsulated a cytotoxic agent, doxorubicin (DXR). Repeated injection of PEG-coated liposomes in rats induced the ABC phenomenon, while repeated injection of PG-coated liposomes did not. In addition, DXR-containing PG-coated liposomes showed antitumor activity that was superior to that of free DXR and similar to that of DXR-containing PEG-coated liposomes upon repeated administration. These results indicate that polyglycerol (PG) might represent a promising alternative to PEG via enhancing the in vivo performance of liposomes by not eliciting the ABC phenomenon upon repeated administration.

  1. Morphine dependence and withdrawal induced changes in cholinergic signaling

    Science.gov (United States)

    Neugebauer, Nichole M.; Einstein, Emily B.; Lopez, Maria B.; McClure-Begley, Tristan D.; Mineur, Yann S.; Picciotto, Marina R.

    2013-01-01

    Cholinergic signaling is thought to be involved in morphine dependence and withdrawal, but the specific mechanisms involved remain unclear. The current study aimed to identify alterations in the cholinergic system that may contribute to the development of morphine dependence and withdrawal. Acetylcholinesterase (AChE) activity and [3H]-epibatidine binding were evaluated in order to determine if morphine dependence and withdrawal induces alterations in cholinergic signaling or expression of high affinity nicotinic acetylcholine receptors (nAChRs) in the midbrain (MB), medial habenula (MHb) and interpeduncular nucleus (IPN). The effect of cholinergic signaling through nAChRs on morphine-withdrawal induced jumping behavior was then determined. Lastly, the contribution of β4-containing nAChRs receptors in the MHb to morphine-withdrawal induced jumping behavior and neuronal activity as indicated by c-fos expression was assessed. Chronic morphine administration decreased AChE activity in MB and MHb, an effect that was no longer present following precipitated withdrawal. Morphine dependent mice showed increased nicotinic acetylcholine receptor (nAChR) levels in MB. Further, nicotine (0.4 mg/kg) and lobeline (3 mg/kg) decreased jumping behavior while mecamylamine (1 mg/kg) had no effect. Knock-down of β4 subunit-containing nAChRs in the MHb attenuated c-fos activation, but did not decrease morphine withdrawal-induced jumping. Thus, morphine withdrawal induces cholinergic signaling in the MHb, but this does not appear to be responsible for the effects of cholinergic drugs on somatic signs of opiate withdrawal, as measured by jumping behavior. PMID:23651795

  2. Inhibition of Spinal Oxidative Stress by Bergamot Polyphenolic Fraction Attenuates the Development of Morphine Induced Tolerance and Hyperalgesia in Mice.

    Directory of Open Access Journals (Sweden)

    Filomena Lauro

    Full Text Available Citrus Bergamia Risso, commonly known as Bergamot, is a fruit whose Essential Oil and Bergamot Polyphenolic Fraction have numerous medicinal properties. It is also an excellent antioxidant and in this study, for the first time, its potential effect on morphine induced tolerance in mice has been investigated. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice is consistently associated with increased formation of superoxide, malondialdehyde and tyrosine-nitrated proteins in the dorsal horn of the spinal cord such as the enzyme glutamine synthase. Nitration of this protein is intimately linked to inactivation of its biological function and resulting increase of glutamate levels in the spinal cord. Administration of Bergamot Polyphenolic Fraction (5-50 mg/kg attenuated tolerance development. This effect was accompanied by reduction of superoxide and malondialdehyde production, prevention of GS nitration, re-establishment of its activity and of glutamate levels. Our studies confirmed the main role of free radicals during the cascade of events induced by prolonged morphine treatment and the co-administration of natural derivatives antioxidant such as Bergamot Polyphenolic Fraction can be an important therapeutic approach to restore opioids analgesic efficacy.

  3. Inhibition of Spinal Oxidative Stress by Bergamot Polyphenolic Fraction Attenuates the Development of Morphine Induced Tolerance and Hyperalgesia in Mice.

    Science.gov (United States)

    Lauro, Filomena; Giancotti, Luigino Antonio; Ilari, Sara; Dagostino, Concetta; Gliozzi, Micaela; Morabito, Chiara; Malafoglia, Valentina; Raffaeli, William; Muraca, Maurizio; Goffredo, Bianca M; Mollace, Vincenzo; Muscoli, Carolina

    2016-01-01

    Citrus Bergamia Risso, commonly known as Bergamot, is a fruit whose Essential Oil and Bergamot Polyphenolic Fraction have numerous medicinal properties. It is also an excellent antioxidant and in this study, for the first time, its potential effect on morphine induced tolerance in mice has been investigated. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice is consistently associated with increased formation of superoxide, malondialdehyde and tyrosine-nitrated proteins in the dorsal horn of the spinal cord such as the enzyme glutamine synthase. Nitration of this protein is intimately linked to inactivation of its biological function and resulting increase of glutamate levels in the spinal cord. Administration of Bergamot Polyphenolic Fraction (5-50 mg/kg) attenuated tolerance development. This effect was accompanied by reduction of superoxide and malondialdehyde production, prevention of GS nitration, re-establishment of its activity and of glutamate levels. Our studies confirmed the main role of free radicals during the cascade of events induced by prolonged morphine treatment and the co-administration of natural derivatives antioxidant such as Bergamot Polyphenolic Fraction can be an important therapeutic approach to restore opioids analgesic efficacy.

  4. The effect of repeated nicotine administration on the performance of drug-naive rats in a five-choice serial reaction time task.

    Science.gov (United States)

    Blondel, A; Simon, H; Sanger, D J; Moser, P

    1999-11-01

    Nicotine improves cognitive performance both in animals and in humans, particularly in tests involving attentional processes. The five-choice serial reaction time task (5-CSRTT) is widely used as a model of attentional performance in rats, and previous studies have demonstrated effects of nicotine in this task on measures such as improved reaction time. Using a modified version of this task (in which rats were required to respond to the disappearance of one of five stimulus lights), we evaluated the effects of repeated nicotine administration (0.3 mg/kg, intraperitoneally, on three occasions over 7 days) in drug-naive rats. After the first administration, nicotine increased accuracy and reduced inappropriate responding (anticipatory responses and responses during time-out) compared to performance following vehicle administration on the preceding day. However, with repeated administration the improvement in accuracy disappeared, and other effects became apparent. Thus, after the third administration the main effects of nicotine were to increase inappropriate responding and to reduce reaction times. A fourth administration 1-2 weeks later produced similar results to the third administration, suggesting that the effects of nicotine were now constant. Despite the general increase in inappropriate responding, there was no impairment in accuracy. In contrast to the response to repeated nicotine, the performance of the rats on the 3 vehicle days remained constant. These data demonstrate that the administration of nicotine to drug-naive subjects improves performance in the 5-CSRTT but that with repeated administration this effect disappears and is replaced by a profile in which inappropriate and impulsive responding predominate.

  5. Paradoxical reaction of raynaud phenomenon following the repeated administration of iloprost in a patient with diffuse cutaneous systemic sclerosis.

    Science.gov (United States)

    Barreira, Rebeca Iglesias; García, Belén Bardán; López, Mónica Granero; Legazpi, Iria Rodríguez; Díaz, Hortensia Álvarez; Penín, Isaura Rodríguez

    2012-10-01

    To report a paradoxical reaction of Raynaud phenomenon following the repeated administration of iloprost in a patient with diffuse cutaneous systemic sclerosis with vascular involvement. In January 2006, a 40-year-old male was diagnosed with diffuse cutaneous systemic sclerosis with pulmonary, esophageal, cutaneous, and vascular involvement (Raynaud phenomenon, with digital ulcers on his hands). In December 2008, treatment with iloprost was started due to worsening disease. Nine cycles of iloprost were administered at a rate of 0.5-1 ng/kg/min (6 hours per day, for 5 days every 6-8 weeks); the patient tolerated this treatment well. However, on the fourth day of cycles 10 and 11, the patient developed paradoxical Raynaud phenomenon in the hand with perfusion when the infusion was increased to 1 ng/kg/min, requiring treatment to be stopped. Treatment was continued during cycles 12 and 13 at 0.5 ng/kg/min; the patient tolerated the treatment well, although paradoxical Raynaud phenomenon occurred when the rate of infusion was increased. Raynaud phenomenon is extremely common in patients with scleroderma, and often is severe. Iloprost has vasodilating, antiplatelet, cytoprotective, and immunomodulating properties, and has been found to be an efficacious alternative to nifedipine for the treatment of Raynaud phenomenon in patients with scleroderma. The Naranjo probability scale indicated that iloprost was the probable cause of the paradoxical Raynaud phenomenon in this patient. This case demonstrates a probable relationship between the rate of infusion of iloprost and the paradoxical reaction of Raynaud phenomenon.

  6. Effect of repeated oral administration of levofloxacin, enrofloxacin, and meloxicam on antioxidant parameters and lipid peroxidation in rabbits.

    Science.gov (United States)

    Khan, Adil Mehraj; Rampal, Satyavan; Sood, Naresh Kumar

    2016-03-09

    The effect of 21 days of repeated oral administration of levofloxacin and enrofloxacin both alone and in combination with meloxicam, on the oxidative balance in blood was evaluated in rabbits. Rabbits were randomly allocated to six groups of four animals each. Control group was gavaged 5% dextrose and 2% benzyl alcohol. Three groups were exclusively gavaged meloxicam (0.2 mg/kg body weight o.d.), levofloxacin hemihydrate (10 mg/kg body weight b.i.d 12 h), and enrofloxacin (20 mg/kg body weight o.d.), respectively. Two other groups were co-gavaged meloxicam with levofloxacin hemihydrate and enrofloxacin, respectively. A reduction (p meloxicam both alone and in combination with levofloxacin, whereas an increase (p meloxicam-alone treated group and inhibited (p meloxicam co-treated group. The activity of catalase was non-significantly different between various groups. Enrofloxacin-treated groups had higher (p meloxicam both alone and in combination with levofloxacin (p meloxicam.

  7. Upregulation of nucleoside triphosphate diphosphohydrolase-1 and ecto-5'-nucleotidase in rat hippocampus after repeated low-dose dexamethasone administration.

    Science.gov (United States)

    Drakulić, Dunja; Stanojlović, Miloš; Nedeljković, Nadežda; Grković, Ivana; Veličković, Nataša; Guševac, Ivana; Mitrović, Nataša; Buzadžić, Ivana; Horvat, Anica

    2015-04-01

    Although dexamethasone (DEX), a synthetic glucocorticoid receptor (GR) analog with profound effects on energy metabolism, immune system, and hypothalamic-pituitary-adrenal axis, is widely used therapeutically, its impact on the brain is poorly understood. The aim of the present study was to explore the effect of repeated low-dose DEX administration on the activity and expression of the ectonucleotidase enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft. Ectonucleotidases tested were ectonucleoside triphosphate diphosphohydrolase 1-3 (NTPDase1-3) and ecto-5'-nucleotidase (eN), whereas the effects were evaluated in two brain areas that show different sensitivity to glucocorticoid action, hippocampus, and cerebral cortex. In the hippocampus, but not in cerebral cortex, modest level of neurodegenerative changes as well as increase in ATP, ADP, and AMP hydrolysis and upregulation of NTPDase1 and eN mRNA expression ensued under the influence of DEX. The observed pattern of ectonucleotidase activation, which creates tissue volume with enhanced capacity for adenosine formation, is the hallmark of the response after different insults to the brain.

  8. Proteome Analysis of Rat Hippocampus Following Morphine-induced Amnesia and State-dependent Learning.

    Science.gov (United States)

    Jafarinejad-Farsangi, Saeideh; Farazmand, Ali; Rezayof, Ameneh; Darbandi, Niloufar

    2015-01-01

    Morphine's effects on learning and memory processes are well known to depend on synaptic plasticity in the hippocampus. Whereas the role of the hippocampus in morphine-induced amnesia and state-dependent learning is established, the biochemical and molecular mechanisms underlying these processes are poorly understood. The present study intended to investigate whether administration of morphine can change the expression level of rat hippocampal proteins during learning of a passive avoidance task. A step-through type passive avoidance task was used for the assessment of memory retention. To identify the complex pattern of protein expression induced by morphine, we compared rat hippocampal proteome either in morphine-induced amnesia or in state-dependent learning by two-dimensional gel electerophoresis and combined mass spectrometry (MS and MS/MS). Post-training administration of morphine decreased step-through latency. Pre-test administration of morphine induced state-dependent retrieval of the memory acquired under post-training morphine influence. In the hippocampus, a total of 18 proteins were identified whose MASCOT (Modular Approach to Software Construction Operation and Test) scores were inside 95% confidence level. Of these, five hippocampal proteins altered in morphine-induced amnesia and ten proteins were found to change in the hippocampus of animals that had received post-training and pre-test morphine. These proteins show known functions in cytoskeletal architecture, cell metabolism, neurotransmitter secretion and neuroprotection. The findings indicate that the effect of morphine on memory formation in passive avoidance learning has a morphological correlate on the hippocampal proteome level. In addition, our proteomicscreensuggests that morphine induces memory impairment and state-dependent learning through modulating neuronal plasticity.

  9. Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord

    Science.gov (United States)

    Dai, Wen-Ling; Xiong, Feng; Yan, Bing; Cao, Zheng-Yu; Liu, Wen-Tao; Liu, Ji-Hua; Yu, Bo-Yang

    2016-01-01

    Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Blockade of D2DR with its antagonist (sulpiride and L-741,626, i.t.) attenuated morphine antinociceptive tolerance without affecting basal pain perception. Sulpiride (i.t.) also down-regulated the expression of phosphorylation of NR1, PKC, MAPKs and suppressed the activation of astrocytes and microglia induced by chronic morphine administration. Particularly, D2DR was found to interact with μ opioid receptor (MOR) in neurons, and chronic morphine treatment enhanced the MOR/D2DR interactions. Sulpiride (i.t.) could disrupt the MOR/D2DR interactions and attenuate morphine tolerance, indicating that neuronal D2DR in the spinal cord may be involved in morphine tolerance possibly by interacting with MOR. These results may present new opportunities for the treatment and management of morphine-induced antinociceptive tolerance which often observed in clinic. PMID:28004735

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

    Science.gov (United States)

    Aminian, Atefeh; Javadi, Shiva; Rahimian, Reza; Dehpour, Ahmad Reza; Asadi Amoli, Fahimeh; Moghaddas, Payman; Ejtemaei Mehr, Shahram

    2016-07-01

    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.

  11. Role of dorsal hippocampal orexin-1 receptors in associating morphine reward with contextual stimuli.

    Science.gov (United States)

    Riahi, Esmail; Khodagholi, Fariba; Haghparast, Abbas

    2013-08-01

    In this study, we evaluated the role of orexin receptors in the dorsal hippocampus (dHPC) in the development of morphine-induced conditioned place preference (CPP) and modification of hippocampal c-Fos and cyclic AMP response element-binding protein (CREB) levels. Orexin-A (0.5, 5, and 50 pmol) and the orexin-1 receptor antagonist, SB334867 (10, 20, and 40 nmol), were bilaterally infused into the dHPC immediately before conditioning with morphine (0.5 or 7.5 mg/kg) using the CPP task. Western blotting was then used to measure the protein levels of c-Fos, total CREB, and phosphorylated CREB (pCREB) in the hippocampus. Orexin did not enhance the rewarding efficacy of morphine (0.5 mg/kg), but caused a reduction in hippocampal c-Fos. Successful conditioning with morphine (7.5 mg/kg) was associated with increased levels of hippocampal c-Fos and CREB, but with decreased CREB phosphorylation. Intrahippocampal administration of SB334867 before conditioning sessions disrupted the rewarding effect of morphine (7.5 mg/kg) and blocked morphine-induced increases in hippocampal CREB protein levels. The results suggest that orexin signaling within the dHPC is necessary for the development of morphine CPP. Morphine reward is related to altered levels of hippocampal c-Fos and CREB. Inhibition of morphine-induced increases in CREB levels might be the underlying mechanism for the disruption of morphine CPP.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. PKC-mediated potentiation of morphine analgesia by St. John's Wort in rodents and humans.

    Science.gov (United States)

    Galeotti, Nicoletta; Farzad, Mersedeh; Bianchi, Enrica; Ghelardini, Carla

    2014-01-01

    Our purpose was to combine the use of morphine with clinically available inhibitors of protein kinase C (PKC), finally potentiating morphine analgesia in humans. Thermal tests were performed in rodents and humans previously administered with acute or chronic morphine combined or not with increasing doses of the PKC-blocker St. John's Wort (SJW) or its main component hypericin. Phosphorylation of the γ subunit of PKC enzyme was assayed by western blotting in the periaqueductal grey matter (PAG) from rodents co-administered with morphine and hypericin and was prevented in rodent PAG by SJW or hypericin co-administration with morphine, inducing a potentiation of morphine analgesia in thermal pain. The score of pain assessment in healthy volunteers were decreased by 40% when morphine was co-administered with SJW at a dose largely below those used to obtain an antidepressant or analgesic effect in both rodents and humans. The SJW/hypericin potentiating effect lasted in time and preserved morphine analgesia in tolerant mice. Our findings indicate that, in clinical practice, SJW could reduce the dose of morphine obtaining the same analgesic effect. Therefore, SJW and one of its main components, hypericin, appear ideal to potentiate morphine-induced analgesia.

  14. Morphine Does Not Affect Myocardial Salvage in ST-Segment Elevation Myocardial Infarction

    Science.gov (United States)

    Song, Young Bin; Kim, Eun Kyoung; Jang, Woo Jin; Yang, Jeong Hoon; Hahn, Joo-Yong; Choi, Seung-Hyuk; Choi, Jin-Ho; Lee, Sang Hoon; Choe, Yeon Hyeon; Ahn, Joonghyun; Carriere, Keumhee Chough; Gwon, Hyeon-Cheol

    2017-01-01

    Recent studies have proposed intravenous (IV) morphine is associated with delayed action of antiplatelet agents in acute myocardial infarction. However, it is unknown whether morphine results in increased myocardial damage in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). We investigated myocardial salvage index (MSI) to determine whether IV morphine affects myocardial injury adversely in STEMI patients undergoing primary PCI. 299 STEMI patients underwent contrast-enhanced magnetic resonance imaging a median of 3 days after PCI. Infarct size was measured on delayed-enhancement imaging, and area at risk was quantified on T2-weighted imaging. MSI was calculated as ‘[area at risk–infarct size] X 100 / area at risk’. IV morphine was administrated in 32.1% of patients. Patients treated with morphine had shorter symptom to balloon time and higher prevalence of Thrombolysis in Myocardial Infarction flow grade 0 or 1. The morphine group showed a trend toward larger MSI and infarct size and significantly greater area at risk than the non-morphine group. After propensity score matching (90 pairs), MSI was similar between the morphine and non-morphine group (46.1% versus 43.5%, P = .11), and infarct size and area at risk showed no difference. In propensity score-matched analysis, IV morphine prior to primary PCI in STEMI patients did not cause adverse impacts on myocardial salvage. PMID:28081269

  15. Peripheral morphine analgesia in dental surgery.

    Science.gov (United States)

    Likar, R; Sittl, R; Gragger, K; Pipam, W; Blatnig, H; Breschan, C; Schalk, H V; Stein, C; Schäfer, M

    1998-05-01

    The recent identification of opioid receptors on peripheral nerve endings of primary afferent neurons and the expression of their mRNA in dorsal root ganglia support earlier experimental data about peripheral analgesic effects of locally applied opioids. These effects are most prominent under localized inflammatory conditions. The clinical use of such peripheral analgesic effects of opioids was soon investigated in numerous controlled clinical trials. The majority of these have tested the local, intraarticular administration of morphine in knee surgery and have demonstrated potent and long-lasting postoperative analgesia. As the direct application of morphine into the pain-generating site of injury and inflammation appears most promising, we examined direct morphine infiltration of the surgical site in a unique clinical model of inflammatory tooth pain. Forty-four patients undergoing dental surgery entered into this prospective, randomized, double-blind study. Before surgery they received, together with a standard local anesthetic solution (articaine plus epinephrine) a submucous injection of either 1 mg of morphine (group A) or saline (group B). Postoperative pain intensity was assessed using the visual analog scale (VAS) and numeric rating scale (NRS) at 2, 4, 6, 8, 10, 12, 16, 20 and 24 h after surgery. In addition, patients recorded the occurrence of side effects and the supplemental consumption of diclofenac tablets. Results of 27 patients were analyzed (group A: n=14, group B: n=13). Pain scores which were moderate to severe preoperatively were reduced to a similar extent in both groups up to 8 h postoperatively. Thereafter, pain scores in group A were significantly lower than those in group B for up to 24 h, demonstrating the analgesic efficacy of additional morphine. The time to first analgesic intake and the total amount of supplemental diclofenac were less in group A than in group B. No serious side effects were reported. Our results show that 1 mg of

  16. 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

  17. Dynamic bioluminescence imaging for quantitative tumour burden assessment using IV or IP administration of d-luciferin: effect on intensity, time kinetics and repeatability of photon emission

    Energy Technology Data Exchange (ETDEWEB)

    Keyaerts, Marleen; Vanhove, Chris; Caveliers, Vicky; Bossuyt, Axel; Lahoutte, Tony [Vrije Universiteit Brussel (VUB), In Vivo Cellular and Molecular Imaging (ICMI) Laboratory, Brussels (Belgium); University Hospital Brussels (UZ-Brussel), Department of Nuclear Medicine, Brussels (Belgium); Verschueren, Jacob [University of Antwerp, Bio-Imaging lab, Department of Biomedical Sciences, Antwerp (Belgium); Bos, Tomas J. [Vrije Universiteit Brussel (VUB), Department of Haematology and Immunology, Brussels (Belgium); Tchouate-Gainkam, Lea O.; Peleman, Cindy [Vrije Universiteit Brussel (VUB), In Vivo Cellular and Molecular Imaging (ICMI) Laboratory, Brussels (Belgium); Breckpot, Karine [Vrije Universiteit Brussel (VUB), Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Brussels (Belgium)

    2008-05-15

    In vivo bioluminescence imaging (BLI) is a promising technique for non-invasive tumour imaging. d-luciferin can be administrated intraperitonealy or intravenously. This will influence its availability and, therefore, the bioluminescent signal. The aim of this study is to compare the repeatability of BLI measurement after IV versus IP administration of d-luciferin and assess the correlation between photon emission and histological cell count both in vitro and in vivo. Fluc-positive R1M cells were subcutaneously inoculated in nu/nu mice. Dynamic BLI was performed after IV or IP administration of d-luciferin. Maximal photon emission (PE{sub max}) was calculated. For repeatability assessment, every acquisition was repeated after 4 h and analysed using Bland-Altman method. A second group of animals was serially imaged, alternating IV and IP administration up to 21 days. When mice were killed, PE{sub max} after IV administration was correlated with histological cell number. The coefficients of repeatability were 80.2% (IV) versus 95.0% (IP). Time-to-peak is shorter, and its variance lower for IV (p < 0.0001). PE{sub max} was 5.6 times higher for IV. A trend was observed towards lower photon emission per cell in larger tumours. IV administration offers better repeatability and better sensitivity when compared to IP. In larger tumours, multiple factors may contribute to underestimation of tumour burden. It might, therefore, be beneficial to test novel therapeutics on small tumours to enable an accurate evaluation of tumour burden. (orig.)

  18. Usefulness of the dopamine system-stabilizer aripiprazole for reducing morphine-induced emesis.

    Science.gov (United States)

    Shiokawa, Mitsuru; Narita, Minoru; Nakamura, Atsushi; Kurokawa, Kazuhiro; Inoue, Tadao; Suzuki, Tsutomu

    2007-09-10

    In the management of pain, nausea and vomiting are some of the most distressing adverse effects induced by opioids. In the present study, we investigated the effect of the dopamine system-stabilizer aripiprazole on morphine-induced emesis. Morphine induced retching and vomiting in a dose-dependent manner in ferrets. The emetic effect of morphine was significantly suppressed by pretreatment with either the dopamine receptor antagonist haloperidol or aripiprazole. These results suggest that the co-administration of aripiprazole may be useful for reducing the severity of morphine-induced emesis.

  19. 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.

  20. Repeated administration of D-amphetamine induces loss of [I-123]FP-CIT binding to striatal dopamine transporters in rat brain: a validation study

    NARCIS (Netherlands)

    J. Booij; K. de Bruin; W.B. Gunning

    2006-01-01

    In recent years, several PET and SPECT studies have shown loss of striatal dopamine transporter (DAT) binding in arnphetamine (AMPH) users. However, the use of DAT SPECT tracers to detect AMPH-induced changes in DAT binding has not been validated. We therefore examined if repeated administration of

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

    Science.gov (United States)

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

    2016-08-22

    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.

  2. Use of Morphine Sulphate by South African Paramedics for Prehospital Pain Management

    Directory of Open Access Journals (Sweden)

    Craig Vincent-Lambert

    2015-01-01

    Full Text Available BACKGROUND: Evidence in the literature highlights the fact that acute pain in the prehospital setting remains poorly managed. Morphine remains the most commonly used analgesic agent in the South African prehospital emergency care setting. Although guidelines and protocols relating to the dosage and administration of morphine exist, little data are available describing its use by South African paramedics.

  3. Morphine: oxycodone interventions in Denmark

    DEFF Research Database (Denmark)

    Munk Mikkelsen, Camilla; Andersen, Stig Ejdrup

    2012-01-01

    In the years of the late 2000s, the use of oxycodone in both primary care and hospital care increased significantly in Denmark while the use of morphine decreased. Although oxycodone and morphine are considered equally effective and safe, oxycodone is much more expensive than morphine. Therefore...... in hospital care. On this basis, it is economically very important that drug use in both sectors …...

  4. Risk of sensitization in healthy adults following repeated administration of rdESAT-6 skin test reagent by the Mantoux injection technique

    DEFF Research Database (Denmark)

    Lillebaek, Troels; Bergstedt, Winnie; Tingskov, Pernille N;

    2009-01-01

    1 open clinical trial was to assess the sensitization risk and safety of repeated administration of rdESAT-6 reagent in 31 healthy adult volunteers. Three groups of volunteers received two fixed doses of 0.1 microg rdESAT-6 28, 56 or 112 days apart, respectively. After the second injection......Limited specificity of the tuberculin skin test incited the development of the intradermal Mycobacterium tuberculosis-specific rdESAT-6 skin test. Animal studies have shown, however, that there is a possible risk of sensitization when repeated injections of rdESAT-6 are given. The aim of this phase...

  5. Repeated intravenous administrations of teneurin-C terminal associated peptide (TCAP)-1 attenuates reinstatement of cocaine seeking by corticotropin-releasing factor (CRF) in rats.

    Science.gov (United States)

    Erb, Suzanne; McPhee, Matthew; Brown, Zenya J; Kupferschmidt, David A; Song, Lifang; Lovejoy, David A

    2014-08-01

    The teneurin c-terminal associated peptides (TCAP) have been implicated in the regulation of the stress response, possibly via a corticotropin-releasing factor (CRF)-related mechanism. We have previously shown that repeated intracerebroventricular (ICV) injections of TCAP-1 attenuate the reinstatement of cocaine seeking by CRF in rats. Here, we determined whether intravenous (IV) administrations of TCAP-1 would likewise attenuate CRF-induced reinstatement, and whether this effect would vary depending on the rat's history of cocaine self administration. Rats were trained to self-administer cocaine for 10 days, during once daily sessions that were either 3h ("short access"; ShA) or 6h ("long access"; LgA). Rats were then given five daily injections of TCAP-1 (0, 300, or 3,000 pmol, IV) in their home cage. Subsequently, they were returned to the self-administration chambers where extinction of cocaine seeking and testing for CRF-induced reinstatement of cocaine seeking was carried out. Repeated IV administrations of TCAP-1 were efficacious in attenuating CRF-induced reinstatement of cocaine seeking, but at different doses in ShA and LgA rats. Taken together, the findings extend previous work showing a consistent effect of repeated ICV TCAP-1 on CRF-induced reinstatement of cocaine seeking, and point to a potential therapeutic benefit of TCAP-1 in attenuating cocaine seeking behaviors.

  6. 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.

  7. Morphine- and CaMKII-dependent enhancement of GIRK channel signaling in hippocampal neurons.

    Science.gov (United States)

    Nassirpour, Rounak; Bahima, Laia; Lalive, Arnaud L; Lüscher, Christian; Luján, Rafael; Slesinger, Paul A

    2010-10-06

    G-protein-gated inwardly rectifying potassium (GIRK) channels, which help control neuronal excitability, are important for the response to drugs of abuse. Here, we describe a novel pathway for morphine-dependent enhancement of GIRK channel signaling in hippocampal neurons. Morphine treatment for ∼20 h increased the colocalization of GIRK2 with PSD95, a dendritic spine marker. Western blot analysis and quantitative immunoelectron microscopy revealed an increase in GIRK2 protein and targeting to dendritic spines. In vivo administration of morphine also produced an upregulation of GIRK2 protein in the hippocampus. The mechanism engaged by morphine required elevated intracellular Ca(2+) and was insensitive to pertussis toxin, implicating opioid receptors that may couple to Gq G-proteins. Met-enkephalin, but not the μ-selective (DAMGO) and δ-selective (DPDPE) opioid receptor agonists, mimicked the effect of morphine, suggesting involvement of a heterodimeric opioid receptor complex. Peptide (KN-93) inhibition of CaMKII prevented the morphine-dependent change in GIRK localization, whereas expression of a constitutively activated form of CaMKII mimicked the effects of morphine. Coincident with an increase in GIRK2 surface expression, functional analyses revealed that morphine treatment increased the size of serotonin-activated GIRK currents and Ba(2+)-sensitive basal K(+) currents in neurons. These results demonstrate plasticity in neuronal GIRK signaling that may contribute to the abusive effects of morphine.

  8. Effects exerted by otilonium bromide administration on precipitated opioid withdrawal syndrome in rats.

    Science.gov (United States)

    Pinelli, A; Trivulzio, S; Vignati, S

    1997-09-26

    An opioid withdrawal syndrome was induced in rats by repeated morphine administration and final naloxone injection. The withdrawal causes alteration of several physiological signs. The aim of the study was to prevent the altered physiological profiles by utilising otilonium bromide. Morphine was administered in three daily i.p. injections for 4 days at doses of 9, 16 and 25 mg/kg (1st day), 25, 25 and 50 mg/kg (2nd day), 50, 50 and 50 mg/kg (3rd day) and 50, 50 and 100 mg/kg (4th day). Naloxone was injected (30 mg/kg) i.p. 180 min after the last morphine injection. Otilonium bromide was administered orally at 0, 2, 4 and 8 mg/kg, 120 min before the naloxone administration. Signs like faecal and urine excretion, rectal temperature and pain threshold levels, salivation, jumping and wet dog shakes were affected in different ways. Notably the administration of otilonium bromide in rats receiving morphine together with naloxone decreased the intensity of certain withdrawal symptoms, such as excretion of faeces, wet dog shake behaviour, and elevated the nociceptive threshold values. The effects exhibited by otilonium bromide administration may be explained through its calcium antagonist activity interfering with a mechanism involved in the regulation of these previously mentioned withdrawal symptoms. The use of this drug is thus suggested as a possible control of some acute opioid withdrawal signs in heroin addicts.

  9. Planned cesarean delivery and urinary retention associated with spinal morphine.

    Science.gov (United States)

    DiBlasi, Susan M

    2013-06-01

    Cesarean delivery (CD) is the second most commonly performed surgery in the United States. As such, prevention of complications associated with this procedure is a top priority in nursing care. Nurses at the study institution perceived that postcesarean patients experienced increased urinary retention after use of spinal morphine for postoperative pain relief. This observation prompted a review of the literature indicating that limited research had been conducted in this area. The purpose of this study was to explore the relationship of postelective CD urinary retention and dose of spinal morphine. A retrospective, quasi-experimental, three-group design was used. Records of 150 patients, ages 17 to 39, undergoing elective primary or repeat CD were examined. Morphine doses included 100, 150, and 200 mcg. No statistically significant differences were found between the three groups.

  10. Gene Expression Profile of Calcium/Calmodulin-Dependent Protein Kinase IIα in Rat's Hippocampus during Morphine Withdrawal

    OpenAIRE

    Ahmadi, Shamseddin; Amiri, Shahin; Rafieenia, Fatemeh; Rostamzadeh, Jalal

    2013-01-01

    Introduction Calcium/calmodulin-dependent protein kinase II (CaMKII) which is highly expressed in the hippocampus is known to play a pivotal role in reward-related memories and morphine dependence. Methods In the present study, repeated morphine injections once daily for 7 days was done to induce morphine tolerance in male Wistar rats, after which gene expression profile of α-isoform of CaMKII (CaMKIIα) in the hippocampus was evaluated upon discontinuation of morphine injection over 21 days o...

  11. Effects of voluntary exercise on anxiety-like behavior and voluntary morphine consumption in rat pups borne from morphine-dependent mothers during pregnancy.

    Science.gov (United States)

    Haydari, Sakineh; Miladi-Gorji, Hossein; Mokhtari, Amin; Safari, Manouchehr

    2014-08-22

    Exposure to morphine during pregnancy produced long-term effects in offspring behaviors. Recent studies have shown that voluntary exercise decreases the severity of anxiety behaviors in both morphine-dependent and withdrawn rats. Thus, the aims of the present study were to examine whether maternal exercise decreases prenatal dependence-induced anxiety and also, voluntary consumption of morphine in animal models of craving in rat pups. Pregnant rats were made dependent by chronic administration of morphine in drinking water simultaneously with access to a running wheel that lasted at least 21 days. Then, anxiety-like behaviors using the elevated plus-maze (EPM) and voluntary consumption of morphine using a two-bottle choice paradigm (TBC) were tested in male rat pups. The results showed that the rat pups borne from exercising morphine-dependent mothers exhibited an increase in EPM open arm time (Pexercising morphine-dependent mothers was less in the second (Pexercise decreases the severity of the anxiogenic-like behaviors and voluntary consumption of morphine in rat pups.

  12. 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.

  13. Intra-accumbal CB1 receptor blockade reduced extinction and reinstatement of morphine.

    Science.gov (United States)

    Khaleghzadeh-Ahangar, Hossein; Haghparast, Abbas

    2015-10-01

    The limbic dopaminergic reward system is the main target of morphine-like drugs which begins from the ventral tegmental area (VTA) and sends its dopaminergic projections to the nucleus accumbens (NAc), amygdala, hippocampus and prefrontal cortex. Cannabinoid receptors exist in afferent neurons from these areas to the NAc and can modulate glutamate synaptic transmission in the NAc. Cannabinoids can interact with the opiate system in reward-related behaviors; nevertheless these systems' interaction in extinction duration and reinstatement has not been shown. In the present study, the effects of bilateral intra-accumbal administration of AM251, a CB1 receptor antagonist, on the duration of the extinction phase and reinstatement to morphine were investigated by conditioned place preference (CPP) paradigm. Forty eight adult male albino Wistar rats were used. Bilateral intra-accumbal administration of AM251 (15, 45 and 90μM/0.5μl DMSO per side) was performed. Subcutaneous administration of morphine (5mg/kg) in three consecutive days was used to induce CPP. The results showed that administration of the maximal dose of AM251 during the extinction period significantly reduces duration of extinction and reinstatement to morphine. Administration of the middle dose during the extinction period significantly attenuated reinstatement to morphine. A single microinjection of the middle dose just before the reinstatement phase significantly attenuated reinstatement to morphine only, while bilateral intra-accumbal administration of neither the lowest dose nor the vehicle (DMSO) had any effects. These results for the first time indicated that CB1 receptors within the NAc are involved in the maintenance of morphine rewarding properties, and morphine seeking behaviors in extinguished morphine-induced CPP rats.

  14. 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.

  15. Role of hippocampal CA1 area gap junction channels on morphine state-dependent learning.

    Science.gov (United States)

    Beheshti, Siamak; Hosseini, Seyyed Akbar Mir Seyyed; Noorbakhshnia, Maryam; Eivani, Mehdi

    2014-12-15

    Morphine produces a state dependent learning. The hippocampus is involved in this kind of learning. Gap junctions (GJs) are involved in some of the effects of morphine and exist in different areas of the hippocampus. We investigated the effects of blocking GJ channels of the hippocampal CA1 area, by means of pre-test bilateral injection of carbenoxolone (CBX), on morphine state dependent learning, using a passive avoidance task. Post-training subcutaneous administrations of morphine (0.5, 2.5, 5 and 7.5 mg/kg) dose-dependently impaired memory retrieval. Pre-test administration of morphine (0.5, 2.5, 5 and 7.5 mg/kg) induced a state-dependent retrieval of the memory acquired under post-training morphine influence. Pre-test injections of CBX (25, 75 and 150 nM) dose dependently prevented memory retrieval by post-training (7.5 mg/kg) and pre-test (0.5, 2.5, 5, 7.5 mg/kg) injections of morphine. The results suggest that intercellular coupling via GJ channels of the hippocampal CA1 area modulates morphine state dependent learning.

  16. Administration

    DEFF Research Database (Denmark)

    Bogen handler om den praksis, vi kalder administration. Vi er i den offentlige sektor i Danmark hos kontorfolkene med deres sagsmapper, computere, telefoner,, lovsamlinger,, retningslinier og regneark. I bogen udfoldes en mangfoldighed af konkrete historier om det administrative arbejde fra...... forskellige områder i den offentlige sektor. Hensigten er at forstå den praksis og faglighed der knytter sig til det administrative arbejde...

  17. Effects of clozapine and sulpiride on morphine state-dependent memory in the step-down passive avoidance test.

    Science.gov (United States)

    Malekmohamadi, Nazanin; Heidari, Parviz; Sahebgharani, Mousa; Zarrindast, Mohammad-Reza

    2007-01-01

    The effects of antipsychotic drugs sulpiride and clozapine on morphine state-dependent memory of passive avoidance task were examined in mice. Post-training administration of morphine (5 mg/kg) led to state-dependent learning with impaired memory retrieval on the test day which was reversed by pre-test administration of the same dose of the opioid (5 mg/kg). In animals where memory was impaired by post-training morphine, the administration of either sulpiride or clozapine before pre-test morphine reduced the improvement of memory produced by the opioid. Co-administration of sulpiride with clozapine did not potentiate their antagonistic response. In conclusion, the inhibition of improvement of memory retrieval by morphine treatment on the test day by the two dopamine receptor antagonists seems to be induced through two different receptor mechanisms.

  18. Effect of orphanin FQ and morphine on sodium channel current in somatosensory area of rat cerebral cortex

    Institute of Scientific and Technical Information of China (English)

    Lei Yang; Yurong Li; Shuwei Jia; Yunhong Zhang; Lanwei Cui; Lihui Qu

    2007-01-01

    BACKGROUND: Some experiments have demonstrated that injecting orphanin FQ (OFQ) into lateral ventricle, which can obviously decrease the pain threshold. It is indicated that OFQ is an anti-opiate substance. However, whether OFQ has effects on sensory neuron ion channel in cerebral cortex needs to be further studied.OBJECTIVE: To investigate the effects of OFQ, morphine or their combination on sodium channel current of somatosensory neurons in rat cerebral cortex.DESIGN: Repeated measurement trial.SETTING: Department of Physiology, Harbin Medical University.MATERIALS: Fifty healthy Wistar rats, aged 12-16 days, of either gender, were provided by the Experimental Animal Center, Second Hospital Affiliated to Harbin Medical University. OFQ was purchased from Sigma-Aldrich Company, and morphine was provided by the Shenyang First Pharmaceutical Factory.PC2C patch clamp amplifier and LabmasterTLlwere purchased from Yibo Life Science Instrument Co.,Ltd.of Huazhong University of Science and Techgnology.METHODS: This experiment was carried out in the Department of Physiology (provincial laboratory),Harbin Medical University between January 2005 and May 2006. Cortical neurons were acutely isolated from rats, and prepared into cell suspension following culture. ①Sodium channel current of somatosensory neurons in rat cerebral cortex was recorded before and after administration by whole-cell Patch clamptechnique after 50 nmol/L OFQ being added to extracellular fluid.②The amplitude of sodium channel current of somatosensory neurons in rat cerebral cortex was recorded before and after administration by the same method after 20 I mol/L morphine being added to extracellular fluid, and then the change of sodium channel current was recorded after 50 nmol/L OFQ being added.MAIN OUTCOME MEASURES: The amplitude of sodium channel current of somatosensory neurons in rat cerebral cortex following the administration of OFQ, morphine separately or their combination

  19. Enhancement of morphine antinociception by ibogaine and noribogaine in morphine-tolerant mice.

    Science.gov (United States)

    Sunder Sharma, S; Bhargava, H N

    1998-11-01

    The effects of ibogaine, an alkaloid isolated form the bark of the African shrub, Tabernathe iboga, and noribogaine, a metabolite of ibogaine, on morphine antinociception were determined in male Swiss-Webster mice. Mice were rendered tolerant to morphine by implanting them with a pellet containing 25 mg of morphine base for 3 days. Placebo pellet-implanted mice served as controls. The antinociception of morphine (10 mg/kg, s.c.) was determined alone or in combination with an appropriate dose of ibogaine or noribogaine. Tolerance to morphine developed as a result of morphine pellet implantation as evidenced by decreased antinociceptive response to morphine. Both ibogaine and noribogaine dose-dependently enhanced morphine antinociception in morphine-tolerant but not in morphine-naive mice. It is concluded that ibogaine and noribogaine enhance morphine antinociception in morphine-tolerant mice.

  20. Morphine for chronic neuropathic pain in adults.

    Science.gov (United States)

    Cooper, Tess E; Chen, Junqiao; Wiffen, Philip J; Derry, Sheena; Carr, Daniel B; Aldington, Dominic; Cole, Peter; Moore, R Andrew

    2017-05-22

    Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the nervous system. Opioid drugs, including morphine, are commonly used to treat neuropathic pain. Most reviews have examined all opioids together. This review sought evidence specifically for morphine; other opioids are considered in separate reviews. To assess the analgesic efficacy and adverse events of morphine for chronic neuropathic pain in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials from inception to February 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries. We included randomised, double-blind trials of two weeks' duration or longer, comparing morphine (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment. Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables. We identified five randomised, double-blind, cross-over studies with treatment periods of four to

  1. Activation of μ-opioid receptor and Toll-like receptor 4 by plasma from morphine-treated mice.

    Science.gov (United States)

    Xie, Nan; Gomes, Fabio P; Deora, Vandana; Gregory, Kye; Vithanage, Tharindu; Nassar, Zeyad D; Cabot, Peter J; Sturgess, David; Shaw, Paul N; Parat, Marie-Odile

    2017-03-01

    In this study, we quantified the ability of opioids present in biological samples to activate the μ-opioid receptor and TLR4 using cell-based assays. Each assay was standardised, in the presence of plasma, using morphine, its μ receptor-active metabolite morphine-6 glucuronide (M6G) and its μ receptor-inactive, but TLR4-active metabolite morphine-3 glucuronide (M3G). Specificity was verified using antagonists. Morphine- and M6G-spiked plasma samples exhibited μ receptor activation, which M3G-spiked plasma lacked. In contrast, M3G showed moderate but consistent activation of TLR-4. Plasma samples were collected at a number of time points from mice administered morphine (1 or 10mg/kg every 12h for 3days) or saline. Morphine administration led to intermittent μ receptor activation, reversed by μ receptor antagonists, and to TRL4 activation at time points where M3G is measured in plasma. Interestingly, this protocol of morphine administration also led to TLR4-independent NF-κB activation, at time points where M3G was not detected, presumably via elevation of circulating cytokines including, but not limited to, TNFα. Circulating TNFα was increased after three days of morphine administration, and TNFα mRNA elevated in the spleen of morphine-treated mice.

  2. Effects of caerulein and CCK antagonists on tolerance induced to morphine antinociception in mice.

    Science.gov (United States)

    Zarrindast, M R; Zabihi, A; Rezayat, M; Rakhshandeh, H; Ghazi-Khansari, M; Hosseini, R

    1997-09-01

    Different groups of mice received one daily dose (50 mg/kg) of morphine subcutaneously (SC) for 3, 4 or 5 days to develop tolerance to the opioid. The antinociceptive response of morphine (9 mg/kg) was tested in the hot-plate test 24 h after the last dose of the drug. Tolerance to morphine was obtained in all groups. The group of mice that received morphine for 4 days was employed for the rest of the experiments. Pretreatment of animals with a single dose of caerulein (0.025, 0.05, and 0.1 mg/kg, SC) 30 min prior to receiving morphine (50 mg/kg; during the development of tolerance to the opioid) on day 1, 2, 3, 4 or 5 of morphine administration potentiate antinociception induced by morphine (test dose of 9 mg/kg). The dose of 0.05 mg/kg of caerulein, used 30 min before morphine administration on day 3, was also used to evaluate the effects of antagonists on caerulein-induced decrease in tolerance. The selective cholecystokinin (CCK) receptor antagonists, MK-329 [1-methyl-3-(2 indoloyl)amino-5-phenyl-3H-1,4-benzodiazepin-2-one; 0.25 and 0.5 mg/kg] or L-365,260 [3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H- 1,4-benzodiazepin-3-yl)-N-(3-methyl-phenyl)urea: 0.25 and 0.5 mg/kg] decreased potentiation of morphine response induced by caerulein. MK-329 or L-365,260, when were injected 35 min before morphine injection during the development of tolerance and on day 3, decreased the tolerance to morphine. A single administration of MK-329 or L-365,260 (in the absence of caerulein) 35 min and 48 h before the test dose of morphine (9 mg/kg) potentiated the antinociception of morphine in nontolerant animals. In conclusion, CCK mechanism(s) may interact with morphine tolerance.

  3. Morphine reduces local cytokine expression and neutrophil infiltration after incision

    Directory of Open Access Journals (Sweden)

    Li Xiangqi

    2007-10-01

    Full Text Available Abstract Background Inflammation and nociceptive sensitization are hallmarks of tissue surrounding surgical incisions. Recent studies demonstrate that several cytokines may participate in the enhancement of nociception near these wounds. Since opioids like morphine interact with neutrophils and other immunocytes, it is possible that morphine exerts some of its antinociceptive action after surgical incision by altering the vigor of the inflammatory response. On the other hand, keratinocytes also express opioid receptors and have the capacity to produce cytokines after injury. Our studies were directed towards determining if opioids alter cytokine production near incisions and to identify cell populations responsible for producing these cytokines. Results A murine incisional model was used to measure the effects of acute morphine administration (0.1–10 mg/kg on nociceptive thresholds, neutrophil infiltration and cytokine production in hind paw skin 30 minutes and 2 hours after incision. Incised hind paws displayed profound allodynia which was reduced by morphine (0.1–10 mg/kg in the 2 hours following incision. Skin samples harvested from these mice showed enhanced levels of 5 cytokines: IL-1β, IL-6, tumor necrosis factor alpha (TNFα, granulocyte colony stimulating factor (G-CSF and keratinocyte-derived cytokine (KC. Morphine reduced these incision-stimulated levels. Separate analyses measuring myeloperoxidase (MPO and using immunohistochemistry demonstrated that morphine dose-dependently reduced the infiltration of neutrophils into the peri-incisional tissue. The dose of morphine required for reduction of cytokine accumulation, however, was below that required for inhibition of peri-incisional neutrophil infiltration. Additional immunohistochemical studies revealed wound edge keratinocytes as being an important source of cytokines in the acute phase after incision. Conclusion Acute morphine administration of doses as low as 0.1 mg/kg reduces

  4. Effects of morphine dependence and withdrawal on levels of neurosteroids in rat brain

    Institute of Scientific and Technical Information of China (English)

    Cai-zhen YAN; Yan-ning HOU

    2004-01-01

    AIM: To investigate the effects of morphine dependence and withdrawal on the concentrations of neurosteroids in rat brain. METHODS: A method of simultaneous quantification of neurosteroids by gas chromatography-mass spectrometry (GC-MS) had been established. RESULTS: The chronic morphine administration (ip) resulted in a marked decrease in the brain concentrations of pregnenolone (PREG), progesterone (PROG), and pregenenolone sulfate (PREGS) in rats killed 6 h after the last treatment. In contrast, there were no significant effects of morphine dependence on the brain concentrations of allopregnanolone (AP), dihydroepiandrosterone (DHEA), and dihydroepiandrosterone sulfate (DHEAS). Naloxone-induced withdrawal produced a significant increase in the concentrations of PREG, PROG, AP, DHEA, PREGS, and DHEAS as compared with the control group.CONCLUSION: Morphine dependence and withdrawal affected the concentrations of neurosteroids in rat brain,which suggests that endogenous neurosteroids in brain might be related to the development of morphine dependence and withdrawal.

  5. Sensitivity changes to morphine and other drugs induced by cholinergic blockade.

    Science.gov (United States)

    Contreras, E; Tamayo, L; Quijada, L

    1975-04-01

    Mice were given several atropine injections at a high dosage level. After 2 to 5 days of cessation of treatment the effects of morphine, arecoline, amphetamine, pentylenetetrazol, reserpine, and hexobarbital were determined and compared with those found in saline injected controls. The influence of atropine treatment on tolerance development to morphine was also studied. After withdrawal of atropine a reduction of the analgesic responses to morphine and arecoline was observed. A decrease in hexobarbital sleeping time was also found. There was no significant influence on the analgesic effect of amphetamine, on the depressant action of reserpine, and on the convulsant effect of pentylenetetrazol. The influence of the administration and further withdrawal of atropine on tolerance development to morphine was masked by the concomitant reduction of morphine analgesia. It was impossible to observe a supersensitivity to the pharmacological agents studied.

  6. Effects of the histaminergic system on the morphine-induced conditioned place preference in mice.

    Science.gov (United States)

    Suzuki, T; Takamori, K; Misawa, M; Onodera, K

    1995-03-27

    The effects of an H2 receptor antagonist, a histidine decarboxylase inhibitor and a histamine precursor on the morphine-induced place preference in mice were examined. Morphine (1-7 mg/kg) produced a place preference in a dose-dependent manner. This morphine-induced place preference was significantly antagonized by the dopamine (DA) D1 receptor antagonist SCH 23390. The histamine precursor, L-histidine, attenuated the morphine (7 mg/kg)-induced place preference. On the other hand, the histidine decarboxylase inhibitor, alpha-fluoromethylhistidine (alpha-FMH), significantly potentiated the morphine (1 mg/kg)-induced place preference. This potentiation was antagonized by SCH 23390. The H2 receptor antagonist zolantidine (0.3 mg/kg) significantly potentiated the morphine-induced place preference. Surprisingly, zolantidine (1 mg/kg) alone also produced a significant place preference. The zolantidine-induced place preference was antagonized by SCH 23390. In addition, zolantidine (1, 3 and 10 mg/kg) significantly increased DA turnover (DA ratio) in the limbic forebrain (nucleus accumbens and olfactory tubercle), implying that zolantidine may activate the mesolimbic DA system. Moreover, co-administration of zolantidine dose-dependently increased morphine (10 mg/kg)-induced DA turnover in the limbic forebrain. These results suggest that the activation of histaminergic neurons may attenuate the rewarding effect of morphine, while the inhibition of histaminergic neurons may potentiate the rewarding effect of morphine. Furthermore, potentiation of the morphine-induced rewarding effect by inhibition of histaminergic neurons may be mediated by D1 receptors. We also demonstrated that the H2 receptor antagonist zolantidine may activate the mesolimbic DA system, and as a result, zolantidine itself produces a rewarding effect and potentiates the morphine-induced rewarding effect.

  7. Pharmacokinetics of repeated sodium salicylate administration to laying hens: evidence for time dependent increase in drug elimination from plasma and eggs.

    Directory of Open Access Journals (Sweden)

    Błażej Poźniak

    Full Text Available Salicylates were the first non-steroid anti-inflammatory drugs (NSAIDs to be used in any species and are still widely used in humans and livestock. However, the data on their pharmacokinetics in animals is limited, especially after repeated administration. Evidence exist that in chickens (Gallus gallus salicylate (SA may induce its own elimination. The aim of this study was to investigate salicylate pharmacokinetics and egg residues during repeated administration of sodium salicylate (SS to laying hens. Pharmacokinetics of SA was assessed during 14 d oral administration of SS at daily doses of 50 mg/kg and 200 mg/kg body weight to laying hens. On the 1st, 7th and 14th d a 24 h-long pharmacokinetic study was carried out, whereas eggs were collected daily. Salicylate concentrations in plasma and eggs were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model. Mean residence time (MRT, minimal plasma concentration (Cmin, C16h and elimination half-life (T1/2el of SA showed gradual decrease in layers administered with a lower dose. Total body clearance (ClB increased. Layers administered with the higher dose showed a decrease only in the T1/2el. In the low dose group, SA was found only in the egg white and was low throughout the experiment. Egg whites from the higher dose group showed initially high SA levels which significantly decreased during the experiment. Yolk SA levels were lower and showed longer periods of accumulation and elimination. Repeated administration of SS induces SA elimination, although this effect may differ depending on the dose and production type of a chicken. Decreased plasma drug concentration may have clinical implications during prolonged SS treatment.

  8. Intraarticular morphine analgesia in chronic pain patients with osteoarthritis.

    Science.gov (United States)

    Likar, R; Schäfer, M; Paulak, F; Sittl, R; Pipam, W; Schalk, H; Geissler, D; Bernatzky, G

    1997-06-01

    Controlled clinical studies have shown that local administration of morphine can significantly relieve acute postoperative pain. This analgesic effect is long-lasting (up to 48 h) and is mediated by peripheral opioid receptors. Experimental evidence shows that analgesic effects of peripheral opioids and the density of opioid receptors on peripheral sensory nerves increase with the duration of painful inflammatory processes. This study examines the analgesic effects of 1 mg of morphine injected into the arthritic knee joints of two groups of chronic pain patients (n = 23) suffering from osteoarthritis. Using a randomized, double-blind cross-over design, patients received either an intraarticular injection of morphine and intravenous saline (Group A, n = 13) or an intraarticular injection of saline and intravenous morphine (Group B, n = 10) during Phase I. Seven days later, patients crossed over to the opposite treatment (Phase II). During Phase I, intraarticular morphine resulted in significantly greater pain relief than intraarticular saline, and this effect was present at rest as well as during movement. The analgesic effect was surprisingly long-lasting and extended into Phase II, a carry-over effect that prevented the analysis of Phase II. No side effects were reported. The treatment of arthritic pain by peripherally acting opioids may be a promising alternative to currently available medications that have serious side effects.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Intraventricular gabapentin is antinociceptive and enhances systemic morphine antinociception in rat tail flick test

    Directory of Open Access Journals (Sweden)

    Shamsi Meymandi M.

    2007-07-01

    Full Text Available Background: Gabapentin has been recently considered as an analgesic in neurpathic pain through spinal site of action. In addition co-administration of low dose of morphine with gabapentin, is proposed not only to reduce side effects, tolerance, and dependency of morphine but also has some analgesic effects. In this study, the analgesic effect of intracerebroventricular (ICV gabapentin and its effect on morphine antinociception were investigated in tail-flick test.Methods: An intraventricular cannula was surgically inserted into ventricle space of rat brain. The latency time was measured after microinjection of 100,300,600 and 1000 µg of gabapentin or normal saline (sham. After determination of subanalgesic dose of gabapentin (300µg, the combinational groups received subanalgesic and low dose of morphine (2 and 7 mg /kg intraperitoneally, thirty minutes prior to gabapentin administration. Time response curve and Area Under the Curve (AUC, as antinociceptive index, were compared among the groups.Results: Intraventricular gabapentin showed analgesic effects at 600 µg (ICV. The combination of subanalgesic doses of gabapentin (300 µg ICV and morphine (2 mg /kg i.p increased significantly time-response curve and AUC compared to other groups. In addition, the analgesic response following co-administration of gabapentin (300 µg ICV and analgesic dose of morphine was increased significantly compared to the sham and gabapentin group.Conclusion: The results demonstrated that intraventricular gabapentin has analgesic effect in transient model of pain and enhances morphine antinociception through cerebral site of action.

  11. Morphine Reduces Expression of TRPV1 Receptors in the Amygdala but not in the Hippocampus of Male Rats

    Directory of Open Access Journals (Sweden)

    Elham Hakimizadeh

    2014-05-01

    Full Text Available Background: Chronic use of opioids usually results in physical dependence. The underlying mechanisms for this dependence are still being evaluated. Transient receptor potential vanilloid type 1 (TRPV1 are important receptors of pain perception. Their role during opioid dependence has not been studied well. The aim of this study was to evaluate the effect of morphine-dependence on the expression of TRPV1 receptors in the amygdala and CA1 region of the hippocampus. Methods: This study used four groups of rats. Two groups of rats (morphine and morphine+naloxone received morphine based on the following protocol: 10 mg/kg (twice daily, 3 days followed by 20, 30, 40 and 50 mg/kg (twice daily, respectively, for 4 consecutive days. Another group received vehicle (1 ml/kg instead of morphine given using the same schedule. The morphine+naloxone group of rats additionally received naloxone (5 mg/kg at the end of the protocol. The control group rats received no injections or intervention. The amygdala and CA1 regions of the morphine, saline-treated and intact animals were isolated and prepared for real-time PCR analysis. Results: Administration of naloxone induced withdrawal signs in morphine-treated animals. The results showed a significant decrease in TRPV1 gene expression in the amygdala (P<0.05 but not the CA1 region of morphine dependent rats. Conclusion: TRPV1 receptors may be involved in morphine-induced dependence.

  12. Switching from morphine to fentanyl attenuates the decline of μ-opioid receptor expression in periaqueductal gray of rats with morphine tolerance

    Institute of Scientific and Technical Information of China (English)

    DONG Yan-peng; SUN Li; LIU Xiao-yan; LIU Ruo-shan

    2013-01-01

    Background Opioid switching is a therapeutic maneuver to improve analgesic response and/or reduce adverse side effects although the underlying mechanisms remain unknown.The μ-opioid receptor (MOR) has an important role in mediating the actions of morphine and other analgesic agents.This study is aimed at exploring the changes of MOR in the periaqueductal gray (PAG) in rats when morphine is substituted for equianalgesic fentanyl.Methods Forty rats were randomly assigned to five treatment groups:7 days normal saline group (N group),7 days fentanyl group (F group),7 days morphine group (M group),7 days morphine and 7 days fentanyl-switching group (MF group),and 14 days morphine group (MM group).Rats repeatedly received subcutaneous injections of morphine sulfate (10 mg/kg) or equianalgesic fentanyl sulfate (0.1 mg/kg) twice daily.Rats' antinociceptive response to thermal pain was evaluated by the tail flick latency assay.MOR mRNA and protein expression in the PAG were measured using RT-PCR and Western blotting analyses respectively.Results This study showed that after morphine was substituted with fentanyl on day 8,the tail flick latency (TFL) increased from (3.9±0.4) seconds to (11.4±0.4) seconds.The results also demonstrated that both MOR mRNA and protein expression in the PAG of rats in the MF group were less than that in the M group (P<0.05) but more than that in MM group (P<0.05).Conclusions Equianalgesic fentanyl was still antinociceptive effective in rats with morphine tolerance,which may be due to the switching from morphine to fentanyl attenuating the decline of MOR expression in the PAG of rats.

  13. Repeated administration of alpha7 nicotinic acetylcholine receptor (nAChR) agonists, but not positive allosteric modulators, increases alpha7 nAChR levels in the brain

    DEFF Research Database (Denmark)

    Christensen, Ditte Z; Mikkelsen, Jens D; Hansen, Henrik H;

    2010-01-01

    -induced phosphorylation of Erk2 in the prefrontal cortex occurs following acute, but not repeated administration. Our results demonstrate that repeated agonist administration increases the number of alpha7 nAChRs in the brain, and leads to coupling versus uncoupling of specific intracellular signaling....... Here we investigate the effects of repeated agonism on alpha7 nAChR receptor levels and responsiveness in vivo in rats. Using [(125)I]-alpha-bungarotoxin (BTX) autoradiography we show that acute or repeated administration with the selective alpha7 nAChR agonist A-582941 increases the number of alpha7 n......-120596 and NS1738 do not increase [(125)I]-BTX binding. Furthermore, A-582941-induced increase in Arc and c-fos mRNA expression in the prefrontal cortex is enhanced and unaltered, respectively, after repeated administration, demonstrating that the alpha7 nAChRs remain responsive. Contrarily, A-582941...

  14. Food deprivation facilitates reinstatement of morphine-induced conditioned place preference: Role of intra-accumbal dopamine D2-like receptors in associating reinstatement of morphine CPP with stress.

    Science.gov (United States)

    Sadeghzadeh, Fatemeh; Babapour, Vahab; Haghparast, Abbas

    2017-04-01

    The high rate of relapse to drug use is one of the main problems in the treatment of addiction. Stress plays the essential role in drug abuse and relapse; nevertheless, little is known about the mechanisms underlying stress and relapse. Accordingly, the effects of intra-accumbal administration of Sulpiride, as a dopamine D2-like receptor antagonist, on an ineffective morphine dose + food deprivation(FD)- and morphine priming-induced reinstatement of conditioned place preference (CPP). About 104 adult male albino Wistar rats weighing 200-280 g were bilaterally implanted by cannula into the nucleus accumbens (NAc). Subcutaneous (sc) injection of morphine (5 mg kg(-1) ) was used daily during a 3-day conditioning phase. After a 24-hr "off" period following achievement of extinction criterion, rats were tested for FD- and priming-induced reinstatement of morphine CPP by an ineffective (0.5 mg kg(-1) , sc) and priming (1 mg kg(-1) , sc) dose of morphine, respectively. In the next experiments, animals received different doses of intra-accumbal Sulpiride (0.25, 1, and 4 µg/0.5 µL saline) bilaterally and were subsequently tested for morphine reinstatement. Our findings indicated that the 24-hr FD facilitated reinstatement of morphine CPP. Furthermore, the D2-like receptor antagonist attenuated the ineffective morphine dose+ FD- and priming-induced reinstatement of morphine CPP dose-dependently. Also, contribution of D2-like receptors in mediation of the ineffective morphine dose+ FD-induced reinstatement of CPP was greater than morphine priming-induced reinstatement of CPP. The role of dopaminergic system in morphine reinstatement through a neural pathway in the NAc provides the evidence that D2-like receptor antagonist can be useful therapeutic targets for reinstatement of morphine CPP. © 2016 Wiley Periodicals, Inc.

  15. The effect of tramadol plus paracetamol on consumption of morphine after coronary artery bypass grafting.

    Science.gov (United States)

    Altun, Dilek; Çınar, Özlem; Özker, Emre; Türköz, Ayda

    2017-02-01

    To compare the effects of oral tramadol+paracetamol combination on morphine consumption following coronary artery bypass grafting (CABG) in the patient-controlled analgesia (PCA) protocol. A prospective, double-blind, randomized, clinical study. Single-institution, tertiary hospital. Fifty cardiac surgical patients undergoing primary CABG surgery. After surgery, the patients were allocated to 1 of 2 groups. Both groups received morphine according to the PCA protocol after arrival to the coronary intensive care unit (bolus 1 mg, lockout time 15 minutes). In addition to morphine administration 2 hours before operation and postoperative 2nd, 6th, 12th, 18th, 24th, 30th, 36th, 42th, and 48th hours, group T received tramadol+paracetamol (Zaldiar; 325 mg paracetamol, 37.5 mg tramadol) and group P received placebo. Sedation levels were measured with the Ramsay Sedation Scale, whereas pain was assessed with the Pain Intensity Score during mechanical ventilation and with the Numeric Rating Scale after extubation. If the Numeric Rating Scale score was ≥3 and Pain Intensity Score was ≥3, 0.05 mg/kg morphine was administered additionally. Preoperative patient characteristics, risk assessment, and intraoperative data were similar between the groups. Cumulative morphine consumption, number of PCA demand, and boluses were higher in group P (PTramadol+paracetamol combination along with PCA morphine improves analgesia and reduces morphine requirement up to 50% after CABG, compared with morphine PCA alone. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Up-regulation of -opioid receptors in the spinal cord of morphine-tolerant rats

    Indian Academy of Sciences (India)

    Subrata Basu Ray; Himanshu Gupta; Yogendra Kumar Gupta

    2004-03-01

    Though morphine remains the most powerful drug for treating pain, its effectiveness is limited by the development of tolerance and dependence. The mechanism underlying development of tolerance to morphine is still poorly understood. One of the factors could be an alteration in the number of m-receptors within specific parts of the nervous system. However, reports on changes in the -opioid receptor density in the spinal cord after chronic morphine administration are conflicting. Most of the studies have used subcutaneously implanted morphine pellets to produce tolerance. However, it does not simulate clinical conditions, where it is more common to administer morphine at intervals, either by injections or orally. In the present study, rats were made tolerant to morphine by injecting increasing doses of morphine (10–50 mg/kg, subcutaneously) for five days. In vitro tissue autoradiography for localization of -receptor in the spinal cord was done using [3H]-DAMGO. As compared to the spinal cord of control rats, the spinal cord of tolerant rats showed an 18.8% increase or up-regulation in the density of -receptors in the superficial layers of the dorsal horn. This up-regulation of -receptors after morphine tolerance suggests that a fraction of the receptors have been rendered desensitized, which in turn could lead to tolerance.

  17. Morphine-augmented cholescintigraphy enhances duodenogastric reflux

    Energy Technology Data Exchange (ETDEWEB)

    Shih, Wei-Jen; Magoun, S.; Wierzbinski, B.; Ryo, U-Yun [Kentucky Univ., Lexington, KY (United States). Medical Center; Lee, Jong-Kang

    1995-11-01

    Morphine intervention in cholescintigraphy decreases imaging time to diagnose acute cholecystitis. Not infrequently we observe duodenogastric reflux during scintigraphy with and without morphine intervention. To evaluate occurrence of duodenogastric reflux related to morphine, we reviewed 55 patients who underwent cholescintigraphy with (32) and without (23) morphine intervention. Morphine was injected when there was bowel activity with non-visualization of the gallbladder at 60 min. Duodenogastric reflux was identified by the appearance of activity in the area just below or immediately adjacent to the tip of the left hepatic lobe laterally. Among 32 patients with morphine intervention, 19 had acute cholecystitis and 13 chronic cholecystitis. Eleven of 19 (58%) with acute cholecystitis had duodenogastric reflux and 6 of 13 (46%) had duodenogastric reflux in chronic cholecystitis. The total of duodenogastric reflux in the group with morphine injection was 53%. Two patients` duodenogastric reflux occurred before morphine injection and was more apparent after morphine was given. In the without morphine group, 3 had acute cholecystitis and 20 had chronic cholecystitis; 2 (one acute and one chronic cholecystitis) of these 23 (9%) had duodenogastric reflux. Our results indicate: occurrence of duodenogastric reflux in morphine augmented cholescintigraphy is not significantly different in cholecystitis from that in chronic cholecystitis; duodenogastric reflux in morphine augmentation occurs significantly more often than without morphine intervention (p<0.001). We conclude that cholescintigraphy with morphine enhances duodenogastric reflux. The degree of duodenogastric reflux in the acute cholecystitis patients has been more severe than in the chronic cholecystitis patients. (author).

  18. Involvement of PLC-beta3 in the effect of morphine on memory retrieval in passive avoidance task.

    Science.gov (United States)

    Bianchi, E; Lehmann, D; Vivoli, E; Norcini, M; Ghelardini, C

    2010-06-01

    Phospholipase C (PLC) is one signalling effector enzyme whose activity is directly modulated by opioids. Several physiological studies have implicated PLC-linked pathways in in-vivo pain regulation and opioid tolerance. Co-administration of PLC-beta(2/3) activity blocker M119 with morphine resulted in a dramatic increase in morphine-induced amnesic effect in mice, proving a role for beta subunit of PLC enzyme in these processes. Administration of morphine to mice at amnesic dose increased PLC-beta(3) activity, with respect to basal value, in the membrane-soluble material from anterior cortex and hippocampal formation in brain areas. PLC-beta(3) appears to be simultaneously implicated in both analgesic and amnesic effects induced by administration of morphine to mice suggesting a commonality in the molecular mechanisms of morphine-induced analgesia and memory impairment.

  19. Effects of the fruit essential oil of Cuminum cyminum Linn. (Apiaceae) on acquisition and expression of morphine tolerance and dependence in mice.

    Science.gov (United States)

    Haghparast, Abbas; Shams, Jamal; Khatibi, Ali; Alizadeh, Amir-Mohammad; Kamalinejad, Mohammad

    2008-08-01

    The problem of morphine tolerance and dependence is a universal phenomenon threatening social health everywhere the world. The major objective of this paper was to investigate the effects of fruit essential oil (FEO) of Cuminum cyminum on acquisition and expression of morphine tolerance and dependence in mice. Animals were rendered dependent on morphine using the well-established method in which was morphine (50, 50, 75 mg/kg; s.c.) injected three times daily for 3 days. In experimental groups, administration of FEO (0.001, 0.01, 0.1, 0.5, 1 and 2%; 5 ml/kg; i.p.) or Tween-80 (5 ml/kg; i.p.) was performed 60 min prior to each morphine injection (for acquisition) or the last injection of morphine on test day (for expression). Morphine tolerance was measured by tail-flick before and after administration of a single dose of morphine (50 mg/kg; s.c.) in test day (4th day). Morphine dependence was also evaluated by counting the number of jumps after injection of naloxone (5 mg/kg; i.p.) on the test day. The results showed that Cumin FEO, only at the dose of 2%, significantly attenuated the development of morphine tolerance (PCuminum cyminum seems to ameliorate the morphine tolerance and dependence in mice.

  20. Impact of tramadol and morphine abuse on the activities of acetylcholine esterase, Na+/K+-ATPase and related parameters in cerebral cortices of male adult rats

    OpenAIRE

    El-Hamid Mohamed Elwy, Abd; Tabl, Ghada

    2017-01-01

    Objective To determine the effect of the most commonly abused drugs (tramadol and morphine), on acetylcholine esterase (AChE), Na+/K+-ATPase activities and related parameters, Na+ and K+ as biomarkers of neurotoxicity. Methods Tramadol - as a weak μ opioid receptor agonist- and morphine - as opiate analgesic drugs, were chosen for the present study. Four series of experimental animals were conducted for either tramadol or morphine: control series; repeated single equal doses (therapeutic dose...

  1. Individual differences in initial morphine sensitivity as a predictor for the development of opiate addiction in rats.

    Science.gov (United States)

    Nishida, Kevin S; Park, Thomas Y; Lee, Bong Hyo; Ursano, Robert J; Choi, Kwang H

    2016-10-15

    Individuals report a wide range of analgesia to similar doses of opiates, and not all opiate users become addicted. This suggests that there may be certain predispositions that influence one to develop opiate addiction. We investigated the relationship between the individual differences in initial morphine sensitivity and the subsequent development of opiate addiction-like behavior using a hot plate test and an intravenous morphine self-administration (MSA) paradigm in rats. Using a median split of initial morphine antinociception, animals were defined as low antinociception (LA) and high antinociception (HA) groups. Thus, the LA group represents the animals that were less sensitive to initial morphine antinociception as compared to those of the HA group. The animals were allowed to self-administer either saline or morphine (0.5mg/kg/infusion, 4hr/day) 5days per week for 3 weeks. Spontaneous locomotor activity was measured on self-administration days 10 and 15. Individual differences in initial morphine sensitivity were not correlated with the amount of morphine self-administered by the animals on day 1. In the second-week of MSA, the LA group exhibited increased morphine intake and locomotor hyperactivity as compared to those of the HA group. Therefore, certain animals that are less sensitive to initial morphine antinociception may be susceptible to developing opiate addiction. The current findings may have clinical implications for future research on the biological mechanisms of opiate addiction and preclinical medication development.

  2. Effects of morphine and β-endorphin on basal and elevated plasma levels of α-MSH and vasopressin

    NARCIS (Netherlands)

    Wimersma Greidanus, T.B. van; Thody, A.J.; Verspaget, H.; Rotte, G.A. de; Goedemans, H.J.H.; Croiset, G.; Ree, J.M. van

    1979-01-01

    Morphine induced an increase of plasma α-MSH levels and a decrease of AVP levels after peripheral or intracerebroventricular administration. This increase of α-MSH levels and decrease of AVP levels after morphine treatment was observed in non-stimulated animals as well as in rats in which the hormon

  3. Rapid reversal by naloxone of the chronic effects of morphine on rat liver and brain tryptophan metabolism.

    OpenAIRE

    Badawy, A. A.; Evans, M.

    1981-01-01

    The chronic morphine-induced inhibition of rat liver tryptophan pyrrolase activity and the resultant increases in tryptophan availability to the brain and brain 5-hydroxytryptamine (5-HT) synthesis are reversed within 10 min after naloxone administration. The possible involvement of hepatic tryptophan metabolism in morphine dependence is briefly discussed.

  4. Repeated intrathecal administration of plasmid DNA complexed with polyethylene glycol-grafted polyethylenimine led to prolonged transgene expression in the spinal cord.

    Science.gov (United States)

    Shi, L; Tang, G P; Gao, S J; Ma, Y X; Liu, B H; Li, Y; Zeng, J M; Ng, Y K; Leong, K W; Wang, S

    2003-07-01

    Gene delivery into the spinal cord provides a potential approach to the treatment of spinal cord traumatic injury, amyotrophic lateral sclerosis, and spinal muscular atrophy. These disorders progress over long periods of time, necessitating a stable expression of functional genes at therapeutic levels for months or years. We investigated in this study the feasibility of achieving prolonged transgene expression in the rat spinal cord through repeated intrathecal administration of plasmid DNA complexed with 25 kDa polyethylenimine (PEI) into the lumbar subarachnoid space. With a single injection, DNA/PEI complexes could provide transgene expression in the spinal cord 40-fold higher than naked plasmid DNA. The transgene expression at the initial level persisted for about 5 days, with a low-level expression being detectable for at least 8 weeks. When repeated dosing was tested, a 70% attenuation of gene expression was observed following reinjection at a 2-week interval. This attenuation was associated with apoptotic cell death and detected even using complexes containing a noncoding DNA that did not mediate any gene expression. When each component of the complexes, PEI polymer or naked DNA alone, were tested in the first dosing, no reduction was found. Using polyethylene glycol (PEG)-grafted PEI for DNA complexes, no attenuation of gene expression was detected after repeated intrathecal injections, even in those rats receiving three doses, administered 2 weeks apart. Lumbar puncture is a routine and relatively nontraumatic clinical procedure. Repeated administration of DNA complexed with PEG-grafted PEI through this less invasive route may prolong the time span of transgene expression when needed, providing a viable strategy for the gene therapy of spinal cord disorders.

  5. Acute and repeated intranasal oxytocin administration exerts anti-aggressive and pro-affiliative effects in male rats

    NARCIS (Netherlands)

    Calcagnoli, Federica; Kreutzmann, Judith C.; de Boer, Sietse F.; Althaus, Monika; Koolhaas, Jaap M.

    2015-01-01

    Socio-emotional deficits and impulsive/aggressive outbursts are prevalent symptoms of many neuropsychiatric disorders, and intranasal administration of oxytocin (OXT) is emerging as a putative novel therapeutic approach to curb these problems. Recently, we demonstrated potent anti-aggressive and pro

  6. Morphine metabolism in neonates and infants.

    OpenAIRE

    Choonara, I.; Lawrence, A.; Michalkiewicz, A; Bowhay, A; J. Ratcliffe

    1992-01-01

    The metabolism of morphine was studied in seven fullterm neonates and five infants receiving a continuous infusion of morphine. All the patients had detectable plasma concentrations of morphine 3-glucuronide (M3G) and 10 had detectable concentrations of morphine 6-glucuronide (M6G). The mean plasma clearance of morphine was 20.1 ml min-1 kg-1 in neonates and 23.4 ml min-1 kg-1 in the group as a whole. The M3G/morphine ratio (7.3) was higher than that previously reported for preterm neonates (...

  7. Drug-seeking behavior in an invertebrate system: evidence of morphine-induced reward, extinction and reinstatement in crayfish.

    Science.gov (United States)

    Nathaniel, Thomas I; Panksepp, Jaak; Huber, Robert

    2009-02-11

    Several lines of evidence suggest that exploring the neurochemical basis of reward in invertebrate species may provide clues for the fundamental behavioral and neurobiology underpinnings of drug addiction. How the presence of drug-sensitive reward relates to a decrease in drug-seeking behavior and reinstatement of drug-seeking behavior in invertebrate systems is not known. The present study of a conditioned place preference (CPP) paradigm in crayfish (Orconectes rusticus) explores morphine-induced reward, extinction and reinstatement. Repeated intra-circulatory infusions of 2.5 microg/g, 5.0 microg/g and 10.0 microg/g doses of morphine over 5 days serve as a reward when paired with a distinct visual or tactile environment. Morphine-induced CPP was extinguished after repeated saline injections for 5 days in the previously morphine-paired compartment. After the previously established CPP had been eliminated during the extinction phase, morphine-experienced crayfish were challenged with 2.5 microg/g, 5.0 microg/g and 10.0 microg/g, respectively. The priming injections of morphine reinstated CPP in all training doses, suggesting that morphine-induced CPP is unrelenting, and that with time, it can be reinstated by morphine following extinction in an invertebrate model just like in mammals. Together with other recent studies, this work demonstrates the advantage of using crayfish as an invertebrate animal model to investigate the basic biological processes that underline exposure to mammalian drugs of abuse.

  8. Repeated 2% sevoflurane administration in 7‑ and 60-day-old rats : Neurotoxicity and neurocognitive dysfunction.

    Science.gov (United States)

    Huang, He; Liu, Cun-Ming; Sun, Jie; Jin, Wen-Jie; Wu, Yu-Qing; Chen, Jing

    2017-09-15

    Sevoflurane is one of the most widely used inhalation anesthetics in pediatric anesthesia. A large number of studies have demonstrated that repeated treatment with high concentrations or long durations of sevoflurane anesthesia during the neonatal period can induce neuroapoptosis and long-term learning disability. In clinical practice, we observed that a subset of patients underwent minor surgery under sevoflurane anesthesia more than once from birth to adolescence. Therefore, this research was conducted to investigate whether a 2% concentration of sevoflurane (clinically relevant usage of sevoflurane) for 1 h (a short duration) can induce neuroapoptosis and neurocognitive dysfunction in adolescent rats that received sevoflurane (2% for 1 h) during the neonatal period. Group I: neonatal rats at postnatal day 7 (PND-7) were treated with oxygen under controlled conditions and then raised to PND-60. Group II: PND-7 rats were treated with 2% sevoflurane for 1 h and then raised to PND-60. Group III: the PND-60 rats were treated with 2% sevoflurane for 1 h and in group IV the PND-7 rats were treated with 2% sevoflurane for 1 h and then anesthetized with 2% sevoflurane for 1 h at PND-60 again. The expression of caspase-3, Bax and Bcl-2 in the hippocampal dentate gyrus (DG) were measured by Western blot analysis. Neuroapoptosis in the hippocampal DG was assessed using NeuN/caspase-3 double-immunofluorescence staining. Spatial reference memory was tested by the Morris water maze test. The present data showed that sevoflurane (2% for 1 h) did not induce obvious hippocampal neuroapoptosis in the PND-7 rats and PND-60 rats; their performance in hippocampal-dependent spatial memory was not significantly impaired; however, the rats in group IV showed poor performance in the Morris water maze test and the neuroapoptosis in group IV was significantly increased. Our findings suggested that sevoflurane can induce neuroapoptosis and cognitive dysfunction in

  9. Effect of repeated oral administration of Bifidobacterium longum BB536 on apomorphine-induced rearing behavior in mice

    OpenAIRE

    ORIKASA, Shuzo; NABESHIMA, Kazumi; Iwabuchi, Noriyuki; Xiao, Jin-zhong

    2016-01-01

    Schizophrenia is a chronic psychiatric illness. Disruption of the dopaminergic system has been suggested to be the pathogenic cause of this disease. The effect of Bifidobacterium longum BB536 (BB536) on schizophrenic behavior was investigated in an animal model. Daily administration of BB536 (109 CFU/mouse, p.o. for 2 weeks) was found to reduce rearing behavior augmented by the dopamine receptor agonist apomorphine and to decrease the resting level of plasma corticosterone and the ratio of ky...

  10. Biodistribution of BPA and BSH after single, repeated and simultaneous administrations for neutron-capture therapy of cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ichikawa, H. [Faculty of Pharmaceutical Sciences and Cooperative Research Center of Life Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586 (Japan)], E-mail: ichikawa@pharm.kobegakuin.ac.jp; Taniguchi, E. [Faculty of Pharmaceutical Sciences and Cooperative Research Center of Life Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586 (Japan); Fujimoto, T. [Department of Orthopaedic Surgery, Hyogo Cancer Center, Akashi 673-0021 (Japan); Fukumori, Y. [Faculty of Pharmaceutical Sciences and Cooperative Research Center of Life Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586 (Japan)

    2009-07-15

    The effect of administration mode of L-BPA and BSH on the biodistribution in the melanoma-bearing hamsters was investigated. In single intravenous (i.v.) administration, BSH (100 mg BSH/kg) showed no significant retention of {sup 10}B in all the tissues, including tumors, while long-term retention of {sup 10}B in the tumor, muscle and brain was observed with L-BPA (500 mg BPA/kg). The dose escalation of L-BPA and the simultaneous single administration of L-BPA and BSH were not so effective at increasing boron accumulation in tumor after bolus i.v. injection. The boron concentration in tumor was 41 {mu}g B/g after single bolus i.v. injection even at the dose of 1000 mg BPA/kg. In contrast, two sequential bolus i.v. injections of L-BPA with the dose of 500 mg BPA/kg each was found to be effective at increasing {sup 10}B accumulation in the tumor; the maximum {sup 10}B concentration in the tumor reached 52 {mu}g B/g at 3 h after the second i.v. injection.

  11. Catatonia and jaw dislocation in the postoperative period with epidural morphine

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    Satyen Parida

    2011-01-01

    Full Text Available We report a case of temporomandibular joint dislocation occurring in the postoperative period in a patient, who developed catatonia following administration of a single dose of epidural morphine. The catatonic response to epidural morphine was delayed by several hours in the postoperative period, and might have resulted from intrathecal migration of the drug, through an initial dural puncture while locating the epidural space. The temporomandibular joint dislocation was diagnosed only after reversal of the effects of morphine with naloxone, when the patient complained of inability to fully close her mouth.

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

    Science.gov (United States)

    2011-01-01

    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. PMID:21861871

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Changes of dopamine neurotransmitter and its receptor in striatum from conditioned place preference of rats administrated of morphine%吗啡条件性位置偏爱大鼠纹状体多巴胺递质和多巴胺D2受体表达的变化

    Institute of Scientific and Technical Information of China (English)

    杨培润; 钱刚; 罗素元; 杨明理; 白威峰; 吴明松

    2012-01-01

    目的 观察吗啡条件性位置偏爱(conditioned place preference,CPP)大鼠纹状体中多巴胺(DA)递质和多巴胺D2受体的同步变化,从神经递质和受体分子水平探讨通过纹状体多巴胺能系统的阿片类精神依赖机制.方法 吗啡剂量递增注射10d,建立大鼠吗啡CPP模型,生理盐水对照组和吗啡模型组各取10只断头处死取脑纹状体,采用高效液相色谱法测定其多巴胺含量;另各取6只采用免疫组化检测纹状体中D2受体的表达.结果 与生理盐水对照组比较[DA:(5.23±1.01);D2受体:(0.08±0.02)],模型组大鼠纹状体多巴胺递质含量增加(7.63±0.98);多巴胺D2受体平均吸光度值下调(0.06±0.02),均差异有统计学意义(P<0.01).结论 纹状体多巴胺递质含量上升和D2受体表达水平下调的同步变化在一定程度上参与了吗啡精神依赖的形成.%Objective To observe the level of dopamine and its receptor in striatum from conditioned place preference (CPP) of rats administrated of morphine.And explore the mechanism of opioid-psychic dependence involving the levels of neurotransmitter and receptor.Methods CPP model was validated in morphine-dependence rats for 10 days.Striatum samples were harvested from two separate groups involving the saline group and morphine treated group (n =10 per experiment).The DA contents in striatum were detected in rats with colorimetry.Immunohistochemistry was applied to detect the differential expression levels of dopamine receptor 2 (DRD2)in samples.Results Compared with the saline group,higher content of neurotransmitter dopamine was observed in the morphine dependent rats (7.63 ±0.98 vs 5.23 ± 1.01,P<0.01),while the expression level of DRD2 was down regulated (0.06 ± 0.02 vs 0.08 ± 0.02,P < 0.01).Conclusion The increased expression of neurotransmitter dopamine and the decreased of DRD2 may be contributed to morphine-induced psychological dependence in morphine dependent rats.

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

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    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.

  16. The effects of repeated administration of camphor-crataegus berry extract combination on blood pressure and on attentional performance - a randomized, placebo-controlled, double-blind study.

    Science.gov (United States)

    Erfurt, L; Schandry, R; Rubenbauer, S; Braun, U

    2014-09-25

    The present study investigated the effects of repeated administration of Korodin(®), a combination of camphor and crataegus berry extract, on blood pressure and attentional functioning. This study was conducted based on a randomized, placebo-controlled, double-blind design. 54 persons participated (33 female, 21 male) with a mean age of 24.3 years. Blood pressure and body mass index were in the normal range. Participants received 20 drops of either Korodin(®) or a placebo for four times with interjacent time intervals of about 10 min. Blood pressure was measured sphygmomanometrically before and after each administration. Attentional performance was quantified by using two paper-and-pencil tests, the d2 Test of Attention and Digit Symbol Test. Greater increases in blood pressure occurred after the four Korodin(®) administrations in comparison to the four placebo administrations. The performance in two parameters of d2 Test of Attention was consistently superior after the intake of Korodin(®). The excellent tolerability and safety of Korodin(®), even after a total consumption of 80 drops, was confirmed. Copyright © 2014 Elsevier GmbH. All rights reserved.

  17. Effect of repeated oral administration of Bifidobacterium longum BB536 on apomorphine-induced rearing behavior in mice.

    Science.gov (United States)

    Orikasa, Shuzo; Nabeshima, Kazumi; Iwabuchi, Noriyuki; Xiao, Jin-Zhong

    2016-01-01

    Schizophrenia is a chronic psychiatric illness. Disruption of the dopaminergic system has been suggested to be the pathogenic cause of this disease. The effect of Bifidobacterium longum BB536 (BB536) on schizophrenic behavior was investigated in an animal model. Daily administration of BB536 (10(9) CFU/mouse, p.o. for 2 weeks) was found to reduce rearing behavior augmented by the dopamine receptor agonist apomorphine and to decrease the resting level of plasma corticosterone and the ratio of kynurenine to tryptophan. These results suggest the potential of BB536 for supplemental treatment of the symptoms of schizophrenia.

  18. Repeated post-exercise administration with a mixture of leucine and glucose alters the plasma amino acid profile in Standardbred trotters

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    Nostell Katarina EA

    2012-02-01

    Full Text Available Abstract Background The branched chain amino acid leucine is a potent stimulator of insulin secretion. Used in combination with glucose it can increase the insulin response and the post exercise re-synthesis of glycogen in man. Decreased plasma amino acid concentrations have been reported after intravenous or per oral administration of leucine in man as well as after a single per oral dose in horses. In man, a negative correlation between the insulin response and the concentrations of isoleucine, valine and methionine have been shown but results from horses are lacking. This study aims to determine the effect of repeated per oral administration with a mixture of glucose and leucine on the free amino acid profile and the insulin response in horses after glycogen-depleting exercise. Methods In a crossover design, after a glycogen depleting exercise, twelve Standardbred trotters received either repeated oral boluses of glucose, 1 g/kg body weight (BW at 0, 2 and 4 h with addition of leucine 0.1 g/kg BW at 0 and 4 h (GLU+LEU, or repeated boluses of water at 0, 2 and 4 h (CON. Blood samples for analysis of glucose, insulin and amino acid concentrations were collected prior to exercise and over a 6 h post-exercise period. A mixed model approach was used for the statistical analyses. Results Plasma leucine, isoleucine, valine, tyrosine and phenylalanine concentrations increased after exercise. Post-exercise serum glucose and plasma insulin response were significantly higher in the GLU+LEU treatment compared to the CON treatment. Plasma leucine concentrations increased after supplementation. During the post-exercise period isoleucine, valine and methionine concentrations decreased in both treatments but were significantly lower in the GLU+LEU treatment. There was no correlation between the insulin response and the response in plasma leucine, isoleucine, valine and methionine. Conclusions Repeated post-exercise administration with a mixture of leucine

  19. Differential Regulation of MAPK Phosphorylation in the Dorsal Hippocampus in Response to Prolonged Morphine Withdrawal-Induced Depressive-Like Symptoms in Mice.

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    Wei Jia

    Full Text Available Depression is one of the most frequent neuropsychiatric comorbidities associated with opiate addiction. Mitogen activated protein kinase (MAPK and MAPK phosphatase (MKP are involved in drug addiction and depression. However, the potential role of MAPK and MKP in depression caused by morphine withdrawal remains unclear. We utilized a mouse model of repeated morphine administration to examine the molecular mechanisms that contribute to prolonged withdrawal induced depressive-like behaviors. Depressive-like behaviors were significant at 1 week after withdrawal and worsened over time. Phospho-ERK (extracellular signal-regulated protein kinase was decreased and MKP-1 was elevated in the hippocampus, and JNK (c-Jun N-terminal protein kinase, p38 (p38 protein kinase and MKP-3 were unaffected. A pharmacological blockade of MKP-1 by intra-hippocampal sanguinarine (SA infusion prevented the development of depressive-like behaviors and resulted in relatively normal levels of MKP-1 and phospho-ERK after withdrawal. Our findings support the association between hippocampal MAPK phosphorylation and prolonged morphine withdrawal-induced depression, and emphasize the MKP-1 as an negative regulator of the ERK phosphorylation that contributes to depression.

  20. Loss of phenotype of parvalbumin interneurons in rat prefrontal cortex is involved in antidepressant- and propsychotic-like behaviors following acute and repeated ketamine administration.

    Science.gov (United States)

    Zhou, ZhiQiang; Zhang, GuangFen; Li, XiaoMin; Liu, XiaoYu; Wang, Nan; Qiu, LiLi; Liu, WenXue; Zuo, ZhiYi; Yang, JianJun

    2015-04-01

    Accumulating evidence has demonstrated that single subanesthetic dose of ketamine exerts rapid, robust, and lasting antidepressant-like effects. Nevertheless, repeated subanesthetic doses of ketamine produce psychosis-like effects with dysfunction of parvalbumin (PV) interneurons. We hypothesized that PV interneurons play an important role in the antidepressant-like actions of ketamine, and different changes in PV interneurons occur with the antidepressant-like and propsychotic-like effects of ketamine. To test this hypothesis, ketamine's antidepressant-like effects were evaluated by the forced swimming test. Ketamine-induced stereotyped behaviors and hyperactivity actions and the function of PV interneurons were also assessed. We demonstrated that an acute dose of 10 mg/kg ketamine induced significant antidepressant-like effects and reduced the levels of PV and the gamma-aminobutyric acid (GABA)-producing enzyme GAD67 in the rat prefrontal cortex. Moreover, inhibition of ketamine-induced loss of PV by apocynin blocked these antidepressant-like effects. Repeated administration of 30 mg/kg ketamine elicited stereotyped behaviors and hyperactivity actions as well as a longer duration of PV and GAD67 loss, higher brain glutamate levels, and lower brain GABA levels than acute single dose of ketamine. Our results reveal that the loss of phenotype of PV interneurons in the prefrontal cortex contributes to the antidepressant-like actions and is also involved in the propsychotic-like behaviors following acute and repeated ketamine administration, which may be partially mediated by the disinhibition of glutamate signaling. The different degrees and durations of the actions on PV interneurons produced by the two regimens of ketamine may partly underline the behavioral variance between the antidepressant- and propsychotic-like effects.

  1. Spinal morphine anesthesia and urinary retention.

    Science.gov (United States)

    Mahan, K T; Wang, J

    1993-11-01

    Spinal anesthetic is a common form of surgical anesthetic used in foot and ankle surgery. Spinal morphine anesthetic is less common, but has the advantage of providing postoperative analgesia for 12 to 24 hr. A number of complications can occur with spinal anesthesia, including urinary retention that may be a source of severe and often prolonged discomfort and pain for the patient. Management of this problem may require repeated bladder catheterization, which may lead to urinary tract infections or impairment of urethrovesicular function. This study reviews the incidence of urinary retention in 80 patients (40 after general anesthesia and 40 after spinal anesthesia) who underwent foot and ankle surgery at Saint Joseph's Hospital, Philadelphia, PA. Twenty-five percent of the patients who had spinal anesthesia experienced urinary retention, while only 7 1/2% of the group who had general anesthesia had this complication. Predisposing factors, treatment regimen, and recommendations for the prevention and management of urinary retention are presented.

  2. A validated hybrid quadrupole linear ion-trap LC-MS method for the analysis of morphine and morphine glucuronides applied to opiate deaths.

    Science.gov (United States)

    Taylor, Kerry; Elliott, Simon

    2009-05-30

    A hybrid quadrupole linear ion-trap mass spectrometer using an electrospray ionisation ion source coupled to a HPLC system has been used to develop a method which can accurately measure morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in plasma, whole blood and post-mortem blood following solid-phase extraction. The method can also qualitatively detect various other opioids and related compounds including: codeine, dihydrocodeine (and metabolites), noscapine, papaverine and 6-acetylmorphine (6-AM). The method has been favourably compared to an existing laboratory method using a now discontinued radio-immunoassay technique. The advantage of measuring the glucuronides directly rather than following deconjugation by beta-glucuronidase has also been shown. Detection and quantification of compounds was achieved using multiple reaction monitoring (MRM) incorporating the use of deuterated morphine and M3G as internal standards. Precision and accuracy was determined to be less than 10% at both high and low levels for all analytes and the calibration curve was deemed linear over an acceptable range. Recovery in blood was greater than 90% and ion suppression/enhancement was shown to be less than 15%. This method was applied to over 130 post-mortem cases involving the use of heroin, prescribed morphine and codeine. The range of concentrations of morphine, M3G and M6G was large (particularly in heroin and prescribed morphine cases), reflecting the many different factors involved with therapeutic use or fatal opiate poisonings, including tolerance associated with regular use, variable dose regimens and co-administration of other drugs. Detection of other constituents of the opium poppy such as noscapine and papaverine and metabolites of diacetylmorphine in the blood (6-AM) was useful in determining the source of the morphine (i.e. illicit heroin) and the rapidity of death after administration.

  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...... not change, except for a minor increase in the latencies of the onset and the P2 components following S1 stimulation....

  4. Focused review: neuraxial morphine and oral herpes reactivation in the obstetric population.

    Science.gov (United States)

    Bauchat, Jeanette R

    2010-11-01

    Neuraxial morphine administration is a common strategy for providing postcesarean delivery analgesia. Morphine delivered via this route increases the risk of herpes labialis (oral herpes) reactivation, a disease common in women of childbearing age. A primary concern is risk of transmission to the neonate from maternal reactivation. The benefits to the mother of this form of analgesia outweigh the risk of neonatal herpes acquired postpartum from maternal recurrence because serious neonatal morbidity from recurrent herpes has not been described.

  5. Proteome Analysis of Rat Hippocampus Following Morphine-induced Amnesia and State-dependent Learning

    OpenAIRE

    Jafarinejad-Farsangi, Saeideh; Farazmand, Ali; Rezayof, Ameneh; Darbandi, Niloufar

    2015-01-01

    Morphine’s effects on learning and memory processes are well known to depend on synaptic plasticity in the hippocampus. Whereas the role of the hippocampus in morphine-induced amnesia and state-dependent learning is established, the biochemical and molecular mechanisms underlying these processes are poorly understood. The present study intended to investigate whether administration of morphine can change the expression level of rat hippocampal proteins during learning of a passive avoidance t...

  6. EFFECTS OF MELATONIN ON MORPHINE DEPENDENCE

    Institute of Scientific and Technical Information of China (English)

    WEIYiming; YUChangxi; XIEJieming

    2004-01-01

    AIM: To study the effects of melatonin (MT) on morphine dependence. METHODS: Morphine hydrochloride was administered (sc) to mice for 8 days to establish morphine dependence model. Withdrawal syndromes were precipitated by naloxone (ip). Different doses of MT were given either before or after the model established. Isolated guinea-pig ileums

  7. TRPV1 modulates morphine-induced conditioned place preference via p38 MAPK in the nucleus accumbens.

    Science.gov (United States)

    Hong, Sa-Ik; Nguyen, Thi-Lien; Ma, Shi-Xun; Kim, Hyoung-Chun; Lee, Seok-Yong; Jang, Choon-Gon

    2017-09-15

    Emerging evidence suggests that the transient receptor potential vanilloid type 1 channel (TRPV1) is a novel target for the treatment of drug addiction, such as cocaine and morphine. Previously we reported that TRPV1 inhibition reduced morphine reward in the dorsal striatum (DSt) of mice and morphine self-administration through a decrease in accumbal activity in rats. However, the role of TRPV1 on morphine-conditioned reward in addiction-related brain regions, such as the nucleus accumbens (NAc), has not been previously established. Here, we investigated the effects of TRPV1 on morphine conditioned place preference (CPP) and intracellular mechanisms of TRPV1 using Western blot analysis and immunohistochemistry (IHC) in morphine-administered mice. TRPV1 knockout mice did not exhibit morphine reward responses, and both i.p. and intra-NAc injections of SB366791, a selective TRPV1 antagonist, reduced morphine-induced CPP in wild-type mice. Furthermore, i.p. injection of SB203580, a selective p38 MAPK inhibitor, also dampened morphine-induced CPP. To determine the molecular mechanisms of the TRPV1/p38 MAPK pathway in morphine CPP, we investigated the expression of adenylyl cyclase type 1 (AC1) and phospho-p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) in the NAc. Either SB366791 or SB203580 decreased the protein expression levels of phospho-p38 MAPK, phosphor-NF-κB, and AC1 in the NAc of morphine CPP mice. Taken together, our findings suggest that TRPV1 may modulate morphine-induced conditioned reward effects via the p38 MAPK signaling pathway in the NAc. Therefore, blockade of TRPV1 may provide a novel therapeutic approach for the prevention and treatment of opioid addiction. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. The Effect of Acute Stress on Formed Memory Recall after Prescription of Very Low to Regular Doses of Morphine in Rats

    Directory of Open Access Journals (Sweden)

    Zeinab Kavoosi

    2012-03-01

    Full Text Available Background: Hippocampus is rich in corticosteroid and opioid receptors and is involved in memory. Both acute stress and morphine have a different effect on different stages of memory. Thus, the effect of acute forced swim stress on formed memory recall was investigated after prescription of morphine different doses.Materials and Methods : In this experimental study, adult male Wistar rats (200-250 g were classified into three categories (for each group, n=7: 1 repeated morphine groups, 30 minutes before each training, they were intraperitoneally prescribed morphine for 4 days in Morris water maze, (1, 10,100 μg/kg and 1, 10 mg/kg and the recall test was performed on 5th day. 2 Acute stress group, they were on training for 4 days without morphine and on the fifth day, 30 minutes before the recall test, they were subjected to forced swim stress for 5 min. 3 Repeated morphine plus acute stress groups, they were first treated same as first category and on the 5th day, they were behaved like the second category. On the day 12th, the same test as the 5th day was conducted, but the groups received no treatment.Results: In the repeated morphine groups, apparently only 10 mg/kg of morphine significantly disturbed learning (p < 0.001. But during the 5th and 12th day no significant difference was observed between all groups and the control group in memory recall. In the group treated with morphine plus acute stress, only 10 mg/kg of morphine significantly decreased memory recall during the 5th and 12th day compared to the control group (p<0.05.Conclusion: Repeated prescription of 10 mg/kg morphine plus acute stress intensifies the deleterious effects of stress on memory

  9. Hepatotoxicity assessment of Mn-doped ZnS quantum dots after repeated administration in mice

    Directory of Open Access Journals (Sweden)

    Yang YJ

    2015-09-01

    Full Text Available Yanjie Yang,1,2 Shuang-Yu Lv,2 Bianfei Yu,1 Shuang Xu,1 Jianmin Shen,3 Tong Zhao,1 Haixia Zhang1 1Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou University, Lanzhou, Gansu, 2School of Medicine, Henan University, Kaifeng, Henan, 3Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, Gansu, People’s Republic of China Abstract: Doped ZnS quantum dots (QDs have a longer dopant emission lifetime and potentially lower cytotoxicity compared to other doped QDs. The liver is the key organ for clearance and detoxification of xenobiotics by phagocytosis and metabolism. The present study was designed to synthesize and evaluate the hepatotoxicity of Mn-doped ZnS QDs and their polyethylene glycol-coated counterparts (1 mg/kg and 5 mg/kg in mice. The results demonstrated that daily injection of Mn-doped ZnS QDs and polyethylene glycol-coated QDs via tail vein for 7 days did not influence body weight, relative liver weight, serum aminotransferases (alanine aminotransferase and aspartate aminotransferase, the levels of antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase, or malondialdehyde in the liver. Analysis of hepatocyte ultrastructure showed that Mn-doped ZnS QDs and polyethylene glycol-coated QDs mainly accumulated in mitochondria at 24 hours after repeated intravenous injection. No damage to cell nuclei or mitochondria was observed with either of the QDs. Our results indicate that Mn-doped ZnS QDs did not cause obvious damage to the liver. This study will assist in the development of Mn-doped ZnS QDs-based bioimaging and biomedical applications in the future. Keywords: liver, serum aminotransferases, antioxidant enzymes, ultrastructure

  10. Morphine-Induced Constipation Develops With Increased Aquaporin-3 Expression in the Colon via Increased Serotonin Secretion.

    Science.gov (United States)

    Kon, Risako; Ikarashi, Nobutomo; Hayakawa, Akio; Haga, Yusuke; Fueki, Aika; Kusunoki, Yoshiki; Tajima, Masataka; Ochiai, Wataru; Machida, Yoshiaki; Sugiyama, Kiyoshi

    2015-06-01

    Aquaporin-3 (AQP3) is a water channel that is predominantly expressed in the colon, where it plays a critical role in the regulation of fecal water content. This study investigated the role of AQP3 in the colon in morphine-induced constipation. AQP3 expression levels in the colon were analyzed after oral morphine administration to rats. The degree of constipation was analyzed after the combined administration of HgCl(2) (AQP3 inhibitor) or fluoxetine (5-HT reuptake transporter [SERT] inhibitor) and morphine. The mechanism by which morphine increased AQP3 expression was examined in HT-29 cells. AQP3 expression levels in rat colon were increased during morphine-induced constipation. The combination of HgCl(2) and morphine improved morphine-induced constipation. Treatment with morphine in HT-29 cells did not change AQP3 expression. However, 5-HT treatment significantly increased the AQP3 expression level and the nuclear translocation of peroxisome proliferator-activated receptor gamma (PPARγ) 1 h after treatment. Pretreatment with fluoxetine significantly suppressed these increases. Fluoxetine pretreatment suppressed the development of morphine-induced constipation and the associated increase in AQP3 expression in the colon. The results suggest that morphine increases the AQP3 expression level in the colon, which promotes water absorption from the luminal side to the vascular side and causes constipation. This study also showed that morphine-induced 5-HT secreted from the colon was taken into cells by SERT and activated PPARγ, which subsequently increased AQP3 expression levels.

  11. 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.

  12. Enhanced antinociceptive effects of morphine in histamine H2 receptor gene knockout mice.

    Science.gov (United States)

    Mobarakeh, Jalal Izadi; Takahashi, Kazuhiro; Sakurada, Shinobu; Kuramasu, Atsuo; Yanai, Kazuhiko

    2006-09-01

    We have previously shown that antinociceptive effects of morphine are enhanced in histamine H1 receptor gene knockout mice. In the present study, involvement of supraspinal histamine H2 receptor in antinociception by morphine was examined using histamine H2 receptor gene knockout (H2KO) mice and histamine H2 receptor antagonists. Antinociception was evaluated by assays for thermal (hot-plate, tail-flick and paw-withdrawal tests), mechanical (tail-pressure test) and chemical (formalin and capsaicin tests) stimuli. Thresholds for pain perception in H2KO mice were higher than wild-type mice. Antinociceptive effects of intracerebroventricularly administered morphine were enhanced in the H2KO mice compared to wild-type mice. Intracerebroventricular co-administration of morphine and cimetidine produced significant antinociceptive effects in the wild-type mice when compared to morphine or cimetidine alone. Furthermore, zolantidine, a selective and hydrophobic H2 receptor antagonist, enhanced the effects of morphine in all nociceptive assays examined. These results suggest that histamine exerts inhibitory effects on morphine-induced antinociception through H2 receptors at the supraspinal level. Our present and previous studies suggest that H1 and H2 receptors cooperatively function to modulate pain perception in the central nervous system.

  13. Endogenous opioids are involved in morphine and dipyrone analgesic potentiation in the tail flick test in rats.

    Science.gov (United States)

    Hernández-Delgadillo, Gloria P; Cruz, Silvia L

    2006-09-28

    The combined administration of low doses of opiates with non-steroidal anti-inflammatory drugs can produce additive or supra-additive analgesic effects while reducing unwanted side effects. We have recently reported that co-administration of morphine with dipyrone (metamizol) produces analgesic potentiation both in naïve and in morphine-tolerant rats. The purpose of this work was to determine the role of opioids on the acute potentiation observed between morphine and dipyrone i.v. in the rat tail flick test. To do this, two experiments were done. In the first one, naloxone was administered 10 min before morphine (3.1 mg/kg), dipyrone (600 mg/kg) or their combination at the same doses. Control animals received saline instead of naloxone. In the second experiment, naloxone (or saline) was given 2 min after reaching the maximal peak effect with each individual analgesic treatment. When naloxone was i.v. administered prior to analgesics, it completely blocked morphine effects, partially prevented morphine/dipyrone antinociception and delayed dipyrone-induced nociception. At 3.1 mg/kg, naloxone produced an increased nociception. When naloxone was given after analgesics, it dose-dependently blocked the effects of morphine alone and in combination with dipyrone but with different potency in each case. As to dipyrone, naloxone delayed the time to antinociceptive peak effect. Taken together, these results support the notion that endogenous opioids are involved in the analgesic potentiation observed with the combination of morphine plus dipyrone.

  14. Effects of concurrent intravenous morphine sulfate and naltrexone hydrochloride on end-tidal carbon dioxide

    Directory of Open Access Journals (Sweden)

    Goli Veeraindar

    2012-03-01

    Full Text Available Abstract Background Respiratory depression, a potentially fatal side-effect of opioid-overdose, may be reversed by timely administration of an opioid antagonist, such as naloxone or naltrexone. Tampering with a formulation of morphine sulfate and sequestered naltrexone hydrochloride extended release capsules (MS-sNT releases both the opioid morphine and the antagonist naltrexone. A study in recreational opioid-users indicated that morphine and naltrexone injected in the 25:1 ratio (duplicating the ratio of the formulation found MS-sNT reduced morphine-induced euphoric effects vs intravenous (IV morphine alone. In the same study, the effects of morphine + naltrexone on end-tidal carbon dioxide (EtCO2, a measure of respiratory-depression, were evaluated and these data are reported here. Methods Single-center, placebo-controlled, double-blind crossover study. Non-dependent male opioid users were randomized to receive single IV doses of placebo, 30 mg morphine alone, and 30 mg morphine + 1.2 mg naltrexone. EtCO2 was measured by noninvasive capnography. Results Significant differences in EtCO2 least-squares means across all treatments for maximal effect (Emax and area under the effect curve (AUE0-2, AUE0-8, AUE0-24 were detected (all p ≤ 0.0011. EtCO2 Emax values for morphine + naltrexone were significantly reduced vs morphine alone (42.9 mm Hg vs 47.1 mm Hg, p max was delayed for morphine + naltrexone vs morphine alone (5.0 h vs 1.0 h. Conclusions Results provide preliminary evidence that the naltrexone:morphine ratio within MS-sNT is sufficient to significantly reduce EtCO2 when administered intravenously to non-dependent male recreational opioid-users. Further studies with multiple measures of respiratory-function are warranted to determine if risk of respiratory depression is also reduced by naltrexone in the tampered formulation.

  15. Differences in the morphine-induced inhibition of small and large intestinal transit: Involvement of central and peripheral μ-opioid receptors in mice.

    Science.gov (United States)

    Matsumoto, Kenjiro; Umemoto, Hiroyuki; Mori, Tomohisa; Akatsu, Ryuya; Saito, Shinichiro; Tashima, Kimihito; Shibasaki, Masahiro; Kato, Shinichi; Suzuki, Tsutomu; Horie, Syunji

    2016-01-15

    Constipation is the most common side effect of morphine. Morphine acts centrally and on peripheral sites within the enteric nervous system. There are a few comprehensive studies on morphine-induced constipation in the small and large intestine by the activation of central and peripheral μ-opioid receptors. We investigated the differences in the inhibition of the small and large intestinal transit in normal and morphine-tolerant mice. Morphine reduced the geometric center in the fluorescein isothiocyanate-dextran assay and prolonged the bead expulsion time in a dose-dependent manner. The inhibitory effects of morphine were blocked by μ-opioid antagonist β-funaltrexamine, but not by δ- and κ-opioid antagonists. The peripheral opioid receptor antagonist, naloxone methiodide, partially blocked morphine's effect in the small intestine and completely blocked its effect in the large intestine. The intracerebroventricular administration of naloxone significantly reversed the delay of small intestinal transit but did not affect morphine-induced inhibition of large intestinal transit. Naloxone methiodide completely reversed the inhibition of large intestinal transit in normal and morphine-tolerant mice. Naloxone methiodide partially reversed the morphine-induced inhibition of small intestinal transit in normal mice but completely reversed the effects of morphine in tolerant mice. Chronic treatment with morphine results in tolerance to its inhibitory effect on field-stimulated contraction in the isolated small intestine but not in the large intestine. These results suggest that peripheral and central opioid receptors are involved in morphine-induced constipation in the small and large intestine during the early stage of treatment, but the peripheral receptors mainly regulate constipation during long-term morphine treatment.

  16. Cellular Composition of the Spleen and Changes in Splenic Lysosomes in the Dynamics of Dyslipidemia in Mice Caused by Repeated Administration of Poloxamer 407.

    Science.gov (United States)

    Goncharova, N V; Shurlygina, A V; Mel'nikova, E V; Karmatskikh, O L; Avrorov, P A; Loktev, K V; Korolenko, T A

    2015-11-01

    We studied the effect of dyslipidemia induced by poloxamer 407 (300 mg/kg twice a week for 30 days) on cellular composition of the spleen and splenocyte lysosomes in mice. Changes in blood lipid profile included elevated concentrations of total cholesterol, aterogenic LDL, and triglycerides most pronounced in 24 h after the last poloxamer 407 injection; gradual normalization of lipid profile was observed in 4 days (except triglycerides) and 10 days. The most pronounced changes in the spleen (increase in organ weight and number of cells, inhibition in apoptosis, and reduced accumulation of vital dye acridine orange in lysosomes) were detected on day 4; on day 10, the indices returned to normal. Cathepsin D activity in the spleen also increased at these terms. The relationship between changes in the cellular composition of the spleen and dynamics of serum lipid profile in mice in dyslipidemia caused by repeated administrations of relatively low doses of poloxamer 407 is discussed.

  17. Genetic deletion of microglial Panx1 attenuates morphine withdrawal, but not analgesic tolerance or hyperalgesia in mice.

    Science.gov (United States)

    Burma, Nicole E; Leduc-Pessah, Heather; Trang, Tuan

    2017-07-26

    Opioids are among the most powerful analgesics for managing pain, yet their repeated use can lead to the development of severe adverse effects. In a recent study, we identified the microglial pannexin-1 channel (Panx1) as a critical substrate for opioid withdrawal. Here, we investigated whether microglial Panx1 contributes to opioid-induced hyperalgesia (OIH) and opioid analgesic tolerance using mice with a tamoxifen-inducible deletion of microglial Panx1. We determined that escalating doses of morphine resulted in thermal pain hypersensitivity in both Panx1-expressing and microglial Panx1-deficient mice. In microglial Panx1-deficient mice, we also found that acute morphine antinociception remained intact, and repeated morphine treatment at a constant dose resulted in a progressive decline in morphine antinociception and a reduction in morphine potency. This reduction in morphine antinociceptive potency was indistinguishable from that observed in Panx1-expressing mice. Notably, morphine tolerant animals displayed increased spinal microglial reactivity, but no change of microglial Panx1 expression. Collectively, our findings indicate microglial Panx1 differentially contributes to opioid withdrawal, but not the development of opioid-induced hyperalgesia or tolerance.

  18. An enriched environment reduces the stress level and locomotor activity induced by acute morphine treatment and by saline after chronic morphine treatment in mice.

    Science.gov (United States)

    Xu, Jia; Sun, Jinling; Xue, Zhaoxia; Li, Xinwang

    2014-06-18

    This study investigated the relationships among an enriched environment, stress levels, and drug addiction. Mice were divided randomly into four treatment groups (n=12 each): enriched environment without restraint stress (EN), standard environment without restraint stress (SN), enriched environment with restraint stress (ES), and standard environment with restraint stress (SS). Mice were reared in the respective environment for 45 days. Then, the ES and SS groups were subjected to restraint stress daily (2 h/day) for 14 days, whereas the EN and SN groups were not subjected to restraint stress during this stage. The stress levels of all mice were tested in the elevated plus maze immediately after exposure to restraint stress. After the 2-week stress testing period, mice were administered acute or chronic morphine (5 mg/kg) treatment for 7 days. Then, after a 7-day withdrawal period, the mice were injected with saline (1 ml/kg) or morphine (5 mg/kg) daily for 2 days to observe locomotor activity. The results indicated that the enriched environment reduced the stress and locomotor activity induced by acute morphine administration or saline after chronic morphine treatment. However, the enriched environment did not significantly inhibit locomotor activity induced by morphine challenge. In addition, the stress level did not mediate the effect of the enriched environment on drug-induced locomotor activity after acute or chronic morphine treatment.

  19. Effect of intraoral and subcutaneous morphine on dyspnea at rest in terminal patients with primary lung cancer or lung metastases

    DEFF Research Database (Denmark)

    Gamborg, Helle; Riis, Jette; Christrup, Lona Louring;

    2013-01-01

    Dyspnea is considered as one of the most frequent and distressing symptoms in patients with advanced cancer, and systemic administration of morphine has been reported to have beneficial effect on this complaint.......Dyspnea is considered as one of the most frequent and distressing symptoms in patients with advanced cancer, and systemic administration of morphine has been reported to have beneficial effect on this complaint....

  20. Role of ventral hippocampal NMDA receptors in anxiolytic-like effect of morphine.

    Science.gov (United States)

    Motevasseli, Tahmineh; Rezayof, Ameneh; Zarrindast, Mohammad-Reza; Nayer-Nouri, Touraj

    2010-12-02

    The possible role of ventral hippocampal N-methyl-d-aspartate (NMDA) receptors on morphine-induced anxiolytic-like behavior in an elevated plus maze (EPM) task was investigated in the present study. Adult male mice (7 per group) with cannulas aimed at the ventral hippocampus (VH) received NMDA or a competitive NMDA receptor antagonist D-AP5 with or without morphine and 30min later were subjected to an EPM task. Intraperitoneal injection (i.p.) of morphine (3-9mg/kg) increased the percentage of open arm time (%OAT) and open arm entries (%OAE), which suggested an anxiolytic-like effect. Intra-VH microinjection of NMDA (0.5-1μg/mouse) with an ineffective dose of morphine (3mg/kg, i.p.) significantly increased %OAT and %OAE. However, microinjections of the same doses of NMDA into the VH in the absence of morphine had no effect on %OAT and %OAE. Intra-VH microinjection of D-AP5 (0.5-2μg/mouse) decreased the anxiolytic-like effect of morphine, while intra-VH microinjection of the same doses of D-AP5 alone increased %OAT and %OAE, which indicated an anxiolytic response. Furthermore, intra-VH microinjection of D-AP5 reversed the effect of NMDA response to the administration of a lower morphine dose as seen in the EPM task. It should be noted that intra-VH microinjection of D-AP5 plus NMDA, 5min before morphine increased locomotor activity, while other treatments had no effect on this parameter. The results suggest that VH-NMDA receptors participate in the mediation of morphine-induced anxiolytic-like behavior.

  1. Global changes in the rat heart proteome induced by prolonged morphine treatment and withdrawal.

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    Zdenka Drastichova

    Full Text Available Morphine belongs among the most commonly used opioids in medical practice due to its strong analgesic effects. However, sustained administration of morphine leads to the development of tolerance and dependence and may cause long-lasting alterations in nervous tissue. Although proteomic approaches enabled to reveal changes in multiple gene expression in the brain as a consequence of morphine treatment, there is lack of information about the effect of this drug on heart tissue. Here we studied the effect of 10-day morphine exposure and subsequent drug withdrawal (3 or 6 days on the rat heart proteome. Using the iTRAQ technique, we identified 541 proteins in the cytosol, 595 proteins in the plasma membrane-enriched fraction and 538 proteins in the mitochondria-enriched fraction derived from the left ventricles. Altogether, the expression levels of 237 proteins were altered by morphine treatment or withdrawal. The majority of changes (58 proteins occurred in the cytosol after a 3-day abstinence period. Significant alterations were found in the expression of heat shock proteins (HSP27, α-B crystallin, HSP70, HSP10 and HSP60, whose levels were markedly up-regulated after morphine treatment or withdrawal. Besides that morphine exposure up-regulated MAPK p38 (isoform CRA_b which is a well-known up-stream mediator of phosphorylation and activation of HSP27 and α-B crystallin. Whereas there were no alterations in the levels of proteins involved in oxidative stress, several changes were determined in the levels of pro- and anti-apoptotic proteins. These data provide a complex view on quantitative changes in the cardiac proteome induced by morphine treatment or withdrawal and demonstrate great sensitivity of this organ to morphine.

  2. Global changes in the rat heart proteome induced by prolonged morphine treatment and withdrawal.

    Science.gov (United States)

    Drastichova, Zdenka; Skrabalova, Jitka; Jedelsky, Petr; Neckar, Jan; Kolar, Frantisek; Novotny, Jiri

    2012-01-01

    Morphine belongs among the most commonly used opioids in medical practice due to its strong analgesic effects. However, sustained administration of morphine leads to the development of tolerance and dependence and may cause long-lasting alterations in nervous tissue. Although proteomic approaches enabled to reveal changes in multiple gene expression in the brain as a consequence of morphine treatment, there is lack of information about the effect of this drug on heart tissue. Here we studied the effect of 10-day morphine exposure and subsequent drug withdrawal (3 or 6 days) on the rat heart proteome. Using the iTRAQ technique, we identified 541 proteins in the cytosol, 595 proteins in the plasma membrane-enriched fraction and 538 proteins in the mitochondria-enriched fraction derived from the left ventricles. Altogether, the expression levels of 237 proteins were altered by morphine treatment or withdrawal. The majority of changes (58 proteins) occurred in the cytosol after a 3-day abstinence period. Significant alterations were found in the expression of heat shock proteins (HSP27, α-B crystallin, HSP70, HSP10 and HSP60), whose levels were markedly up-regulated after morphine treatment or withdrawal. Besides that morphine exposure up-regulated MAPK p38 (isoform CRA_b) which is a well-known up-stream mediator of phosphorylation and activation of HSP27 and α-B crystallin. Whereas there were no alterations in the levels of proteins involved in oxidative stress, several changes were determined in the levels of pro- and anti-apoptotic proteins. These data provide a complex view on quantitative changes in the cardiac proteome induced by morphine treatment or withdrawal and demonstrate great sensitivity of this organ to morphine.

  3. Repeated ketamine administration alters N-methyl-d-aspartic acid receptor subunit gene expression: Implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans

    Science.gov (United States)

    Lipsky, Robert H

    2015-01-01

    For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-d-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis. PMID:25245072

  4. 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.

  5. Blockade of dorsal hippocampal orexin-1 receptors impaired morphine-induced state-dependent learning.

    Science.gov (United States)

    Farahmandfar, Maryam; Kadivar, Mehdi; Rastipisheh, Sareh

    2016-12-01

    Behavioral abnormalities associated with opiate addiction include memory and learning deficits, which are the result of some alterations in the neuromodulatory systems. Recently, orexin has shown to influence drug addiction neural circuitry, specifically in mediating reward-related perception and memory. To explore the possible interaction of orexinergic and opioidergic system on modulation of learning and memory, we have investigated the effects of intra-dorsal hippocampal (intra-CA1) administration of orexin-1 receptor agonist and the competitive orexin-1 antagonist, SB-334867, on morphine-induced memory impairment by using step-down passive avoidance task in mice. Pre-training injection of morphine (5mg/kg, i.p.) impaired memory, which was restored when 24h later the same dose of the drug was administered. Pre-test administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) had not a significant effect on the retention latency compared to the saline-treated animals, but it restored the memory impairment induced by pre-training morphine (5mg/kg, i.p.). Pre-test administration of SB-334867 (10, 20 and 40nmol, intra-CA1) by itself decreased the retention latencies of passive avoidance task. Co-administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) and morphine (1mg/kg, i.p.) on the test day induced morphine state-dependent memory. Conversely, pre-test injection of SB-334867 (10, 20 and 40nmol, intra-CA1) inhibited the orexin-1-induced potentiation of morphine state-dependent learning on the test day. It is concluded that dorsal hippocampal orexin-1 receptors may be involved, at least in part, in morphine state-dependent learning in mice.

  6. 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

    Full Text Available Introduction: Although the synergistic effects of opioids and other analgesic drugs such as non-steroidal anti-inflammatory drugs (NSAIDs have been established in relieving acute pain due to renal calculi, no studies today have evaluated the concomitant administration of opiates and other drugs with analgesic effects, such as serotonin re-uptake inhibitors. Considering the high prevalence of renal colic, the present study was carried out to compare the effect of concomitant prescription of morphine and a placebo with that of morphine and citalopram on the management of acute pain due to renal calculi. Methods: The present double-blind randomized clinical trial was carried out from October 2012 to March 2013 in the Al-Zahra educational Hospital in Isfahan, Iran. A total of 90 patients with acute renal colic pain were randomly divided into two groups of 45 subjects. The subjects in one group received morphine/ placebo and another one morphine/citalopram. The patients’ pain severity was determined by visual analogue scale (VAS before and 20 minutes after administration of medications. In case of persistent pain the second or even third dose was administered and the pain severity was once again determined. Data were analyzed with STATA 11.0 using chi-squared, two-way ANOVA, Bonferroni post hoc test, and log rank test. Results: The decrease in pain severity in the morphine/citalopram group was significantly compared to the morphine/placebo group and the time before administration of the medications (p<0.001. In contrast, administration of morphine/placebo did not have a significant effect on pain severity at this interval (p=0.32. Kaplan-Meier curve showed that the first injection was successful in relieving pain in 15 (33.3% and 26 (57.8% subjects in the morphine/placebo and morphine/citalopram groups, respectively. The second injection of these medications resulted in therapeutic success in 35 (87.8% and 42 (95.6% subjects in the above groups

  7. Effect of Acetaminophen Alone and in Combination with Morphine and Tramadol on the Minimum Alveolar Concentration of Isoflurane in Rats.

    Directory of Open Access Journals (Sweden)

    Julio R Chavez

    Full Text Available It has been observed that acetaminophen potentiates the analgesic effect of morphine and tramadol in postoperative pain management. Its capacity as an analgesic drug or in combinations thereof to reduce the minimum alveolar concentration (MAC of inhalational anesthetics represents an objective measure of this effect during general anesthesia. In this study, the effect of acetaminophen with and without morphine or tramadol was evaluated on the isoflurane MAC.Forty-eight male Wistar rats were anesthetized with isoflurane in oxygen. MACISO was determined from alveolar gas samples at the time of tail clamping without the drug, after administering acetaminophen (300 mg/kg, morphine (3 mg/kg, tramadol (10 mg/kg, acetaminophen (300 mg/kg + morphine (3 mg/kg, and acetaminophen (300 mg/kg + tramadol (10 mg/kg.The control and acetaminophen groups did not present statistically significant differences (p = 0.98. The values determined for MACISO after treatment with acetaminophen + morphine, acetaminophen + tramadol, morphine, and tramadol were 0.98% ± 0.04%, 0.99% ± 0.009%, 0.97% ± 0.02%, and 0.99% ± 0.01%, respectively.The administration of acetaminophen did not reduce the MAC of isoflurane and did not potentiate the reduction in MACISO by morphine and tramadol in rats, and therefore does not present a sparing effect of morphine or tramadol in rats anesthetized with isoflurane.

  8. 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.

  9. Effect of Acetaminophen Alone and in Combination with Morphine and Tramadol on the Minimum Alveolar Concentration of Isoflurane in Rats

    Science.gov (United States)

    Chavez, Julio R.; Ibancovichi, José A.; Sanchez-Aparicio, Pedro; Acevedo-Arcique, Carlos M.; Moran-Muñoz, Rafael; Recillas-Morales, Sergio

    2015-01-01

    Background It has been observed that acetaminophen potentiates the analgesic effect of morphine and tramadol in postoperative pain management. Its capacity as an analgesic drug or in combinations thereof to reduce the minimum alveolar concentration (MAC) of inhalational anesthetics represents an objective measure of this effect during general anesthesia. In this study, the effect of acetaminophen with and without morphine or tramadol was evaluated on the isoflurane MAC. Methods Forty-eight male Wistar rats were anesthetized with isoflurane in oxygen. MACISO was determined from alveolar gas samples at the time of tail clamping without the drug, after administering acetaminophen (300 mg/kg), morphine (3 mg/kg), tramadol (10 mg/kg), acetaminophen (300 mg/kg) + morphine (3 mg/kg), and acetaminophen (300 mg/kg) + tramadol (10 mg/kg). Results The control and acetaminophen groups did not present statistically significant differences (p = 0.98). The values determined for MACISO after treatment with acetaminophen + morphine, acetaminophen + tramadol, morphine, and tramadol were 0.98% ± 0.04%, 0.99% ± 0.009%, 0.97% ± 0.02%, and 0.99% ± 0.01%, respectively. Conclusions The administration of acetaminophen did not reduce the MAC of isoflurane and did not potentiate the reduction in MACISO by morphine and tramadol in rats, and therefore does not present a sparing effect of morphine or tramadol in rats anesthetized with isoflurane. PMID:26605541

  10. The acceptability of repeat Internet-based hybrid diet assessment of previous 24-h dietary intake: administration of the Oxford WebQ in UK Biobank.

    Science.gov (United States)

    Galante, Julieta; Adamska, Ligia; Young, Alan; Young, Heather; Littlejohns, Thomas J; Gallacher, John; Allen, Naomi

    2016-02-28

    Although dietary intake over a single 24-h period may be atypical of an individual's habitual pattern, multiple 24-h dietary assessments can be representative of habitual intake and help in assessing seasonal variation. Web-based questionnaires are convenient for the participant and result in automatic data capture for study investigators. This study reports on the acceptability of repeated web-based administration of the Oxford WebQ--a 24-h recall of frequency from a set food list suitable for self-completion from which energy and nutrient values can be automatically generated. As part of the UK Biobank study, four invitations to complete the Oxford WebQ were sent by email over a 16-month period. Overall, 176 012 (53% of those invited) participants completed the online version of the Oxford WebQ at least once and 66% completed it more than once, although only 16% completed it on all four occasions. The response rate for any one round of invitations varied between 34 and 26%. On most occasions, the Oxford WebQ was completed on the same day that they received the invitation, although this was less likely if sent on a weekend. Participants who completed the Oxford WebQ tended to be white, female, slightly older, less deprived and more educated, which is typical of health-conscious volunteer-based studies. These findings provide preliminary evidence to suggest that repeated 24-h dietary assessment via the Internet is acceptable to the public and a feasible strategy for large population-based studies.

  11. Extensive neuroadaptive changes in cortical gene-transcript expressions of the glutamate system in response to repeated intermittent MDMA administration in adolescent rats

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    Malki Rana

    2008-04-01

    Full Text Available Abstract Background Many studies have focused on the implication of the serotonin and dopamine systems in neuroadaptive responses to the recreational drug 3,4-methylenedioxy-metamphetamine (MDMA. Less attention has been given to the major excitatory neurotransmitter glutamate known to be implicated in schizophrenia and drug addiction. The aim of the present study was to investigate the effect of repeated intermittent MDMA administration upon gene-transcript expression of the glutamate transporters (EAAT1, EAAT2-1, EAAT2-2, the glutamate receptor subunits of AMPA (GluR1, GluR2, GluR3, the glutamate receptor subunits of NMDA (NR1, NR2A and NR2B, as well as metabotropic glutamate receptors (mGluR1, mGluR2, mGluR3, mGluR5 in six different brain regions. Adolescent male Sprague Dawley rats received MDMA at the doses of 3 × 1 and 3 × 5 mg/kg/day, or 3× vehicle 3 hours apart, every 7th day for 4 weeks. The gene-transcript levels were assessed using real-time PCR validated with a range of housekeeping genes. Results The findings showed pronounced enhancements in gene-transcript expression of GluR2, mGluR1, mGluR5, NR1, NR2A, NR2B, EAAT1, and EAAT2-2 in the cortex at bregma +1.6. In the caudate putamen, mRNA levels of GluR3, NR2A, and NR2B receptor subunits were significantly increased. In contrast, the gene-transcript expression of GluR1 was reduced in the hippocampus. In the hypothalamus, there was a significant increase of GluR1, GluR3, mGluR1, and mGluR3 gene-transcript expressions. Conclusion Repeated intermittent MDMA administration induces neuroadaptive changes in gene-transcript expressions of glutamatergic NMDA and AMPA receptor subunits, metabotropic receptors and transporters in regions of the brain regulating reward-related associative learning, cognition, and memory and neuro-endocrine functions.

  12. Social influences on morphine sensitization in adolescent females

    OpenAIRE

    2010-01-01

    We recently observed that social interactions influence morphine responsiveness in adolescent males. Given sex-related differences in both social interactions and responses to morphine, the present study examines social influences on morphine sensitization in adolescent female mice. Four experimental groups were examined: [1] morphine-treated mice (twice daily, 10–40 mg/kg, s.c.) housed physically and visually separated from saline-treated mice (‘morphine only’), [2] morphine-treated mice hou...

  13. Socially induced morphine pseudosensitization in adolescent mice.

    Science.gov (United States)

    Hodgson, Stephen R; Hofford, Rebecca S; Roberts, Kris W; Wellman, Paul J; Eitan, Shoshana

    2010-03-01

    Given that social influences are among the strongest predictors of adolescents' drug use, this study examined the effect of social interaction on morphine-induced hyperlocomotion in both adolescent and adult mice. Three experimental groups of adolescent and adult male mice were examined (i) morphine-treated mice (twice daily, 10-40 mg/kg, subcutaneous), (ii) saline-injected mice housed together with the morphine-treated mice ('saline cage-mates'), and (iii) saline-injected mice housed physically and visually separated from the morphine-treated mice ('saline alone'). After the treatment period, mice were tested individually for their locomotor response to 10 mg/kg morphine (subcutaneous). Adolescent saline cage-mates, though administered morphine for the very first time, exhibited an enhanced hyperlocomotion response similar to the locomotor sensitization response exhibited by the morphine-treated mice. This was not observed in adults. In adults, there were no significant differences in morphine-induced hyperlocomotion between saline alone and saline cage-mates. As expected, morphine-treated adults and adolescents both exhibited locomotor sensitization. These results show a vulnerability to social influences in adolescent mice, which does not exist in adult mice.

  14. Effect of morphine on /sup 3/H-thymidine incorporation in the subependyma of the rat: an autoradiographic study

    Energy Technology Data Exchange (ETDEWEB)

    Miller, C.R.; O' Steen, W.K.; Deadwyler, S.A.

    1982-06-20

    Following morphine treatment, an autoradiographic study investigated the uptake of /sup 3/H-thymidine by the subependymal cells in the rat brain. /sup 3/H-thymidine was administered subcutaneously to adult, male Sprague-Dawley rats 30 minutes after saline or morphine (19 mg/kg) injection. The animals were sacrified 1 hour after /sup 3/H-thymidine administration. In some experiments the opioid antagonist, naloxone, was given alone 45 minutes before /sup 3/H-thymidine or 125 minutes before morphine treatment. Three areas of the subependyma were evaluated in terms of the percentage labeled cells and number of grains per nucleus, and a dorsal-to-ventral gradiant was described. Morphine treatment significantly increased the number of /sup 3/H-thymidine labeled subependymal cells and number of grains/nucleus within labeled cells. Examination of the distribution of grains/nucleus showed that morphine-treated animals had significantly more cells labeled with 30 or more grains than did saline-injected controls. Prior administration of naloxone blocked the increased /sup 3/H-thymidine uptake in morphine-treated animals but had no significant influence on cell proliferation when administered alone. The data are discussed in terms of morphine's possible dual influence on mechanisms which enhance cell transition from G to S phase and/or which accelerate DNA synthesis once these cells have entered the S phase of cell replication.

  15. 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.

  16. Analgesic effect of intra-articular tramadol compared with morphine after arthroscopic knee surgery.

    Science.gov (United States)

    Akinci, Seda B; Saricaoğlu, Fatma; Atay, Ozgur Ahmet; Doral, Mahmut Nedim; Kanbak, Meral

    2005-09-01

    The aim of the study was to compare the analgesic effect of 5 mg intra-articular (IA) morphine with 50 mg IA tramadol. Prospective double-blind randomized trial. Seventy-five patients having elective arthroscopic surgery of the knee were randomized to receive IA tramadol 50 mg (tramadol group), IA morphine 5 mg (morphine group), or IA normal saline (control group), in equivalent volumes (20 mL). The tourniquet was released 10 minutes after analgesic administration. Verbal pain rating score between 0 and 10 (VRS), supplemental analgesic requirements, and incidence of side effects were recorded postoperatively. Results are given as (median [5-95 percentiles]). The control group had a significantly shorter time to first analgesic request (25 min [15-55]) than morphine group, (34 min [15-158], P tramadol group, (33 min [17-728], P tramadol group (VRS 0 [0-9], P = .002). These treatment benefits were especially prominent in the patients who had meniscectomy or in the subgroup of patients with more than 6 months of preoperative pain. There was no statistical difference between the tramadol and morphine groups in the time to first analgesia, postoperative pain scores after arrival at the postanesthesia care unit, consumption of rescue analgesic, or side effects. We conclude that 50 mg IA tramadol provides analgesia equivalent to 5 mg IA morphine. Level II, randomized controlled trial that shows no significant difference and lacks narrow confidence intervals.

  17. Changes induced by sodium cromoglycate on brain serotonin turnover in morphine dependent and abstinent mice.

    Science.gov (United States)

    San-Martin-Clark, O; Leza, J C; Lizasoain, I; Lorenzo, P

    1993-01-01

    This study was designed to explain the action of sodium cromoglycate (CRO) on the brain serotonergic system in control, morphine tolerant (by SC implantation of a 75 mg morphine pellet), and also in morphine dependent mice just before naloxone-precipitated withdrawal. After SC injections of CRO in control mice, morphine tolerant mice (day 4 of addiction), and 1 h before abstinence (withdrawal was induced by SC injection of 1 mg/kg naloxone on day 4 of addiction), animals were decapitated and various brain areas were rapidly removed. 5HT (Serotonin) and 5HIAA (5-hydroxyindole-3-acetic acid) were measured by high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD). The ratio 5HIAA/5HT provided one index by which the turnover of the indoleamine was measured. CRO increased the turnover of 5HT in most of the brain areas studied in both control and morphine dependent mice. Furthermore, previous administration of CRO prior to naloxone challenge induced a significant increase in the 5HIAA/5HT ratio in the hypothalamus and striatum. These results are discussed as the reason for the preventive effect of CRO on jumping behaviour in morphine abstinent mice.

  18. A Clinical Approach to Neuraxial Morphine for the Treatment of Postoperative Pain

    Directory of Open Access Journals (Sweden)

    Borja Mugabure Bujedo

    2012-01-01

    Full Text Available Opioids are considered a “gold standard” in clinical practice for the treatment of postoperative pain. The spinal administration of an opioid drug does not guarantee selective action and segmental analgesia in the spine. Evidence from experimental studies in animals indicates that bioavailability in the spinal cord biophase is negatively correlated with liposolubility, and is higher for hydrophilic opioids, such as morphine, than lipophilic opioids, such as fentanyl, sufentanil and alfentanil. Epidural morphine sulphate has proven analgesic efficacy and superiority over systemically administered morphine for improving postoperative pain. However, pain relief after a single epidural injection of morphine could last less than 24 hours. Techniques used to administered and prolong opioid epidural analgesia, can be costly and inconvenient. Moreover, complications can arise from indwelling epidural catheterization, particularly in patients receiving anticoagulants. Clinical trials have shown that epidural morphine in the form of extended-release liposome injections (EREM gives good analgesia for a period of 48 hours, with no need for epidural catheterisation. Intrathecal morphine produces intense analgesia for up to 24 hours with a single shot, and clinical recommendation is to choose the minimum effective dose and do not exceed 300 μg to prevent the delay respiratory depression.

  19. A clinical approach to neuraxial morphine for the treatment of postoperative pain.

    Science.gov (United States)

    Mugabure Bujedo, Borja

    2012-01-01

    Opioids are considered a "gold standard" in clinical practice for the treatment of postoperative pain. The spinal administration of an opioid drug does not guarantee selective action and segmental analgesia in the spine. Evidence from experimental studies in animals indicates that bioavailability in the spinal cord biophase is negatively correlated with liposolubility, and is higher for hydrophilic opioids, such as morphine, than lipophilic opioids, such as fentanyl, sufentanil and alfentanil. Epidural morphine sulphate has proven analgesic efficacy and superiority over systemically administered morphine for improving postoperative pain. However, pain relief after a single epidural injection of morphine could last less than 24 hours. Techniques used to administered and prolong opioid epidural analgesia, can be costly and inconvenient. Moreover, complications can arise from indwelling epidural catheterization, particularly in patients receiving anticoagulants. Clinical trials have shown that epidural morphine in the form of extended-release liposome injections (EREM) gives good analgesia for a period of 48 hours, with no need for epidural catheterisation. Intrathecal morphine produces intense analgesia for up to 24 hours with a single shot, and clinical recommendation is to choose the minimum effective dose and do not exceed 300 μg to prevent the delay respiratory depression.

  20. Morphine Produces Immunosuppressive Effects in Nonhuman Primates at the Proteomic and Cellular Levels*

    Science.gov (United States)

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

    2012-01-01

    Morphine has long been known to have immunosuppressive properties in vivo, but the molecular and immunologic changes induced by it are incompletely understood. To explore how these changes interact with lentiviral infections in vivo, animals from two nonhuman primate species (African green monkeys and pigtailed macaques) were provided morphine and studied using a systems biology approach. Biological specimens were obtained from multiple sources (e.g. lymph node, colon, cerebrospinal fluid, 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 interorgan, interindividual, and interspecies 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 cell counts. Although 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 lymph nodes, with decreased abundance of protein mediators involved in the functional categories of energy metabolism, signaling, and maintenance of cell structure. These findings have direct relevance for understanding the impact of heroin addiction and the opioids used to treat addiction as well as on the potential interplay between opioid abuse and the immunological response to an infective agent. PMID:22580588

  1. Morphine produces immunosuppressive effects in nonhuman primates at the proteomic and cellular levels.

    Science.gov (United States)

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

    2012-09-01

    Morphine has long been known to have immunosuppressive properties in vivo, but the molecular and immunologic changes induced by it are incompletely understood. To explore how these changes interact with lentiviral infections in vivo, animals from two nonhuman primate species (African green monkeys and pigtailed macaques) were provided morphine and studied using a systems biology approach. Biological specimens were obtained from multiple sources (e.g. lymph node, colon, cerebrospinal fluid, 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 interorgan, interindividual, and interspecies 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 cell counts. Although 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 lymph nodes, with decreased abundance of protein mediators involved in the functional categories of energy metabolism, signaling, and maintenance of cell structure. These findings have direct relevance for understanding the impact of heroin addiction and the opioids used to treat addiction as well as on the potential interplay between opioid abuse and the immunological response to an infective agent.

  2. GHB differentially affects morphine actions on motor activity and social behaviours in male mice.

    Science.gov (United States)

    Maldonado, C; Rodriíuez-Arias, M; Aguilar, M A; Miñarro, J

    2003-09-01

    There are several reports suggesting that gamma-hydroxybutyric acid (GHB) influences the endogenous opioid system. The present study aimed to investigate the effects of GHB on motor and social activities and to examine its influence on morphine's actions on these behaviours. In a first experiment, several doses of GHB were studied but only the highest (200 and 400 mg/kg) produced a decrease in spontaneous motor activity measured in an actimeter cage. When hyperactivity induced by injecting 50 mg/kg of morphine was evaluated, all the GHB doses efficiently counteracted this morphine action. Using the paradigm of isolation-induced aggression, administration of 200 mg/kg of GHB significantly decreased threat and attack without impairing motor activity and, in addition, increased time spent in social contact. GHB increased morphine's suppression of threat or nonsocial exploratory behaviours. In conclusion, the interaction between GHB and the opioid systems was confirmed, with the drug having an additive effect on morphine-affected social behaviours but counteracting morphine-induced increases in motor activity.

  3. Pavlovian conditioning of morphine-induced alterations of immune status: evidence for opioid receptor involvement.

    Science.gov (United States)

    Coussons-Read, M E; Dykstra, L A; Lysle, D T

    1994-12-01

    Prior work in our laboratory has shown that morphine's immunomodulatory effects can become conditioned to environmental stimuli that predict drug administration. These immune alterations include conditioned changes in natural killer cell activity, interleukin-2 production, and mitogen-induced lymphocyte proliferation. The present study examined the involvement of opioid receptor activity in the establishment and expression of conditioned morphine-induced alterations of immune status. During the training phase of the experiment, Lewis rats received two conditioning sessions during which a subcutaneous injection of 15 mg/kg morphine sulfate was paired with exposure to a distinctive environment. On the test day, animals were re-exposed to the distinctive environment alone prior to sacrifice. Saline or naltrexone (0.3, 1.0, 3.0 or 10.0 mg/kg) was administered during either the training or the test session. Administration of naltrexone prior to training antagonized the development of all of the conditioned alterations of immune status including changes in the mitogenic responsiveness of splenocytes, suppression of natural killer cell activity, and interleukin-2 production by splenocytes. Naltrexone administration prior to testing also was effective in antagonizing the expression of a subset of morphine-induced conditioned alterations in immune status. Taken together, these studies indicate that opioid receptor activity is involved in the establishment of conditioned morphine-induced immune alterations, as well as in the expression of a subset of these conditioned alterations of immune status.

  4. 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.

  5. Repeated administration of D-amphetamine induces loss of [{sup 123}I]FP-CIT binding to striatal dopamine transporters in rat brain: a validation study

    Energy Technology Data Exchange (ETDEWEB)

    Booij, Jan [Department of Nuclear Medicine, Academic Medical Center, 1105 AZ Amsterdam (Netherlands)]. E-mail: j.booij@amc.uva.nl; Bruin, Kora de [Department of Nuclear Medicine, Academic Medical Center, 1105 AZ Amsterdam (Netherlands); Gunning, W. Boudewijn [Department of Neurology, Epilepsy Centre Kempenhaeghe, 5590 AB Heeze (Netherlands)

    2006-04-15

    In recent years, several PET and SPECT studies have shown loss of striatal dopamine transporter (DAT) binding in amphetamine (AMPH) users. However, the use of DAT SPECT tracers to detect AMPH-induced changes in DAT binding has not been validated. We therefore examined if repeated administration of D-AMPH or methamphetamine (METH) may induce loss of binding to striatal DATs in rats by using an experimental biodistribution study design and a SPECT tracer for the DAT ([{sup 123}I]FP-CIT). Methods: Groups of male rats (n=10 per group) were treated with D-AMPH (10 mg/kg body weight), METH (10 mg/kg body weight), or saline, twice a day for 5 consecutive days. Five days later, [{sup 123}I]FP-CIT was injected intravenously, and 2 h later, the rats were sacrificed and radioactivity was assayed. Results: In D-AMPH but not METH-treated rats, striatal [{sup 123}I]FP-CIT uptake was significantly lower (approximately 17%) than in the control group. Conclusion: These data show that [{sup 123}I]FP-CIT can be used to detect AMPH-induced changes in DAT binding and may validate the use of DAT radiotracers to study AMPH-induced changes in striatal DAT binding in vivo.

  6. The effect of repeated administrations of llama ovulation-inducing factor (OIF/NGF) during the peri-ovulatory period on corpus luteum development and function in llamas.

    Science.gov (United States)

    Fernández, A; Ulloa-Leal, C; Silva, M; Norambuena, C; Adams, G P; Guerra, M; Ratto, M H

    2014-10-01

    The objective of the study was to test the hypothesis that repeated administrations of OIF/NGF during the peri-ovulatory period (pre-ovulatory, ovulatory, early post-ovulatory), will enhance the luteotrophic effect in llamas. Female llamas were examined daily by transrectal ultrasonography in B- and Doppler-mode using a scanner equipped with a 7.5-MHz linear-array transducer to monitor ovarian follicle and luteal dynamics. When a growing follicle ≥7mm was detected, llamas were assigned randomly to one of the three groups and given 1mg of purified OIF/NGF im (intramuscular) (a) pre-ovulation (single dose; n=12), (b) pre-ovulation and at the time of ovulation (2 doses, n=10), or (c) pre-ovulation, at the time of ovulation, and 24h after ovulation (3 doses, n=10). The pre-ovulatory follicle diameter at the time of treatment, ovulation rate and the first day of CL detection did not differ (P=0.3) among groups. However, maximum CL diameter was greatest (P=0.003) in llamas in the 2-dose group, and smallest in the 3-dose group. Accordingly, the 2 dose-group had the largest day-to-day profile for CL diameter (Pllama seminal plasma is luteotrophic and the effect on CL size and function is affected by the number and timing of treatments during the peri-ovulatory period.

  7. An In Vivo Evaluation of the Effect of Repeated Administration and Clearance of Targeted Contrast Agents on Molecular Imaging Signal Enhancement

    Directory of Open Access Journals (Sweden)

    Jason E. Streeter, Paul A. Dayton

    2013-01-01

    Full Text Available Competitive inhibition diminishes ligand adhesion as receptor sites become occupied with competing ligands. It is unknown if this effect occurs in ultrasound molecular imaging studies where endothelial binding sites become occupied with adherent bubbles or bubble fragments. The goal of this pilot study was to assess the effect that repeated administration and clearance of targeted agents has on successive adhesion. Two groups of animals were imaged with 3-D ultrasonic molecular imaging. Injections and imaging were performed on Group 1 at time 0 and 60 minutes. Group 2 received injections of microbubbles at 0, 15, 30, 45 and 60 minutes with imaging at 0 and 60 minutes. At 60 minutes, Group 1 targeting relative to baseline was not significantly different from Group 2 (1.06±0.27 vs. 1.08±0.34, p=0.93. Data suggest that multiple injections of targeted microbubbles do not block sufficient binding sites to bias molecular imaging data in serial studies.

  8. Morphine Withdrawal Modifies Prion Protein Expression in Rat Hippocampus

    Science.gov (United States)

    Mattei, Vincenzo; Martellucci, Stefano; Santilli, Francesca; Manganelli, Valeria; Garofalo, Tina; Candelise, Niccolò; Caruso, Alessandra; Sorice, Maurizio; Scaccianoce, Sergio

    2017-01-01

    The hippocampus is a vulnerable brain structure susceptible to damage during aging and chronic stress. Repeated exposure to opioids may alter the brain so that it functions normally when the drugs are present, thus, a prolonged withdrawal might lead to homeostatic changes headed for the restoration of the physiological state. Abuse of morphine may lead to Reacting Oxygen Species-induced neurodegeneration and apoptosis. It has been proposed that during morphine withdrawal, stress responses might be responsible, at least in part, for long-term changes of hippocampal plasticity. Since prion protein is involved in both, Reacting Oxygen Species mediated stress responses and synaptic plasticity, in this work we investigate the effect of opiate withdrawal in rats after morphine treatment. We hypothesize that stressful stimuli induced by opiate withdrawal, and the subsequent long-term homeostatic changes in hippocampal plasticity, might modulate the Prion protein expression. Our results indicate that abstinence from the opiate induced a time-dependent and region-specific modification in Prion protein content, indeed during morphine withdrawal a selective unbalance of hippocampal Prion Protein is observable. Moreover, Prion protein overexpression in hippocampal tissue seems to generate a dimeric structure of Prion protein and α-cleavage at the hydrophobic domain. Stress factors or toxic insults can induce cytosolic dimerization of Prion Protein through the hydrophobic domain, which in turn, it stimulates the α-cleavage and the production of neuroprotective Prion protein fragments. We speculate that this might be the mechanism by which stressful stimuli induced by opiate withdrawal and the subsequent long-term homeostatic changes in hippocampal plasticity, modulate the expression and the dynamics of Prion protein. PMID:28081197

  9. Comparative of Therapeutic Efficacy of Oxycodone Hydrochloride Sustained-release Tablets vs. Morphine Sulfate Sustained-release Tablets for Severe Cancer Pain Control with Rectal Administration%盐酸羟考酮缓释片与硫酸吗啡缓释片直肠给药控制重度癌性疼痛的疗效比较

    Institute of Scientific and Technical Information of China (English)

    滕箭; 杨梅英; 沈季元; 王建华; 毛睿

    2012-01-01

    目的:比较盐酸羟考酮缓释片与硫酸吗啡缓释片经直肠给药治疗重度癌性疼痛的疗效和不良反应.方法:将102例伴有中、重度疼痛的癌症患者随机分为A组(50例)与B组(52例),分别经直肠给予盐酸羟考酮缓释片和硫酸吗啡缓释片,比较2组药物起效时间、癌痛类型和药品不良反应的差异.结果:A组患者治疗1、3h时的疼痛与B组同期比较,差异有统计学意义(P<0.05),2组内脏痛和躯体痛比较差异分别有统计学意义(P<0.05),2组的不良反应如恶心、呕吐、便秘比较分别有显著性差异(P<0.05),A组均优于B组.结论:盐酸羟考酮缓释片经直肠给药控制重度癌性疼痛,安全、有效、简便.%OBJECTIVE: To compare the efficacy and adverse drug reactions of oxycodone hydrochloride sustained-release tablets (Oxycontin, Oxycodone hydrochloride prolonged-release tablets) and Morphine sulfate sustained-release tablets (MS Contin, Morphine sulfate) with rectal administration in the treatment of severe cancer pain. METHODS: Clinical information of 102 cases of moderate to severe cancer pain were analyzed, and they were divided into 2 groups. 50 cases were given oxycodone hydrochloride sustained-release tablets with rectal administration group A and 52 cases were given morphine sulfate sustained-release tablets group B. The differences of onset time, the type of cancer pain and side effects were compared between 2 groups. RESULTS: There was statistical significance in the difference of cancer pain between 2 groups, after 1 h and 3 h treatment (P<0.05), there were statistical significance in the differences of visceral pain and somatic pain between 2 groups (P<0.05) ; there were significant differences in adverse drug reactions between 2 groups, such as nausea, vomiting, constipation (P<0.05), and group A was better than group B. CONCLUSION: As for non-hospitalized patients, dying patients and not oral due to various reasons, transrectal

  10. Expression of BDNF and TrkB Phosphorylation in the Rat Frontal Cortex During Morphine Withdrawal are NO Dependent.

    Science.gov (United States)

    Peregud, Danil I; Yakovlev, Alexander A; Stepanichev, Mikhail Yu; Onufriev, Mikhail V; Panchenko, Leonid F; Gulyaeva, Natalia V

    2016-08-01

    Nitric oxide (NO) mediates pharmacological effects of opiates including dependence and abstinence. Modulation of NO synthesis during the induction phase of morphine dependence affects manifestations of morphine withdrawal syndrome, though little is known about mechanisms underlying this phenomenon. Neurotrophic and growth factors are involved in neuronal adaptation during opiate dependence. NO-dependent modulation of morphine dependence may be mediated by changes in expression and activity of neurotrophic and/or growth factors in the brain. Here, we studied the effects of NO synthesis inhibition during the induction phase of morphine dependence on the expression of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and insulin-like growth factor 1 (IGF1) as well as their receptors in rat brain regions after spontaneous morphine withdrawal in dependent animals. Morphine dependence in rats was induced within 6 days by 12 injections of morphine in increasing doses (10-100 mg/kg), and NO synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) (10 mg/kg) was given 1 h before each morphine injection. The expression of the BDNF, GDNF, NGF, IGF1, and their receptors in the frontal cortex, striatum, hippocampus, and midbrain was assessed 40 h after morphine withdrawal. L-NAME treatment during morphine intoxication resulted in an aggravation of the spontaneous morphine withdrawal severity. Morphine withdrawal was accompanied by upregulation of BDNF, IGF1, and their receptors TrkB and IGF1R, respectively, on the mRNA level in the frontal cortex, and only BDNF in hippocampus and midbrain. L-NAME administration during morphine intoxication decreased abstinence-induced upregulation of these mRNAs in the frontal cortex, hippocampus and midbrain. L-NAME prevented from abstinence-induced elevation of mature but not pro-form of BDNF polypeptide in the frontal cortex. While morphine abstinence did not affect Trk

  11. Chronic morphine drinking establishes morphine tolerance, but not addiction in Wistar rats*

    OpenAIRE

    Binsack, Ralf; Zheng, Ming-lan; Zhang, Zhan-Sai; Yang, Liu; Zhu, Yong-ping

    2006-01-01

    Objective: Some animal models apply morphine in the drinking water to generate addiction, but related reports are not free of conflicting results. Accordingly, this study aimed to figure out if chronic consumption of morphine in the drinking water can induce morphine addiction in Wistar rats. Methods: For 3 weeks, the animals received a daily morphine dose of 35 mg/kg by offering a calculated volume of sugar water (5% sucrose) with morphine (0.1 mg/ml) to each rat; animals receiving just suga...

  12. Varied behavioral responses induced by morphine in the tree shrew: a possible model for human opiate addiction.

    Science.gov (United States)

    Shen, Fang; Duan, Ying; Jin, Shubo; Sui, Nan

    2014-01-01

    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.

  13. Short term morphine exposure in vitro alters proliferation and differentiation of neural progenitor cells and promotes apoptosis via mu receptors.

    Directory of Open Access Journals (Sweden)

    Dafna Willner

    Full Text Available Chronic morphine treatment inhibits neural progenitor cell (NPC progression and negatively effects hippocampal neurogenesis. However, the effect of acute opioid treatment on cell development and its influence on NPC differentiation and proliferation in vitro is unknown. We aim to investigate the effect of a single, short term exposure of morphine on the proliferation, differentiation and apoptosis of NPCs and the mechanism involved.Cell cultures from 14-day mouse embryos were exposed to different concentrations of morphine and its antagonist naloxone for 24 hours and proliferation, differentiation and apoptosis were studied. Proliferating cells were labeled with bromodeoxyuridine (BrdU and cell fate was studied with immunocytochemistry.Cells treated with morphine demonstrated decreased BrdU expression with increased morphine concentrations. Analysis of double-labeled cells showed a decrease in cells co-stained for BrdU with nestin and an increase in cells co-stained with BrdU and neuron-specific class III β-tubuline (TUJ1 in a dose dependent manner. Furthermore, a significant increase in caspase-3 activity was observed in the nestin- positive cells. Addition of naloxone to morphine-treated NPCs reversed the anti-proliferative and pro-apoptotic effects of morphine.Short term morphine exposure induced inhibition of NPC proliferation and increased active caspase-3 expression in a dose dependent manner. Morphine induces neuronal and glial differentiation and decreases the expression of nestin- positive cells. These effects were reversed with the addition of the opioid antagonist naloxone. Our results demonstrate the effects of short term morphine administration on the proliferation and differentiation of NPCs and imply a mu-receptor mechanism in the regulation of NPC survival.

  14. Effect of morphine and lacosamide on levels of dopamine and 5-HIAA in brain regions of rats with induced hypoglycemia.

    Science.gov (United States)

    Guzman, D Calderon; Garcia, E Hernandez; Mejia, G Barragan; Olguin, H Juarez; Gonzalez, J A Saldivar; Labra Ruiz, N A

    2014-01-15

    The study aimed to determine the effect of morphine and lacosamide on levels of dopamine and 5-HIAA in a hypoglycemic model. Female Wistar rats (n = 30), mean weight of 180 g were treated as follow: Group 1 (control) received 0.9% NaCl, Group II; morphine (10 mg kg(-1)), Group III; lacosamide (10 mg kg(-1)), Group IV; insulin (10 U.I. per rat), Group V; morphine (10 mg kg(-1))+insulin, Group VI; lacosamide (10 mg kg(-1))+ insulin. All administrations were made intraperitoneally every 24 h, for 5 days. Animals were sacrificed after the last dose to measure the levels of glucose in blood; dopamine and 5-HIAA in cortex, hemispheres and cerebellum/medulla oblongata regions. Levels of glucose decreased significantly in animals treated with morphine, lacosamide and all groups that received insulin alone or combined with respect to control group. Levels of Dopamine diminished significantly in cortex and increased significantly in hemispheres of animals that received morphine. In cortex, 5-HIAA increase significantly in the groups treated with morphine, morphine+insulin and lacosamide+insulin, however a significant decrease of the same substance was witnessed in cerebellum and medulla oblongata of animals that received morphine or lacosamide plus insulin. GSH increased significantly in cortex and cerebellum/medulla oblongata of animals treated with morphine and lacosamide alone or combined with insulin. Lipid peroxidation decreased significantly in cortex and cerebellum/medulla oblongata of groups that received lacosamide alone or combined with insulin. These results indicate that hypoglycemia induced changes in cellular regulation while morphine and lacosamide are accompanied by biochemical responses.

  15. 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.

  16. The effect of chronic morphine or methadone exposure and withdrawal on clock gene expression in the rat suprachiasmatic nucleus and AA-NAT activity in the pineal gland.

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    Pačesová, D; Novotný, J; Bendová, Z

    2016-07-18

    The circadian rhythms of many behavioral and physiological functions are regulated by the major circadian pacemaker in the suprachiasmatic nucleus. Long-term opiate addiction and drug withdrawal may affect circadian rhythmicity of various hormones or the sleep/activity pattern of many experimental subjects; however, limited research has been done on the long-term effects of sustained opiate administration on the intrinsic rhythmicity in the suprachiasmatic nucleus and pineal gland. Here we compared the effects of repeated daily treatment of rats with morphine or methadone and subsequent naloxone-precipitated withdrawal on the expression of the Per1, Per2, and Avp mRNAs in the suprachiasmatic nucleus and on arylalkylamine N-acetyltransferase activity in the pineal gland. We revealed that 10-day administration and withdrawal of both these drugs failed to affect clock genes and Avp expression in the SCN. Our results indicate that opioid-induced changes in behavioral and physiological rhythms originate in brain structures downstream of the suprachiasmatic nucleus regulatory output pathway. Furthermore, we observed that acute withdrawal from methadone markedly extended the period of high night AA-NAT activity in the pineal gland. This suggests that withdrawal from methadone, a widely used drug for the treatment of opioid dependence, may have stronger impact on melatonin synthesis than withdrawal from morphine.

  17. Chronic morphine drinking establishes morphine tolerance, but not addiction in Wistar rats

    Institute of Scientific and Technical Information of China (English)

    BINSACK Ralf; ZHENG Ming-lan; ZHANG Zhan-sai; YANG Liu; ZHU Yong-ping

    2006-01-01

    Objective: Some animal models apply morphine in the drinking water to generate addiction, but related reports are not free of conflicting results. Accordingly, this study aimed to figure out if chronic consumption of morphine in the drinking water can induce morphine addiction in Wistar rats. Methods: For 3 weeks, the animals received a daily morphine dose of 35 mg/kg by offering a calculated volume of sugar water (5% sucrose) with morphine (0.1 mg/ml) to each rat; animals receiving just sugar water served as controls. Immediately after the treatment phase, the tail immersion test was used to check for morphine tolerance,and all animals were then kept on tap water for one week (withdrawal phase). Afterwards, all rats were allowed to choose their drinking source by offering two bottles, containing sugar water without and with morphine, simultaneously for two days (preference phase). Results: While the chronic consumption of morphine led to a reduction in body weight and to morphine tolerance,the morphine-treated Wistar rats did not show any preference for the opiate-containing sugar water. Conclusion: Body weight loss and tolerance do not reveal a condition of drug craving, and current animal models should be re-evaluated regarding their potential to establish morphine addicted animals.

  18. Morphine induces μ opioid receptor endocytosis in guinea pig enteric neurons following prolonged receptor activation

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    Patierno, Simona; Anselmi, Laura; Jaramillo, Ingrid; Scott, David; Garcia, Rachel; Sternini, Catia

    2010-01-01

    Background & Aims The μ opioid receptor (μOR) undergoes rapid endocytosis following acute stimulation with opioids and most opiates, but not with morphine. We investigated whether prolonged activation of μOR affects morphine’s ability to induce receptor endocytosis in enteric neurons. Methods We compared the effects of morphine, a poor μOR-internalizing opiate, and [D-Ala2, MePhe4,Gly-ol5] enkephalin (DAMGO), a potent μOR-internalizing agonist, on μOR trafficking in enteric neurons and on the expression of dynamin and β-arrestin immunoreactivity in the ileum of guinea pigs rendered tolerant by chronic administration of morphine. Results Morphine (100 µM) strongly induced endocytosis of μOR in tolerant but not naïve neurons (55.7%±9.3% vs. 24.2%±7.3%, P<0.001) whereas DAMGO (10 µM) strongly induced internalization of μOR in neurons from tolerant and naïve animals (63.6%±8.4% and 66.5%±3.6%). Morphine- or DAMGO-induced μOR endocytosis resulted from direct interactions between the ligand and the μOR, because endocytosis was not affected by tetrodotoxin, a blocker of endogenous neurotransmitter release. Ligand-induced μOR internalization was inhibited by pretreatment with the dynamin inhibitor, dynasore. Chronic morphine administration resulted in a significant increase in dynamin and translocation of dynamin immunoreactivity from the intracellular pool to the plasma membrane, but did not affect β arrestin immunoreactivity. Conclusion Chronic activation of μORs increases the ability of morphine to induce μOR endocytosis in enteric neurons, which depends on the level and cellular localization of dynamin, a regulatory protein that has an important role in receptor-mediated signal transduction in cells. PMID:21070774

  19. α-Terpineol attenuates morphine-induced physical dependence and tolerance in mice: role of nitric oxide

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    Parvardeh, Siavash; Moghimi, Mahsa; Eslami, Pegah; Masoudi, Alireza

    2016-01-01

    Objective(s): 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. Materials and Methods: 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. Results: 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. Conclusion: These findings indicate that α-terpineol prevents the development of dependence and tolerance to morphine probably through the influence on NO production. PMID:27081466

  20. Activation of JNK pathway in spinal astrocytes contributes to acute ultra-low-dose morphine thermal hyperalgesia.

    Science.gov (United States)

    Sanna, Maria Domenica; Ghelardini, Carla; Galeotti, Nicoletta

    2015-07-01

    Accumulating evidence suggests that opioid analgesics can lead to paradoxical sensitization to pain when delivered in different administration patterns. Although opioid tolerance-induced hyperalgesia is largely studied, little is known about the mechanisms underlying acute ultra-low-dose morphine hyperalgesia. Activation of spinal glial cells is reported to regulate pain hypersensitivity. To elucidate the mechanism involved in acute ultra-low-dose morphine hyperalgesia, we tested whether an opioid agonist promoted the activation of spinal astrocytes and microglia and investigated the cellular pathways involved. Ultra-low-dose morphine activated spinal astrocytes with no effect on microglia. The astrocyte activation was selectively prevented by the opioid antagonist naloxone, the μ-opioid receptor (MOR) silencing and the JNK inhibitor SP600125. Morphine elevated spinal JNK1, JNK2, and c-Jun phosphorylation. Conversely, phosphorylation of cAMP response element-binding protein (CREB) and signal transducer and activator of transcription-1 (STAT-1) was not elevated, and nuclear factor kappa B (NF-κB) levels remained unmodified. Administration of SP600125 and the N-methyl-D-aspartate (NMDA) antagonist MK801 prevented morphine hyperalgesia. Ultra-low-dose morphine increased protein kinase C (PKC) γ phosphorylation. Pretreatment with a PKC inhibitor prevented morphine hyperalgesia and JNK and c-Jun overphosphorylation, indicating PKC is a JNK upstream modulator and illustrating the presence of a pathway involving PKC, NMDA, and JNK activated by morphine. Immunofluorescence experiments indicated the neuronal localization of spinal MOR. However, JNK was not detected in MOR-expressing cells, showing the presence of a neuron-astrocyte signaling pathway. These results illustrate the selective activation of an astrocyte JNK pathway after the stimulation of neuronal MOR, which contributes to ultra-low-dose morphine hyperalgesia.

  1. 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.

  2. Proteomic analysis of rat cerebral cortex, hippocampus and striatum after exposure to morphine.

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    Bierczynska-Krzysik, Anna; Pradeep John, Julius Paul; Silberring, Jerzy; Kotlinska, Jolanta; Dylag, Tomasz; Cabatic, Maureen; Lubec, Gert

    2006-10-01

    Although a series of proteins in the brain have been shown to be qualitatively or quantitatively dysregulated following morphine administration, a systematic proteomic study has not been carried out so far. We therefore aimed to show the effect of morphine on protein levels in the rat brain. For this purpose rats were given a morphine base in subcutaneously placed pellets and subsequently the cerebral cortex, hippocampus and striatum were taken for proteomic studies after three days. Extracted proteins were run on two-dimensional gel electrophoresis, scanned and quantified by specific software. Proteins with significantly different levels were analysed by mass spectrometry (MALDI-TOF-TOF). Twenty-six proteins were found to be differentially expressed and were unambiguously identified. Dysregulated proteins were from several protein pathways and cascades including signaling, metabolic, protein handling, antioxidant and miscellaneous classes. These findings represent an initial approach to the generation of a 'morphinome' and may form the basis for further protein chemical studies as a valuable analytical tool. Moreover, the study reveals morphine-regulated proteins in different brain areas and indicates the pathways involved following morphine administration in the rat, the main species for pharmacological studies in the field.

  3. Brain Reward Circuits in Morphine Addiction

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    Kim, Juhwan; Ham, Suji; Hong, Heeok; Moon, Changjong; Im, Heh-In

    2016-01-01

    Morphine is the most potent analgesic for chronic pain, but its clinical use has been limited by the opiate’s innate tendency to produce tolerance, severe withdrawal symptoms and rewarding properties with a high risk of relapse. To understand the addictive properties of morphine, past studies have focused on relevant molecular and cellular changes in the brain, highlighting the functional roles of reward-related brain regions. Given the accumulated findings, a recent, emerging trend in morphine research is that of examining the dynamics of neuronal interactions in brain reward circuits under the influence of morphine action. In this review, we highlight recent findings on the roles of several reward circuits involved in morphine addiction based on pharmacological, molecular and physiological evidences. PMID:27506251

  4. RACK1 affects morphine reward via BDNF.

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    Wan, Lihong; Xie, Yizhou; Su, Lan; Liu, Yanyou; Wang, Yuhui; Wang, Zhengrong

    2011-10-06

    Chronic morphine addiction may trigger functional changes in the mesolimbic dopamine system, which is believed to be the neurobiological substrate of opiate addiction. Brain derived neurotrophic factor (BDNF) has been implicated in addiction-related pathology in animal studies. Our previous studies have shown that RACK1 is involved in morphine reward in mice. The recent research indicates nuclear RACK1 by localizing at the promoter IV region of the BDNF gene and the subsequent chromatin modifications leads to the activation of the promoter and transcription of BDNF. The present study was designed to investigate if shRACK1 (a short hairpin RNA of RACK1) could reverse the mice's behavioral responses to morphine and BDNF expression in hippocampus and prefrontal cortex. No significant changes were observed in vehicle-infused mice which received no morphine treatment (CONC) and shRACK1-infused mice which received no morphine treatment (CONR), whereas vehicle-infused mice preceded the morphine injection (MIC) showed increased BDNF expression in hippocampus and prefrontal cortex, as compared to vehicle-infused mice which received no morphine treatment (CONC). Intracerebroventricular shRACK1 treatment reversed these, and in fact, ShRACK1-infused mice preceded the morphine injection (MIR) showed reduced BDNF expression in hippocampus and prefrontal cortex, as compared to MIC. In the conditioned place preference (CPP) test, inactivating RACK1 markedly reduces morphine-induced conditioned place preference. Non-specific changes in CPP could not account for these effects since general CPP of shRACK1- and vehicle-infused animals was not different. Combined behavioral and molecular approaches have support the possibility that the RACK1-BDNF system plays an important role in the response to morphine-induced reward.

  5. Inhibition of morphine metabolism by ketamine.

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    Qi, Xiaoxin; Evans, Allan M; Wang, Jiping; Miners, John O; Upton, Richard N; Milne, Robert W

    2010-05-01

    Clinical observation of a synergistic effect of ketamine on morphine analgesia remains controversial. Although a pharmacodynamic basis for an interaction has been explored in animal and clinical studies, the possibility of a pharmacokinetic mechanism has not been investigated. Whereas both morphine and morphine-6-glucuronide are effective analgesics, morphine-3-glucuronide (M3G) lacks activity. Thus, changes in the metabolism and disposition of morphine may result in an altered response. First, we investigated the interaction between morphine and ketamine in the isolated perfused rat liver preparation. The clearance of morphine was decreased from 16.8 +/- 4.6 ml/min in the control period to 7.7 +/- 2.8 ml/min in the ketamine-treatment period, with the formation clearance of M3G decreasing from 8.0 +/- 4.1 ml/min to 2.1 +/- 1.1 ml/min. Fractional conversion of morphine to M3G was significantly decreased from 0.46 +/- 0.17 in the control period to 0.28 +/- 0.14 upon the addition of ketamine. The possible mechanism of the interaction was further investigated in vitro with rat liver microsomes as the enzyme source. The formation of M3G followed single-enzyme Michaelis-Menten kinetics, with a mean apparent K(m) of 2.18 +/- 0.45 mM and V(max) of 8.67 +/- 0.59 nmol/min/mg. Ketamine inhibited morphine 3-glucuronidation noncompetitively, with a mean K(i) value of 33.3 +/- 7.9 microM. The results demonstrate that ketamine inhibits the glucuronidation of morphine in a rat model.

  6. 21 CFR 862.3640 - Morphine test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  7. The measurement and interpretation of morphine in blood.

    Science.gov (United States)

    Logan, B K; Oliver, J S; Smith, H

    1987-01-01

    A method for the determination of morphine is post-mortem blood by HPLC with electrochemical detection is described. Blood morphine levels in post-mortem cases are reported and the importance of these in causing death is discussed. These post-mortem levels are compared further with morphine levels in the blood of patients receiving morphine as an analgesic.

  8. 河豚毒素与吗啡联合用药对吗啡依赖性与镇痛耐受作用的影响%EFFECTS OF TETRODOTOXIN COMBINED WITH MORPHINE ON MORPHINE'S DEPENDENCE AND ANALGESIC TOLERANCE

    Institute of Scientific and Technical Information of China (English)

    徐开俊; 周娟; 翟清波; 赵继红

    2012-01-01

    Objective: To study the effect of tetrodotoxin ( TTX) combined with morphine on the dependence and analgesic tolerance acting of morphine. Methods-. The mouse model of morphine dependency and hot plate experiment were used in this research to investigate the effects of morphine alone< morphine 2. 5 ml · kg-1) and morphine combined with TTX ( morphine 2. 5 mg · kg + TTX 0. 5 μg· kg-1, morphine 2. 5 mg · kg-1 + TTX 1. 0 μg· kg-1) on the withdrawal symptoms induced by naloxone and the analgesic tolerance of morphine. Results-. Administration of morphine combined with TTX could inhibit the weight loose of mice, significantly inhibit the jumping effect after the withdrawal experiment induced by naloxone and reduce the increase of the response latency in the hot - plate experiment. Conclusion-. Administration of morphine combined with TTX can inhibit the effect of dependence and analgesic tolerance acting of morphine.%目的:研究河豚毒素(tetrodotoxin,TTX)与吗啡联合使用对吗啡依赖性及镇痛耐受作用的影响.方法:采用吗啡依赖性小鼠模型及热板实验,评价单独使用吗啡(2.5 ml·kg-1)以及联合给药(吗啡2.5 mg·kg-1+TTX0.5μg·kg-1、吗啡2.5 mg·kg-1TTX1.0μg·kg-1)对纳洛酮催促戒断症状及镇痛耐受性的影响.结果:联合用药可以抑制吗啡依赖性小鼠戒断后体重的丢失,明显抑制吗啡依赖小鼠纳洛酮催促后的跳跃反应,抑制小鼠热板实验的潜伏期时间的增加.结论:TTX与吗啡联合用药可以抑制吗啡的依赖性与镇痛耐受作用的产生.

  9. D1- and D2-like dopamine receptors in the CA1 region of the hippocampus are involved in the acquisition and reinstatement of morphine-induced conditioned place preference.

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    Assar, Nasim; Mahmoudi, Dorna; Farhoudian, Ali; Farhadi, Mohammad Hasan; Fatahi, Zahra; Haghparast, Abbas

    2016-10-01

    The hippocampus plays a vital role in processing contextual memories and reward related learning tasks, such as conditioned place preference (CPP). Among the neurotransmitters in the hippocampus, dopamine is deeply involved in reward-related processes. This study assessed the role of D1- and D2-like dopamine receptors within the CA1 region of the hippocampus in the acquisition and reinstatement of morphine-CPP. To investigate the role of D1 and D2 receptors in morphine acquisition, the animals received different doses of D1- and/or D2-like dopamine receptor antagonists (SCH23390 and sulpiride, respectively) into the CA1, 5min before the administration of morphine (5mg/kg, subcutaneously) during a 3-days conditioning phase. To evaluate the involvement of these receptors in morphine reinstatement, the animals received different doses of SCH23390 or sulpiride (after extinction period) 5min before the administration of a low dose of morphine (1mg/kg) in order to reinstate the extinguished morphine-CPP. Conditioning scores were recorded by Ethovision software. The results of this study showed that the administration of SCH23390 or sulpiride, significantly decreased the acquisition of morphine-CPP. Besides, the injection of these antagonists before the administration of a priming dose of morphine, following the extinction period, decreased the reinstatement of morphine-CPP in sacrificed rats. However, the effect of sulpiride on the acquisition and reinstatement of morphine-CPP was more significant than that of SCH23390. These findings suggested that D1- and D2-like dopamine receptors in the CA1 are involved in the acquisition and reinstatement of morphine-CPP, and antagonism of these receptors can reduce the rewarding properties of morphine.

  10. Activation of TLR4/STAT3 signaling in VTA contributes to the acquisition and maintenance of morphine-induced conditioned place preference.

    Science.gov (United States)

    Chen, Jia-Xin; Huang, Kang-Mei; Liu, Meng; Jiang, Jin-Xiang; Liu, Jian-Peng; Zhang, Yu-Xiang; Yang, Chen; Xin, Wen-Jun; Zhang, Xue-Qin

    2017-09-29

    Morphine, commonly used to relieve the acute or chronic pain, has a high potential for addiction and exerts rewarding effects via a critical role for mesolimbic dopamine system. Studies suggest that addiction-related behavior is highly associated with inflammatory immune response, but the mechanisms are poorly understood. The present study showed that intra-VTA microinjection of TLR4 antagonist LPS-RS prevented the acquisition and maintenance, but not the expression, of morphine-induced CPP in rats. In addition, chronic morphine treatment significantly activated STAT3 on day 6 and 11 in VTA, and bilateral microinjection of STAT3 inhibitor S3I-201 into the VTA suppressed the acquisition and maintenance of morphine-induced CPP in rats. Furthermore, local knockout of STAT3 by injection of the AAV-Cre-GFP into the VTA area of STAT3(flox/flox) mice also significantly impaired the acquisition of morphine CPP. Importantly, the TLR4 expression is colocalized with p-STAT3-positive cell in VTA, and repeated injection of LPS-RS significantly attenuated the STAT3 activation in VTA induced by chronic morphine treatment. Collectively, these data suggest that TLR4/STAT3 signaling pathway in VTA might play a critical role in the acquisition and maintenance of morphine CPP, and provides new evidence that TLR4/STAT3 signaling pathway might be a potential target for treatment of morphine addiction. Copyright © 2017. Published by Elsevier B.V.

  11. Differential expression of endocannabinoid system-related genes in the dorsal hippocampus following expression and reinstatement of morphine conditioned place preference in mice.

    Science.gov (United States)

    Li, Wei; Zhang, Cong-Li; Qiu, Zheng-Guo

    2017-03-16

    The endocannabinoid signaling plays a critical role in mediating rewarding effects to morphine. The relative stability for the expression and reinstatement of morphine conditioned place preference (CPP) suggests the involvement of differential neuroadaptations in learned associations between environmental cues and morphine. Changes in gene expression in hippocampus through the endogenous cannabinoid system (eCB) may accompany and mediate the development of such neuroadaptations to repeated morphine stimulation. To test this possibility, we systematically compared the expression of eCB-related genes in the dorsal hippocampus following the expression, extinction, and reinstatement of morphine CPP using quantitative RT-PCR analyses. We found that expression of morphine CPP was associated with significant increases in mRNA expression for the primary clearance routes for anandamide (AEA) and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively), but with reductions in cannabinoid 1 receptors (CB1R) and CB2R in dorsal hippocampus following the expression of CPP. However, our results indicated that decreased in MAGL and increased CB1R mRNA levels were accompanied with morphine CPP reinstatement. No significant changes in mRNA expression for enzymes involved in AEA and 2-AG biosynthesis (N-acylphosphatidylethanolamine phospholipase D [NAPEPLD] and diacylglycerol lipase-α/β [DAGLα/β], respectively) were found in all conditions. These results suggest that differential regulation of the synthesis and/or degradation of the eCB system contribute to the expression and reinstatement of morphine CPP.

  12. Plasma and cerebrospinal fluid alfentanil, butorphanol, and morphine concentrations following caudal epidural administration in horses Concentrações plasmáticas e no líquido cérebro-espinhal de alfentanil, butorfanol e morfina após administração epidural caudal em eqüinos

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    Cláudio Corrêa Natalini

    2006-10-01

    Full Text Available This study was conducted with the objective of determining the plasma and cerebrospinal fluid (CSF concentrations after epidurally administered alfentanil, butorphanol, and morphine in horses. Five clinically healthy adult horses were studied. Morphine 0.1mg kg-1, alfentanil 0.02mg kg-1, and butorphanol 0.08mg kg-1 in equal volumes (20ml were epidurally injected. A 10-ml sample of CSF and blood were drawn at sampling times before the epidural administration and at 5, 10, 20, 30, 40, 50, 60 and 120 minutes, and hourly for 24 hours Enzyme-linked immonosorbent assay (ELISA was used as the screening test to detect the injected opioids. ANOVA and Bonferroni’s test were used with a P values Este estudo foi realizado com o objetivo de se detectar as concentrações plasmáticas e no líquido cérebro-espinhal de alfentanil, butorfanol e morfina administrados por via epidural caudal em cavalos. Foram utilizados cinco eqüinos adultos, clinicamente hígidos. Doses de morfina (0,1mg kg-1, alfentanil (0,02mg kg-1, e butorfanol (0,08mg kg-1, diluídos em volume idêntico de 20ml em solução salina 0,9%, foram administrados por via epidural. Uma amostra de 10ml de sangüe venoso e de líqüido cérebro-espinhal foram colhidas anteriormente à administração epidural e 5, 10, 20, 30, 40, 50, 60 e 120 minutos e a cada hora por 24 horas. O teste enzyme-linked immunosorbent assay (ELISA foi utilizado como método analítico para detecção dos opióides. Os resultados foram avaliados com teste ANOVA e Bonferroni com valor de P<0,05. O teste de ELISA mostrou-se eficiente para detecção plasmática e no LCE de alfentanil, butorfanol, e morfina administrados por via epidural. A administração epidural de alfentanil em eqüinos produz níveis no líquido cérebro-espinhal mais rapidamente que no plasma. Opióides de maior hidrossolubilidade tais como morfina e butorfanol produzem níveis plasmáticos mais rapidamente do que no líquido cérebro-espinhal quando

  13. Can personality traits and gender predict the response to morphine? An experimental cold pain study.

    Science.gov (United States)

    Pud, Dorit; Yarnitsky, David; Sprecher, Elliot; Rogowski, Zeev; Adler, Rivka; Eisenberg, Elon

    2006-02-01

    The aim of the present study was to examine the possible role of personality traits, in accordance with Cloninger's theory, and gender, in the variability of responsiveness to opioids. Specifically, it was intended to test whether or not the three personality dimensions - harm avoidance (HA), reward dependence (RD) and novelty seeking (NS) - as suggested by Cloninger, can predict inter-personal differences in responsiveness to morphine after exposure to experimental cold pain. Thirty-four healthy volunteers (15 females, 19 males) were given the cold pressor test (CPT). Pain threshold, tolerance, and magnitude (VAS) were measured before and after (six measures, 30 min apart) the administration of either 0.5 mg/kg oral morphine sulphate (n=21) or 0.33 mg/kg oral active placebo (diphenhydramine) (n=13) in a randomized, double blind design. Assessment of the three personality traits, according to Cloninger's Tridimensional Personality Questionnaire, was performed before the CPT. A high HA score (but not RD, NS, or baseline values of the three pain parameters) predicted a significantly larger pain relief following the administration of morphine sulphate (but not of the placebo). Women exhibited a larger response in response to both treatments, as indicated by a significantly increased threshold and tolerance following morphine sulphate as well as significantly increased tolerance and decreased magnitude following placebo administration. The present study confirms the existence of individual differences in response to analgesic treatment. It suggests that high HA personality trait is associated with better responsiveness to morphine treatment, and that females respond better than men to both morphine and placebo.

  14. Endogenous histamine inhibits the development of morphine-induced conditioned place preference

    Institute of Scientific and Technical Information of China (English)

    Ying-xia GONG; Min LV; Yong-ping ZHU; Yuan-yuan ZHU; Er-qing WEI; Hong SHI; Qun-li ZENG; Zhong CHEN

    2007-01-01

    Aim:The conditioned place preference (CPP) paradigm was used to investigate the effects of endogenous histamine on the processes leading to morphine-induced reward-seeking behavior in Sprague-Dawley rats. Methods: The model of CPP was used to assess the rewarding effect of morphine. The levels of histamine,glutamate, γ-aminobutyric acid (GABA), dopamine (DA) and 3, 4-dihydroxyphenyl-acetic acid (DOPAC) in rat brains were measured with high-performance liquid chromatography. Immunohistochemistry technique was used to observe the morphological changes of neurons. Results: Intraperitoneal injection of mor-phine (2, 5 or 10 mg/kg) induced the development of CPP in a dose-dependent manner. In addition, morphine administrations (10 mg/kg) decreased the hista-mine content and reduced the number and size of histaminergic neurons in the tuberomammillary nucleus (TM), as well as markedly increasing the DOPAC/DA ratios in the ventral tegmental area (VTA) and nucleus accumbens (NAc). Intra-peritoneal injection of histidine (50, 100 or 200 mg/kg) dose-dependently inhibited the development of morphine-induced CPP. Bilateral lesions of the TM, which decreased the histamine levels in the VTA and NAc, potentiated the development of CPP induced by morphine (1 mg/kg, a dose that produced no appreciable effect when given alone) and increased the DOPAC/DA ratios in the VTA and NAc, but did not change the glutamate or GABA levels in these nuclei. Histidine reversed the effects of the TM lesions. Conclusion: These results indicate that endog-enous histamine plays a role in inhibiting the development of morphine-induced reward-seeking behavior, and the inhibition may involve the modulation of dopa-minergic activity.

  15. Epidural levobupivacaine alone or combined with different morphine doses in bitches under continuous propofol infusion

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    V.B. Albuquerque

    2015-08-01

    Full Text Available The aim of this study was to assess the cardiopulmonary, analgesic, adverse effects, serum concentration of cortisol and plasma levels of levobupivacaine and morphine in bitches undergoing propofol anesthesia and epidural analgesia with levobupivacaine alone or combined with morphine. This was a randomized 'blinded' prospective clinical study using 32 adult bitches weighing 9.8±4.1kg that were admitted for elective ovariohysterectomy. Twenty minutes after administration of acepromazine and midazolam, anesthesia was induced with propofol (4mg kg-1 and maintained by a continuous rate infusion (CRI. Each animal was randomly assigned to one of four epidural groups: GL = levobupivacaine alone (0.33mg kg-1; GLM0.1 = levobupivacaine and morphine (0.1mg kg-1; GLM0.15 = levobupivacaine and morphine (0.15mg kg-1; and GLM0.2 = levobupivacaine and morphine (0.2mg kg-1. Variables obtained during anesthesia were heart rate, respiratory rate, systolic, mean and diastolic arterial blood pressures, oxyhemoglobin saturation, inspired oxygen fraction, end-tidal carbon dioxide tension, blood gases, serum cortisol, and plasma levels of levobupivacaine and morphine. The onset and duration times of the blockade were recorded. Arterial pressures were significantly increased in all groups at the times of ovarian pedicle clamping. There was a decrease in pH, together with an increase in both PaO2and PaCO2 over time. Serum cortisol levels were increased in TESu compared to TB, T30 and TR. Limb spasticity, muscle tremors, opisthotonos and diarrhea were observed in some animals during propofol infusion and ceased with the end of CRI. Reactions happened at different moments and lasted for different periods of time in each individual. Epidural with levobupivacaine alone or combined with morphine allowed for ovariohysterectomy to be performed under low propofol infusion rates, with minimal changes in cardiovascular variables and in serum cortisol levels. Adverse effects were

  16. Behavioral responses to and brain distribution of morphine in mature adult and aged mice

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    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.

  17. Withania somnifera root extract prolongs analgesia and suppresses hyperalgesia in mice treated with morphine.

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    Orrù, Alessandro; Marchese, Giorgio; Casu, Gianluca; Casu, Maria Antonietta; Kasture, Sanjay; Cottiglia, Filippo; Acquas, Elio; Mascia, Maria Paola; Anzani, Nicola; Ruiu, Stefania

    2014-04-15

    Previous studies demonstrated that Withania somnifera Dunal (WS), a safe medicinal plant, prevents the development of tolerance to the analgesic effect of morphine. In the present study, we investigated whether WS extract (WSE) (100 mg/kg, i.p.) may also modulate the analgesic effect induced by acute morphine administration (2.5, 5, 10 mg/kg, s.c.) in the tail-flick and in the hot plate tests, and if it may prevent the development of 2.5 mg/kg morphine-induced rebound hyperalgesia in the low intensity tail-flick test. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for opioid (μ, δ, k), cannabinoid (CB1, CB2), glutamatergic (NMDA), GABAergic (GABAA, GABAB), serotoninergic (5HT2A) and adrenergic (α2) receptors. The results demonstrated that (i) WSE alone failed to alter basal nociceptive threshold in both tests, (ii) WSE pre-treatment significantly protracted the antinociceptive effect induced by 5 and 10 mg/kg of morphine only in tail-flick test, (iii) WSE pre-treatment prevented morphine-induced hyperalgesia in the low intensity tail-flick test, and (iv) WSE exhibited a high affinity for the GABAA and moderate affinity for GABAB, NMDA and δ opioid receptors. WSE prolongs morphine-induced analgesia and suppresses the development of morphine-induced rebound hyperalgesia probably through involvement of GABAA, GABAB, NMDA and δ opioid receptors. This study suggests the therapeutic potential of WSE as a valuable adjuvant agent in opioid-sparing therapies.

  18. [Neurotoxicity of intrathecally administrated agents].

    Science.gov (United States)

    Malinovsky, J M; Pinaud, M

    1996-01-01

    Spinal anaesthetics can induce histopathologic lesions and regional haemodynamic alterations in the spinal cord. There are numerous causes of neurologic lesions, including direct trauma of the spinal cord and nerve roots during puncture or catheter insertion, compromised spinal cord perfusion and direct neurotoxic effect. Histopathologic lesions are localized either in meninges (meningitis or arachnoiditis) or in neuraxis (myelitis or axonal degeneration). Neurotoxicity can result from decrease in neuronal blood supply, elicited by high concentrations of the solutions, long duration exposure to local anaesthetics, and the use of adjuvants. They have been implicated in the occurrence of cauda equina syndrome after continuous spinal anaesthesia using hyperbaric solution of lidocaine and tetracaine given through small diameter catheters. Selective spinal analgesia is induced by spinal opioids without motor blockade except for meperidine. Complications occurred in patients after high doses of morphine, which were related to one of its metabolites, morphine-3-glucuronide. Preservative-free opioid solutions are to be preferred for spinal anaesthesia. There is no report of neurotoxicity neither in animal studies, nor in humans, using spinal clonidine. In order to reduce the incidence of neurotoxicity, some safety rules should be followed. The lowest efficient dose of local anaesthetics must be given. Incomplete blockade should not necessarily lead to a reinjection. Large volume of hyperbaric lidocaine or repeated injections of such solutions must be avoided as well as preservative-containing solutions. The administration of new compounds by the spinal route must be supported by data of spinal neuropharmacology and the lack of neurotoxicity must have been previously checked with animal studies.

  19. Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice.

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    Pedrón, Valeria T; Varani, André P; Balerio, Graciela N

    2016-05-01

    In previous studies we have shown that baclofen, a selective GABAB receptor agonist, prevents the somatic expression and reestablishes the dopamine and μ-opioid receptors levels, modified during naloxone-precipitated morphine withdrawal syndrome in male and female mice. There are no previous reports regarding sex differences in the elevated plus maze (EPM) and the expression of BDNF in morphine-withdrawn mice. The present study analyses the behavioral and biochemical variations during morphine withdrawal in mice of both sexes, and whether these variations are prevented with baclofen. Swiss-Webster albino prepubertal mice received morphine (2 mg/kg, i.p.) twice daily, for 9 consecutive days. On the 10th day, one group of morphine-treated mice received naloxone (opioid receptor antagonist; 6 mg/kg, i.p.) 1 h after the last dose of morphine to precipitate withdrawal. A second group received baclofen (2 mg/kg, i.p.) before naloxone administration. The EPM behavior was measured during 15 min after naloxone injection. The expression of BDNF-positive cells was determined by immunohistochemistry. Withdrawn male mice showed a higher percentage of time spent and number of entries to the open arms compared to withdrawn female mice. Baclofen prevented this behavior in both sexes. BDNF expression decreased in the AcbC, BNST, CeC, and CA3 of the hippocampus while increased in the BLA of morphine withdrawn male. Baclofen pretreatment prevented the BDNF expression observed in morphine withdrawn male mice in all the brain areas studied except in the CeC. Baclofen prevention of the EPM behavior associated to morphine withdrawal could be partially related to changes in BDNF expression.

  20. Intracerebroventricular effects of histaminergic agents on morphine-induced anxiolysis in the elevated plus-maze in rats.

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    Zarrindast, Mohammad-Reza; Rostami, Parvin; Zarei, Morteza; Roohbakhsh, Ali

    2005-11-01

    Some reports indicate that morphine can induce anxiolytic effects both in animal and in man. It has also been reported that histaminergic system can interfere with some pharmacological effects of morphine. The effects of histaminergic agents on morphine-induced anxiolysis in rats, using elevated plus-maze were investigated in the present study. Intraperitoneal injection of morphine (3, 6 and 9 mg/kg) induced antianxiety effects. Intracerebroventricular administration of histamine at the doses of (5, 10 and 20 microg/rat) also increased anxiety-related behaviours. Intracerebroventricular injection of pyrilamine, a H1 receptor antagonist (25, 50 and 100 microg/rat), increased anxiety whereas injection of ranitidine, a H2 receptor antagonist (5, 10 and 20 microg/rat) at the same site, decreased anxiety. Therefore, it seems that histamine induces anxiogenic response through activation of H2 receptors, while the response of H1 blocker may be due to release of histamine. We also evaluated the interactions between morphine and histaminergic agents. Our data show that histamine (10 microg/rat), pyrilamine (50 microg/rat) and ranitidine (5 microg/rat) did not alter the response induced by different doses of morphine (3, 6 and 9 mg/kg). Similarly, a single dose of morphine did not alter the response induced by different doses of histamine (5, 10 and 20 microg/rat), pyrilamine (25, 50 and 100 microg/rat) or ranitidine (5, 10 and 20 microg/rat). In conclusion, the histaminergic system plays an important role in the modulation of anxiety, although in our experiments, no interaction was found between the effects of histaminergic agents and morphine on anxiety-related indices in the elevated plus-maze. This may imply that morphine-induced anxiolysis probably is independent of the histaminergic system.

  1. Ascorbate reduces morphine-induced extracellular DOPAC level in the nucleus accumbens: A microdialysis study in rats.

    Science.gov (United States)

    Rajaei, Z; Alaei, H; Nasimi, A; Amini, H; Ahmadiani, A

    2005-08-16

    Most drugs of abuse increase dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) release in the shell of the nucleus accumbens. The effects of ascorbate, which is known to modulate dopamine neurotransmission, on the extracellular level of DOPAC in the nucleus accumbens of naive rats and of rats treated acutely with morphine were studied by using in vivo microdialysis and high performance liquid chromatography with electrochemical detection (HPLC-ECD). Acute morphine (20 mg/kg ip) treatment increased the level of DOPAC in the nucleus accumbens to approximately 170% of basal level. Acute treatment with ascorbate (500 mg/kg ip) alone did not alter nucleus accumbens' DOPAC level, but pretreatment with ascorbate (500 mg/kg ip) 30 min before morphine administration attenuated the effects of acute morphine on the level of DOPAC. These results suggest that ascorbate modulates the mesolimbic dopaminergic pathway.

  2. Involvement of dynorphin A in the inhibition of morphine physical dependence by N-nitro-L-arginine in rats

    Institute of Scientific and Technical Information of China (English)

    万兴旺; 黄矛; 何雅琴; 李万亥; 由振东; 路长林

    2003-01-01

    Objective To investigate the involvement of immunoreactive-dynorphin A in the inhibitory effect of N-nitro-L-arginine on the morphine physical dependence in rats. Methods The rats were rendered dependent on morphine by subcutaneous administration of morphine solution three times daily in a manner of dose increment of 5 mg*kg-1 for 6 days. The degree of morphine physical dependence was monitored by scoring the abstinence syndromes precipitated by 5 mg*kg-1 naloxone of the rats. The expression levels of immunoreactive dynorphin A in tissues were determined using a radioimmunoassay.Results Intraperitoneal injection of 5 mg*kg-1 N-nitro-L-arginine suppresses most of the withdrawal symptoms of morphine dependent rats. N-nitro-L-arginine can elevate the expression of immunoreactive dynorphin. Conclusions Chronic N-nitro-L-arginine administration can inhibit the development of morphine physical dependence in a manner of dose-dependence, which is significantly related to its role of regulating the endogeneous dynorphin system.

  3. Potentiation of acute morphine-induced analgesia measured by a thermal test in bone cancer-bearing mice.

    Science.gov (United States)

    González-Rodríguez, Sara; Llames, Sara; Hidalgo, Agustín; Baamonde, Ana; Menéndez, Luis

    2012-06-01

    Agonists of μ-opioid receptors are currently used in the management of cancer pain. However, several data suggest that the analgesic effect of morphine can diminish during the development of experimental tumors. By using a thermal test, we have studied whether the analgesic effect evoked by morphine is altered in mice bearing two painful bone tumors. The analgesic effect evoked by systemic morphine remained unaltered after the intratibial inoculation of B16-F10 melanoma cells and was potentiated after the inoculation of NCTC 2472 osteosarcoma cells. Although the number of spinal μ-opioid receptors measured by western blot studies was not augmented in osteosarcoma-bearing mice, the analgesia evoked by intrathecal (i.t.) morphine was also enhanced. The analgesic response produced by the spinal administration of the Gi/o protein activator mastoparan was amplified, whereas the analgesic response evoked by the i.t. administration of the N-type calcium channel blocker ω-conotoxin remained unaltered. The efficacy of the GIRK channel blocker tertiapin-Q to antagonize the analgesic effect produced by a maximal dose of morphine was also increased in osteosarcoma-bearing mice. Our results seem to indicate that the analgesic effect of morphine on thermal nociception can be enhanced in response to the development of particular bone tumors in mice, being this potentiation probably related to a greater efficacy of the transduction system driven by Gi/o proteins and GIRK channels.

  4. Combined Treatment with Morphine and Δ9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal.

    Science.gov (United States)

    Gerak, L R; France, C P

    2016-05-01

    Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated use. Combining opioids with cannabinoids can enhance their analgesic potency, although it is less clear whether combined treatment alters opioid tolerance and dependence. In this study, four monkeys received 3.2 mg/kg morphine alone or in combination with 1 mg/kg Δ(9)-tetrahydrocannabinol (THC) twice daily; the antinociceptive effects (warm water tail withdrawal) of morphine, the cannabinoid receptor agonists WIN 55,212 [(R)-(1)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), and the κ opioid receptor agonist U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate) were examined before, during, and after treatment. To determine whether concurrent THC treatment altered morphine dependence, behavioral signs indicative of withdrawal were monitored when treatment was discontinued. Before treatment, each drug increased tail withdrawal latency to 20 seconds (maximum possible effect). During treatment, latencies did not reach 20 seconds for morphine or the cannabinoids up to doses 3- to 10-fold larger than those that were fully effective before treatment. Rightward and downward shifts in antinociceptive dose-effect curves were greater for monkeys receiving the morphine/THC combination than monkeys receiving morphine alone. When treatment was discontinued, heart rate and directly observable withdrawal signs increased, although they were generally similar in monkeys that received morphine alone or with THC. These results demonstrated that antinociceptive tolerance was greater during treatment with the combination, and although treatment conditions were sufficient to result in the development of dependence on morphine, withdrawal was not

  5. Orexin mediates morphine place preference, but not morphine-induced hyperactivity or sensitization.

    Science.gov (United States)

    Sharf, Ruth; Guarnieri, Douglas J; Taylor, Jane R; DiLeone, Ralph J

    2010-03-04

    Orexin (or hypocretin) has been implicated in mediating drug addiction and reward. Here, we investigated orexin's contribution to morphine-induced behavioral sensitization and place preference. Orexin-/- (OKO) mice and littermate wild-type (WT) controls (n=56) and C57BL/6J mice (n=67) were tested for chronic morphine-induced locomotor sensitization or for conditioned place preference (CPP) for a morphine- or a cocaine-paired environment. C57BL/6J mice received the orexin receptor 1 (Ox1r) antagonist, SB-334867, prior to test sessions. OKO mice did not significantly differ from WT controls in locomotor activity following acute- or chronic-morphine treatments. Similarly, mice treated with the Ox1r antagonist did not differ from vehicle controls in locomotor activity following acute- or chronic-morphine treatments. In contrast, while OKO mice did not differ from WT controls in preference for a morphine-paired environment, the Ox1r antagonist significantly attenuated place preference for a morphine-, but not a cocaine-paired, environment. These data suggest that orexin action is not required for locomotor responses to acute and chronic morphine, but Ox1r signaling can influence morphine-seeking in WT animals. 2009 Elsevier B.V. All rights reserved.

  6. The Effect of Ethanol Extract of Aerial Parts of the Mentha piperita in the Acquisition, Tolerance Expression and Dependence to Morphine in Adult Male Mice

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    N Khajeh

    2015-04-01

    Full Text Available Background & aim: Morphine dependence is a compulsive pattern of drug taking, resulting from the positive reinforcement of the rewarding effects of drug taking and the negative reinforcement of withdrawal syndrome that accompanies the cessation of drug taking. The objective of this study was to investigate the effect of ethanol extract of aerial parts of the Mentha piperita in the acquisition, tolerance expression and dependence to morphine in adult male mice Methods: In the present study, 75 NMRI mice were divided into fifiteen groups. The Hot-plate test was used to survey the morphine activity. Morphine was injected (2.5, 5, 10, 20, 40 mg/kg, i.p. twice daily for seven days, except in 8th day in which morphine was administrated at a single dose (50 mg/kg. The extract (50, 75, 100 mg/kg was injected for eight days. The control animals were intact, and sham animals only received morphine. Naloxone was injected (10 mg/kg five hours after the final dose of morphine and the withdrawal signs were recorded during a 30 minute period. The data were expressed as mean values ± SEM and tested, using analysis of one-way ANOVA test. Results: Peppermint extract at doses of 75 and 100 kg significantly improved the tolerance expression and dependence to morphine in animals and significantly reduced the symptoms of withdrawal. Conclusion: Peppermint extract was commuted morphine tolerance and dependence in mice.The plant contained component(s that alleviate morphine withdrawal syndrome. The extract possibly be effective in improving tolerance to morphine.

  7. Effect of Aqueous Extract of Crocus sativus L. on Morphine-Induced Memory Impairment

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    Sayede Maryam Naghibi

    2012-01-01

    Full Text Available In the present study, the effect of aqueous extracts of saffron on morphine-induced memory impairment was investigated. On the training trial, the mice received an electric shock when the animals were entered into the dark compartment. Twenty-four and forty-eight hours later, the time latency for entering the dark compartment was recorded and defined as the retention trial. The mice were divided into (1 control, (2 morphine which received morphine before the training in the passive avoidance test, (3–5 three groups treated by 50, 150 and 450 mg/kg of saffron extract before the training trial, and (6 and 7 the two other groups received 150 and 450 mg/kg of saffron extract before the retention trial. The time latency in morphine-treated group was lower than control (P < 0.01. Treatment of the animals by 150 and 450 mg/kg of saffron extract before the training trial increased the time latency at 24 and 48 hours after the training trial (P < 0.05 and P < 0.01. Administration of both 150 and 450 mg/kg doses of the extract before retention trials also increased the time latency (P < 0.01. The results revealed that the saffron extract attenuated morphine-induced memory impairment.

  8. Effect of Aqueous Extract of Crocus sativus L. on Morphine-Induced Memory Impairment.

    Science.gov (United States)

    Naghibi, Sayede Maryam; Hosseini, Mahmoud; Khani, Fatemeh; Rahimi, Motahare; Vafaee, Farzaneh; Rakhshandeh, Hassan; Aghaie, Azita

    2012-01-01

    In the present study, the effect of aqueous extracts of saffron on morphine-induced memory impairment was investigated. On the training trial, the mice received an electric shock when the animals were entered into the dark compartment. Twenty-four and forty-eight hours later, the time latency for entering the dark compartment was recorded and defined as the retention trial. The mice were divided into (1) control, (2) morphine which received morphine before the training in the passive avoidance test, (3-5) three groups treated by 50, 150 and 450 mg/kg of saffron extract before the training trial, and (6 and 7) the two other groups received 150 and 450 mg/kg of saffron extract before the retention trial. The time latency in morphine-treated group was lower than control (P < 0.01). Treatment of the animals by 150 and 450 mg/kg of saffron extract before the training trial increased the time latency at 24 and 48 hours after the training trial (P < 0.05 and P < 0.01). Administration of both 150 and 450 mg/kg doses of the extract before retention trials also increased the time latency (P < 0.01). The results revealed that the saffron extract attenuated morphine-induced memory impairment.

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

    Science.gov (United States)

    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.

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

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    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.

  11. Morphine metabolism, transport and brain disposition.

    Science.gov (United States)

    De Gregori, Simona; De Gregori, Manuela; Ranzani, Guglielmina Nadia; Allegri, Massimo; Minella, Cristina; Regazzi, Mario

    2012-03-01

    The chemical structures of morphine and its metabolites are closely related to the clinical effects of drugs (analgesia and side-effects) and to their capability to cross the Blood Brain Barrier (BBB). Morphine-6-glucuronide (M6G) and Morphine-3-glucuronide (M3G) are both highly hydrophilic, but only M6G can penetrate the BBB; accordingly, M6G is considered a more attractive analgesic than the parent drug and the M3G. Several hypotheses have been made to explain these differences. In this review we will discuss recent advances in the field, considering brain disposition of M6G, UDP-glucoronosyltransferases (UGT) involved in morphine metabolism, UGT interindividual variability and transport proteins.

  12. Morphine

    Science.gov (United States)

    ... any of the following symptoms: irritability, hyperactivity, abnormal sleep, high-pitched cry, uncontrollable shaking of a part ... palonosetron (Aloxi); selective serotonin-reuptake inhibitors such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, in Symbyax), ...

  13. Activation of serotonin 5-HT2C receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-dependent mice

    Science.gov (United States)

    Zhang, Gongliang; Wu, Xian; Zhang, Yong-Mei; Liu, Huan; Jiang, Qin; Pang, Gang; Tao, Xinrong; Dong, Liuyi; Stackman, Robert W.

    2015-01-01

    Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and social problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT2C receptor (5-HT2CR) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT2CR agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT2CR activation on the behavioral sensitization and naloxone-precipitated withdrawal symptoms were examined in mice underwent repeated exposure to morphine. Male mice received morphine (10 mg/kg, s.c.) to develop behavioral sensitization. Lorcaserin, a 5-HT2CR agonist, prevented the induction and expression, but not the development, of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. Pretreatment of lorcaserin, or the positive control clonidine (an alpha 2-adrenoceptor agonist), ameliorated the naloxone-precipitated withdrawal symptoms. SB 242084, a selective 5-HT2CR antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT2CR protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT2CR can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT2CR may represent a new avenue for the treatment of opioid addiction. PMID:26432939

  14. Pharmacokinetics of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate. 2nd communication: tissue levels and enzyme activity in rats after repeated administration, and placental and milk transfer after single administration.

    Science.gov (United States)

    Nakamura, A; Hirota, T; Sugihara, K; Watanabe, S; Tougou, K; Morino, A; Ezumi, Y; Takaichi, M

    1997-02-01

    The absorption, distribution and excretion of radioactivity in rats were studied during and after repeated oral administration of 30 mg/kg of NS-21 ((+/-)-4-diethylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate, CAS 129927-33-4) once a day for 21 days. The plasma concentrations of radioactivity 24 h after each administration of 14C-NS-21 reached a steady state on the 5th day. 48 h after the 21st administration, the plasma concentrations of radioactivity were under the detection limit. The plasma concentrations of the radioactivity after the 7th oral administration of 14C-NS-21 was higher than that after the single administration, but similar to those after the 14th and 21st administrations. There were no marked differences in the elimination half-lives after each administration. The urinary and fecal excretion of the radioactivity was 21.5 and 81.3%, respectively, within 168 h after the 21st administration. In most tissues, no radioactivity was observed 336 h after the 21st administration. Repeated oral administration of 30 and 100 mg/kg of NS-21 once a day for 7 days had no effect on the cytochrome P-450 content, aniline hydroxylase and aminopyrine N-demethylase activity in rat liver. The transfer of radioactivity into fetuses and milk was investigated after single oral administration of 14C-NS-21 to female rats. In the 18th day pregnant rats, the radioactivity concentrations were lower in most fetal tissues than in the maternal plasma. After oral administration of 14C-NS-21 to lactating rats, the concentrations of radioactivity were higher in the milk than in the maternal plasma during an 8-h period. No radioactivity was observed in milk 48 h after administration.

  15. Administração inadvertida de 4 mg de morfina por via subaracnóidea: relato de caso Administración inadvertida de 4 mg de morfina por vía subaracnoidea: relato de caso Accidental subarachnoid administration of 4 mg of morphine: case report

    Directory of Open Access Journals (Sweden)

    Bruno Salomé de Morais

    2008-04-01

    sus potenciales efectos adversos.BACKGROUND AND OBJECTIVES: The subarachnoid administration of morphine is a well-established anesthetic technique of postoperative analgesia due to its efficacy, safety and low cost. The objective of this paper was to report the accidental subarachnoid administration of 4 mg of morphine complicated by atrial fibrillation after administration of naloxone. CASE REPORT: A 45-year old male patient with 75 kg, 1.72 m, physical status ASA II, hypertensive, was scheduled for reconstruction of the anterior cruciate ligament of the left knee. After spinal anesthesia, it was noticed that the vial of morphine had been changed resulting in the accidental subarachnoid administration of 4 mg of morphine (0.4 mL of the 10 mg vial. Respiratory rate varied from 12 to 16 bpm and the patient remained hemodynamically stable without intraoperative complaints. Thirty minutes after admission to the post-anesthesia recovery unit the patient developed vomiting and diaphoresis being treated with 0.4 mg of naloxone followed by continuous infusion of 0.2 mg.h-1 until the symptoms had subsided. Continuous naloxone infusion was maintained in the Intensive Care Unit (ICU, where blood pressure, heart rate, respiratory rate and oxygen saturation were monitored as well as the presence of nausea, pruritus, vomiting, sedation, pain and urinary retention. Two hours after arriving at the ICU the patient developed acute atrial fibrillation without hemodynamic instability. Sinus rhythm was reestablished after the administration of 150 mg of amiodarone and discontinuation of the naloxone infusion. During the following 18 hours the patient remained hemodynamically stable and did not experience any other intercurrence until his discharge from the hospital. CONCLUSIONS: The present report is an alert for the risk of inadvertently switching of drugs during anesthesia, stressing the importance of referring patients being treated for opiate overdose to the ICU, due to the potential

  16. Reconstruction of the anterior cruciate ligament: comparison of analgesia using intrathecal morphine, intra-articular morphine and intra-articular levobupivacaine

    Directory of Open Access Journals (Sweden)

    Leandro Queiroz Pinheiro

    2015-06-01

    Full Text Available OBJECTIVE: To compare the analgesic effect of intra-articular administration of morphine and levobupivacaine (separately or in combination with intrathecal administration of morphine in patients undergoing anterior cruciate ligament (ACL reconstruction using autologous grafts from the patellar tendon.METHODS: This was a retrospective analysis on data gathered from the medical files of 60 patients aged 20 to 50 years who underwent knee video arthroscopy for ACL reconstruction. The patients were divided into four groups of 15 individuals (A, B, C and D according to the agent administered into the joint and around the incision: 20 mL of saline solution with 5 mg of morphine in A; 20 mL of 0.5% levobupivacaine solution in B; 10 mL of solution with 2.5 mg of morphine plus 10 mL of 0.5% levobupivacaine solution in C; and morphine administered intrathecally in D.RESULTS: All the groups presented low pain scores during the first 12 h after the surgery. Groups B and C presented significantly greater pain scores than shown by group D (control, 24 h after the surgery. There was no statistical difference in pain scores between group A and group D.CONCLUSION: The patients in group A presented analgesia comparable to that of the patients in group D, whereas the procedure of group C was no capable of reproducing the analgesic effect observed in group D, as observed 24 h after the surgery. Further studies are needed in order to show the exact mechanism of action, along with the ideal dose and concentration for applying opioids to joints.

  17. 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

    The feasibility of achieving buccal delivery of morphine using the prodrug approach was assessed by studies of bioactivation, in vitro permeation and in vivo absorption. The bioactivation of various morphine-3-esters was studied in human plasma and saliva. The in vitro permeation of morphine...... of 0.2. This discrepancy could however be explained by the enzymatic stability of the two esters in saliva, since it was found that morphine-3-propionate was more rapidly hydrolysed in saliva than was morphine-3-acetate. The study demonstrates that the buccal delivery of morphine can be markedly...

  18. An Engineered Endomorphin-2 Gene for Morphine Withdrawal Syndrome

    Science.gov (United States)

    Wu, Fei-xiang; He, Yan; Di, Hui-ting; Sun, Yu-ming; Pan, Rui-rui; Yu, Wei-feng; Liu, Renyu

    2016-01-01

    An optimal therapeutics to manage opioid withdrawal syndrome is desired for opioid addiction treatment. Down-regulation of endogenous endomorphin-2 (EM2) level in the central nervous system after continuous morphine exposure was observed, which suggested that increase of EM2 could be an alternative novel method for opioid dependence. As a short peptide, the short half-life of EM2 limits its clinical usage through conventional administration. In the present study, we engineered an EM2 gene using a signal peptide of mouse growth factor for an out-secretory expression of EM2 and an adenovirus as a vector, which ultimately sustained the release of EM-2. After administration of the adenovirus in central nervous system, a sustained increase of EM2 level in the cerebral spinal fluid (CSF) was observed along with a reduction of morphine withdrawal syndrome. These findings suggest that the engineered EM2 gene delivered to the central nervous system could be a novel therapeutics for withdrawal syndrome in opioid dependent subjects. PMID:27003293

  19. 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...

  20. Repeated Superovulation via PMSG/hCG Administration Induces 2-Cys Peroxiredoxins Expression and Overoxidation in the Reproductive Tracts of Female Mice.

    Science.gov (United States)

    Park, Sun-Ji; Kim, Tae-Shin; Kim, Jin-Man; Chang, Kyu-Tae; Lee, Hyun-Shik; Lee, Dong-Seok

    2015-12-01

    Superovulation induced by exogenous gonadotropin treatment (PMSG/hCG) increases the number of available oocytes in humans and animals. However, Superovulatory PMSG/hCG treatment is known to affect maternal environment, and these effects may result from PMSG/hCG treatment-induced oxidative stress. 2-Cys peroxiredoxins (2-Cys Prxs) act as antioxidant enzymes that protect cells from oxidative stress induced by various exogenous stimuli. Therefore, the objective of this study was to test the hypothesis that repeated PMSG/hCG treatment induces 2-Cys Prx expression and overoxidation in the reproductive tracts of female mice. Immunohistochemistry and western blotting analyses further demonstrated that, after PMSG/hCG treatment, the protein expression levels of 2-Cys Prxs increased most significantly in the ovaries, while that of Prx1 was most affected by PMSG/hCG stimulation in all tissues of the female reproductive tract. Repeated PMSG/hCG treatment eventually leads to 2-Cys Prxs overoxidation in all reproductive organs of female mice, and the abundance of the 2-Cys Prxs-SO2/3 proteins reported here supports the hypothesis that repeated superovulation induces strong oxidative stress and damage to the female reproductive tract. Our data suggest that excessive oxidative stress caused by repeated PMSG/hCG stimulation increases 2-Cys Prxs expression and overoxidation in the female reproductive organs. Intracellular 2-Cys Prx therefore plays an important role in maintaining the reproductive organ environment of female mice upon exogenous gonadotropin treatment.

  1. Dopamine D₄ receptor counteracts morphine-induced changes in µ opioid receptor signaling in the striosomes of the rat caudate putamen.

    Science.gov (United States)

    Suárez-Boomgaard, Diana; Gago, Belén; Valderrama-Carvajal, Alejandra; Roales-Buján, Ruth; Van Craenenbroeck, Kathleen; Duchou, Jolien; Borroto-Escuela, Dasiel O; Medina-Luque, José; de la Calle, Adelaida; Fuxe, Kjell; Rivera, Alicia

    2014-01-21

    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.

  2. The effects of fruit essential oil of the Pimpinella anisum on acquisition and expression of morphine induced conditioned place preference in mice.

    Science.gov (United States)

    Sahraei, Hedayat; Ghoshooni, Hassan; Hossein Salimi, Sayed; Mohseni Astani, Abutaleb; Shafaghi, Bijan; Falahi, Mansoor; Kamalnegad, Mohammad

    2002-04-01

    The problem of drug dependence still remains unresolved. In the present study the effects of an essential oil of Pimpinella anisum (Umbeliferae) on the expression and acquisition of conditioned place preference (CPP) induced by morphine in mice were investigated. Subcutaneous (s.c.) injections of morphine (2-5 mg/kg) produced place preference in a dose-dependent manner. Furthermore, intraperitoneal (i.p.) injection of the essential oil of P. anisum (0.125-0.5 ml/kg) induced conditioned place aversion (CPA). The mice which have received the essential oil of the P. anisum (0.125-0.5 ml/kg, i.p.) as well as the oil with morphine (5 mg/kg, s.c.) reduced the morphine effect. Administration of the essential oil of P. anisum (0.125-0.5 ml/kg, i.p.) on the test day did not show any effect on morphine action. It appeared that pre-administration with bicuculline (GABA(A) receptor antagonist) (1.5 mg/kg, i.p., 20 min before essential oil) diminished the effect of the essential oil of the P. anisum on morphine which induced CPP, but this result was not found for the GABA(B) receptor antagonist, CGP35348 (200 and 400 mg/kg, i.p., 10 min before essential oil). In conclusion, it appeared that the essential oil of the P. anisum may reduce the morphine effects via a GABAergic mechanism.

  3. Pavlovian conditioning of morphine-induced alterations of immune status: evidence for peripheral beta-adrenergic receptor involvement.

    Science.gov (United States)

    Coussons-Read, M E; Dykstra, L A; Lysle, D T

    1994-09-01

    The present studies examined the involvement of peripheral beta-adrenergic receptor activity in the establishment and expression of conditioned morphine-induced alterations of immune status. Previous work in our laboratory has shown that morphine's immunomodulatory effects can become conditioned to environmental stimuli which predict drug administration. These immune alterations include conditioned changes in natural killer cell activity, interleukin-2 production, and mitogen-induced lymphocyte proliferation. During the training phase of these experiments, Lewis rats received two conditioning sessions during which a subcutaneous injection of 15 mg/kg morphine sulfate was paired with exposure to a distinctive environment. On the test day, rats were reexposed to the conditioned stimulus prior to sacrifice. Saline or nadolol (0.002, 0.02, 0.2, or 2.0 mg/kg) was administered either prior to the training sessions or prior to the test session. Administration of nadolol prior to training did not affect the development of conditioned alterations of immune status. Conversely, nadolol administration prior to testing completely attenuated the expression of a subset of the conditioned morphine-induced changes in immune status. Taken together, these studies suggest that whereas peripheral beta-adrenergic receptor activity is not required for the establishment of conditioned morphine-induced alterations of immune status, it is involved in the expression of a subset of these conditioned immunomodulatory effects.

  4. Morphine and yohimbine regulate midkine gene expression in the rat hippocampus.

    Science.gov (United States)

    Ezquerra, Laura; Pérez-García, Carmen; Garrido, Elisa; Díez-Fernández, Carmen; Deuel, Thomas F; Alguacil, Luis F; Herradón, Gonzalo

    2007-02-28

    Pleiotrophin and midkine are two recently discovered growth factors that promote survival and differentiation of catecholaminergic neurons. Chronic opioid stimulation has been reported to induce marked alterations of the locus coeruleus-hippocampus noradrenergic pathway, an effect that is prevented when opioids are coadministered with the alpha2-adrenoceptor antagonist yohimbine. The present work tries to examine a possible link between yohimbine reversal of morphine effects and pleiotrophin/midkine activation in the rat hippocampus by studying the levels of expression of pleiotrophin and midkine in response to acute and chronic administration of morphine, yohimbine and combinations of both drugs. Pleiotrophin gene expression was not altered by any treatment; however midkine mRNA levels were increased after chronic treatment with morphine. Chronic administration of yohimbine alone also increased midkine expression levels, whereas yohimbine and morphine administered together exhibited summatory effects on the upregulation of midkine expression levels. The data suggest that midkine could play a role in the prevention of opioid-induced neuroadaptations in hippocampus by yohimbine.

  5. Metabolic changes in rat prefrontal cortex and hippocampus induced by chronic morphine treatment studied ex vivo by high resolution 1H NMR spectroscopy.

    Science.gov (United States)

    Gao, Hongchang; Xiang, Yun; Sun, Ninglei; Zhu, Hang; Wang, Yaqiang; Liu, Maili; Ma, Yuanye; Lei, Hao

    2007-01-01

    Ex vivo(1)H NMR spectroscopy was used to measure changes in the concentrations of cerebral metabolites in the prefrontal cortex (PFC) and hippocampus of rats subjected to repeated morphine treatment known to cause tolerance/dependence. The results show that repeated morphine exposure induces significant changes in the concentrations of a number of cerebral metabolites, and such changes are region specific. After 10 days of repeated morphine treatment, the concentration of gamma-aminobutyric acid (GABA) increased significantly in the PFC (20+/-11%), but decreased in the hippocampus (-31+/-12%), compared to control. In contrast, the glutamate (Glu) concentrations in both the PFC (-15+/-8%) and hippocampus (-13+/-4%) decreased significantly. Significant changes were also observed in the concentrations of hippocampal glutamine (Gln), myo-inositol, taurine, and N-acetyl aspartate. These morphine-induced changes were reversed during a subsequent 5-day withdrawal period. It is suggested that the observed concentration changes for Glu, Gln and GABA are most likely the result of a shift in the steady-state equilibrium of the Gln-Glu-GABA metabolic cycle. Changes in the metabolism of this neurotransmitter system might be part of the adaptive measures taken by the central nervous system in response to repeated morphine exposure and subsequent withdrawal.

  6. Src Kinase Inhibition Attenuates Morphine Tolerance without Affecting Reinforcement or Psychomotor Stimulation.

    Science.gov (United States)

    Bull, Fiona A; Baptista-Hon, Daniel T; Sneddon, Claire; Wright, Lisa; Walwyn, Wendy; Hales, Tim G

    2017-08-18

    Prolonged opioid administration leads to tolerance characterized by reduced analgesic potency. Pain management is additionally compromised by the hedonic effects of opioids, the cause of their misuse. The multifunctional protein β-arrestin2 regulates the hedonic effects of morphine and participates in tolerance. These actions might reflect µ opioid receptor up-regulation through reduced endocytosis. β-Arrestin2 also recruits kinases to µ receptors. We explored the role of Src kinase in morphine analgesic tolerance, locomotor stimulation, and reinforcement in C57BL/6 mice. Analgesic (tail withdrawal latency; percentage of maximum possible effect, n = 8 to 16), locomotor (distance traveled, n = 7 to 8), and reinforcing (conditioned place preference, n = 7 to 8) effects of morphine were compared in wild-type, µ, µ, and β-arrestin2 mice. The influence of c-Src inhibitors dasatinib (n = 8) and PP2 (n = 12) was examined. Analgesia in morphine-treated wild-type mice exhibited tolerance, declining by day 10 to a median of 62% maximum possible effect (interquartile range, 29 to 92%). Tolerance was absent from mice receiving dasatinib. Tolerance was enhanced in µ mice (34% maximum possible effect; interquartile range, 5 to 52% on day 5); dasatinib attenuated tolerance (100% maximum possible effect; interquartile range, 68 to 100%), as did PP2 (91% maximum possible effect; interquartile range, 78 to 100%). By contrast, c-Src inhibition affected neither morphine-evoked locomotor stimulation nor reinforcement. Remarkably, dasatinib not only attenuated tolerance but also reversed established tolerance in µ mice. The ability of c-Src inhibitors to inhibit tolerance, thereby restoring analgesia, without altering the hedonic effect of morphine, makes c-Src inhibitors promising candidates as adjuncts to opioid analgesics.

  7. 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).

  8. Morphine application to peripheral tissues modulates nociceptive jaw reflex

    DEFF Research Database (Denmark)

    Bakke, M.; Hu, J.W.; Sessle, B.J.

    1998-01-01

    antinociceptive effects, jaw muscle activity, morphine, mustard oil naloxone, peripheral opioid receptors, temporomandibular joint......antinociceptive effects, jaw muscle activity, morphine, mustard oil naloxone, peripheral opioid receptors, temporomandibular joint...

  9. Morphine as a Potential Oxidative Stress-Causing Agent.

    Science.gov (United States)

    Skrabalova, Jitka; Drastichova, Zdenka; Novotny, Jiri

    2013-11-01

    Morphine exhibits important pharmacological effects for which it has been used in medical practice for quite a long time. However, it has a high addictive potential and can be abused. Long-term use of this drug can be connected with some pathological consequences including neurotoxicity and neuronal dysfunction, hepatotoxicity, kidney dysfunction, oxidative stress and apoptosis. Therefore, most studies examining the impact of morphine have been aimed at determining the effects induced by chronic morphine exposure in the brain, liver, cardiovascular system and macrophages. It appears that different tissues may respond to morphine diversely and are distinctly susceptible to oxidative stress and subsequent oxidative damage of biomolecules. Importantly, production of reactive oxygen/nitrogen species induced by morphine, which have been observed under different experimental conditions, can contribute to some pathological processes, degenerative diseases and organ dysfunctions occurring in morphine abusers or morphine-treated patients. This review attempts to provide insights into the possible relationship between morphine actions and oxidative stress.

  10. Non-clinical safety evaluation of single and repeated intramuscular administrations of MAGE-A3 Cancer Immunotherapeutic in rabbits and cynomolgus monkeys.

    Science.gov (United States)

    Destexhe, Eric; Grosdidier, Emilie; Baudson, Nathalie; Forster, Roy; Gerard, Catherine; Garçon, Nathalie; Segal, Lawrence

    2015-07-01

    The MAGE-A3 recombinant protein combined with AS15 immunostimulant (MAGE-A3 Cancer Immunotherapeutic) is under development by GlaxoSmithKline for the treatment of lung cancer and melanoma. We performed non-clinical safety studies evaluating potential local and systemic toxic effects induced by MAGE-A3 Cancer Immunotherapeutic in rabbits (study 1) and cynomolgus monkeys (study 2). Animals were allocated to two groups to receive a single (rabbits) or 25 repeated (every 2 weeks) injections (monkeys) of MAGE-A3 Cancer Immunotherapeutic (treatment groups) or saline (control groups). All rabbits were sacrificed 3 days post-injection and monkeys 3 days following last injection (3/5 per gender per group) or after a 3-month treatment-free period (2/5 per gender per group). Local and systemic reactions and MAGE-A3-specific immune responses (monkeys) were assessed. Macroscopic and microscopic (for rabbits, injection site only) post-mortem examinations were performed on all animals. No systemic toxicity or unscheduled mortalities were recorded. Single (rabbits) and repeated (monkeys; up to four times at the same site) injections were well tolerated. Following five to seven repeated injections, limb circumferences increased up to 26% (5 h post-injection), but returned to normal after 1-8 days. Three days after the last injection, enlargements of iliac, popliteal, axillary and inguinal lymph nodes, and increased incidence or severity of mononuclear inflammatory cell infiltrates was observed in injected muscles of treated monkeys. No treatment-related macroscopic findings were recorded after the treatment-free period. MAGE-A3-specific antibody and T-cell responses were raised in all treated monkeys, confirming test item exposure. Single or repeated intramuscular injections of MAGE-A3 Cancer Immunotherapeutic were well tolerated in rabbits and monkeys.

  11. Enhanced central serotonin release from slices of rat hypothalamus following repeated nialamide administration: evidence supporting the overactive serotonin receptor theory of depression

    Energy Technology Data Exchange (ETDEWEB)

    Offord, S.J.

    1986-01-01

    Researchers are suggesting unipolar affective disorders may be related to an abnormality in biogenic amine receptor-sensitivity. This abnormality may be a result of a dysfunction in central serotonin (5-HT) release mechanisms. 5-HT neurotransmission is modulated by presynaptic autoreceptors, which are members of the 5-HT/sub 1/ receptor subtype. The autoreceptor is thought to play an important role in the homeostasis of the central 5-HT synapse and could be a site at which some antidepressants mediate their therapeutic effect. The number of 5-HT/sub 1/ type receptor binding sites are reduced and behavior mediated by this receptor is abolished following repeated injections of monoamine oxidase inhibitor type antidepressants. These changes did not occur following a single injection. It was hypothesized that repeated treatment with a monoamine oxidase inhibitor would reduce the sensitivity of 5-HT autoreceptors and enhance 5-HT release. Rats were pretreated with single or repeated (twice daily for 7 days) intraperitoneal injections of nialamide (40 mg/kg) or chlorimipramine (10 mg/kg) and the ability of the autoreceptor agonist to inhibit potassium-induced /sup 3/H-5-HT release was evaluated using an in vitro superfusion system. These changes in 5-HT autoreceptor activity are consistent with other reports evaluating monoamine oxidase inhibitors on 5-HT/sub 1/ type receptors. It is hypothesized that the changes in 5-HT neurotransmission are related to the antidepressant mechanism of monoamine oxidase inhibitors.

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

    OpenAIRE

    Gian Maria Pacifici

    2016-01-01

    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...

  13. NMDA receptors of dorsal hippocampus are involved in the acquisition, but not in the expression of morphine-induced place preference.

    Science.gov (United States)

    Zarrindast, Mohammad-Reza; Lashgari, Reza; Rezayof, Ameneh; Motamedi, Fereshteh; Nazari-Serenjeh, Farzaneh

    2007-07-30

    In the present study, involvement of the N-methyl-d-aspartate (NMDA) receptors of the CA1 region of dorsal hippocampus (intra-CA1) in the acquisition or expression of morphine-induced conditioned place preference in rats was studied. Male Wistar rats were used in these experiments. NMDA-receptor agonist (NMDA) and antagonist (MK-801) were injected into the CA1 region of the dorsal hippocampus (intra-CA1) and morphine was injected subcutaneously. An unbiased conditioned place preference paradigm was used to study the effect of these agents. In the first set of experiments, the drugs were used during the development of conditioned place preference by morphine or they were used alone in order to see if they induce conditioned place preference or conditioned place aversion. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (2.5-10 mg/kg) induced conditioned place preference in rat. NMDA (0.1-1 microg/rat) or MK-801 (1-4 microg/rat) did not induce conditioned place preference or conditioned place aversion. Intra-CA1 administration of different doses of NMDA (0.1-1 microg/rat) increased, while MK-801 (1-4 microg/rat) decreased morphine-induced place preference. MK-801 reversed the effect of NMDA on morphine response. In the second set of experiments, when the drugs were used before testing on Day 5, in order to test their effects on the expression of morphine (7.5 mg/kg)-induced place preference, intra-CA1 administration of NMDA or MK-801 did not alter the morphine response. None of the drugs influenced locomotion. It is concluded that NMDA receptor of the CA1 region of hippocampus are involved in the acquisition but not expression of morphine-induced place preference.

  14. Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants

    NARCIS (Netherlands)

    J. Bouwmeester (Nancy); J.N. van den Anker (John); W.C.J. Hop (Wim); K.J.S. Anand (Kanwaljeet); D. Tibboel (Dick)

    2003-01-01

    textabstractBACKGROUND: To investigate clinical variables such as gestational age, sex, weight, the therapeutic regimens used and mechanical ventilation that might affect morphine requirements and plasma concentrations of morphine and its metabolites. METHODS: In a double-blind stu

  15. A specific immunoassay for the determination of morphine and its glucuronides in human blood.

    Science.gov (United States)

    Beike, J; Blaschke, G; Mertz, A; Köhler, H; Brinkmann, B

    1998-01-01

    The development of specific antisera for immunochemical determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide is described. Morphine was N-demethylated to normorphine and N-alkylated to give N-aminopropyl-normorphine as hapten for antisera against morphine. As haptens for antisera against morphine-3-glucuronide and morphine-6-glucuronide, N-aminopropyl-nor-morphine was glucuronidated in position 3 or 6 respectively. Each of these three haptens were coupled to BSA employing the glutaraldehyde method to obtain three different immunogens. Immunisation of rabbits with these conjugates gave anti-morphine, anti-morphine-3-glucuronide and anti-morphine-6-glucuronide antisera, which were tested in a competitive, heterogeneous radioimmunoassay. Tracers for this radioimmunoassay procedure were synthesised by substitution of morphine and morphine-6-glucuronide in position 2 with 125I and indirect iodination of the morphine-3-glucuronide hapten according to the method of Bolton and Hunter. The resulting antisera show very specific reactions with morphine, morphine-3-glucuronide and morphine-6-glucuronide. Cross reactivities of each antiserum with structurally related opiates and opioides are very low. The cross reactivities of the anti-morphine antiserum against morphine-3-glucuronide, morphine-6-glucuronide, codeine, codeine-6-glucuronide or dihydrocodeine were less than 0.3%, the anti-morphine-3-glucuronide antiserum against morphine, morphine-6-glucuronide, codeine, codeine-6-glucuronide or dihydrocodeine less than 0.1% and the anti-morphine-6-glucuronide antiserum against morphine, morphine-3-glucuronide, codeine or dihydrocodeine less than 0.1%, against codeine-6-glucuronide less than 2.3%. The determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide in blood samples (limit of detection= 3, 1, 0.5 ng/g) of nine cases of fatal heroin overdose with this radioimmunoassay method and the comparison with a GC/MS method is described.

  16. Sensitivity changes after morphine treatment in the mouse uterus.

    Science.gov (United States)

    Contreras, E; Tamayo, L; Juica, S

    1982-01-01

    The addition of morphine to a bath containing the vas deferens from chronically morphinized mice induces a facilitatory effect on noradrenaline contractile responses. This facilitatory effect of morphine has been thought to be a dependence-like effect. In the present work the possibility that a pretreatment with morphine might induce a similar effect on the contractile responses of the mouse uterus to acetylcholine and serotonin was examined. The acute effect of morphine on the uteri of untreated mice consisted in an attenuation of the responses to both substances, whereas a long term pretreatment with morphine induced a supersensitivity state. Tolerance to the depressant action of morphine on the contractile responses induced by the stimulating compounds was also observed. Acute morphine in the uteri from morphinized mice did not induce a facilitatory effect on acetylcholine or serotonin responses. Naloxone did not modify the effects of morphine in the naive or chronically treated mice. The supersensitivity state and the intensity of tolerance were unaffected by changes in the concentration of calcium in the bath medium. Caffeine or theophylline decreased the tolerance observed in the uterus from chronically morphinized mice. The attenuation of tolerance suggests that methylxanthines induce effects opposed to those of chronic morphine in the calcium distribution within the cell.

  17. POST-OPERATIVE ANALGESIA IN PATIENTS UNDERGOING MAJOR SURGERIES: EFFECT OF ADDING IV KETAMINE TO MORPHINE IN PRESENCE OF MORPHINE RESISTANT PAIN

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