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Sample records for cfa-induced thermal hyperalgesia

  1. Curcumin attenuates CFA induced thermal hyperalgesia by modulation of antioxidant enzymes and down regulation of TNF-α, IL-1β and IL-6.

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    Singh, Ajeet Kumar; Vinayak, Manjula

    2015-03-01

    Reactive oxygen species are signaling mediators of nociceptive pathways. Exogenous administrations of antioxidants show anti-hyperalgesic effect. However, very little is known about the role of endogenous antioxidant defense system in pain pathology. Curcumin is a dietary antioxidant which shows ameliorative effect on thermal hypersensitivity, however detailed study is lacking. Present study was aimed to analyze the changes in oxidative stress, modulation of antioxidant enzymes and pro-inflammatory cytokines in complete Freund's adjuvant induced inflammatory hyperalgesia and the effect of curcumin on antioxidant defense system and pro-inflammatory cytokines. Anti-hyperalgesic activity of curcumin was evidenced after 6 h of treatment. Oxidative stress was evidenced in paw skin and spinal cord of hyperalgesic rats by high level of lipid peroxidation. A decrease in activity of antioxidant enzymes like catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and an increase in level of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in paw skin was observed as compared to normal rats. However, activity of antioxidant enzymes was enhanced in spinal cord. The changes were brought towards normal level after curcumin treatment. The results suggest that modulation of antioxidant defense system is early event in initiation of inflammatory hyperalgesia which might lead to initiation of other signaling pathways mediated by lipid peroxide, TNF-α, IL-1β and IL-6. Decrease in oxidative stress and down regulation of these cytokines by curcumin is suggested to be involved in its anti-hyperalgesic effect.

  2. Involvement of spinal somatostatin receptor SST(2A) in inflammation-induced thermal hyperalgesia: ultrastructural and behavioral studies in rats.

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    Zhao, Jun; Hu, Jiang-Yuan; Zhang, Yu-Qiu; Zhao, Zhi-Qi

    2008-10-01

    Our previous results have shown that somatostatin receptor subtype SST(2A) is responsible for thermal, but not mechanical nociceptive transmission in the rat spinal cord. The present study was undertaken to further examine the ultrastructural localization of SST(2A) receptor in lamina II of the spinal dorsal horn and the role of SST(2A) receptor in thermal hyperalgesia following Complete Freund's Adjuvant (CFA)-induced inflammation. We found that SST(2A) receptors in lamina II are located primarily in postsynaptic dendrites and soma, but not in axons or synaptic terminals. CFA-induced inflammation markedly increased SST(2A) receptor-like immunoreactivity in lamina II. Paw withdrawal latency (PWL) evoked by noxious heating was obviously shortened 1 h after intraplantar injection of CFA, exhibiting thermal hyperalgesia. Pre-blocking SST(2A) activity by intrathecal pre-administration of CYN154806, a broad-spectrum antagonist of SST(2) receptor, or specific antiserum against SST(2A) receptor (anti-SST(2A)) significantly attenuated thermal hyperalgesia in a dose-dependent fashion in CFA-treated rats. But, administration of anti-SST(2A) or CYN154806 after CFA treatment had no effect upon thermal hyperalgesia. Intrathecal application of SST(2A) agonist SOM-14 at different doses prior to CFA treatment did not influence thermal hyperalgesia in inflamed rats, but at a low dose shortened PWL evoked by noxious heating in normal rats. These results suggest that spinal SST(2A) receptors play a key role in triggering the generation, but not maintenance, of thermal hyperalgesia evoked by CFA-induced inflammation. The up-regulation of SST(2A) receptors in the spinal cord may be one of the mechanisms underlying inflammation-induced thermal hyperalgesia.

  3. Endogenous prolactin generated during peripheral inflammation contributes to thermal hyperalgesia.

    Science.gov (United States)

    Scotland, Phoebe E; Patil, Mayur; Belugin, Sergei; Henry, Michael A; Goffin, Vincent; Hargreaves, Kenneth M; Akopian, Armen N

    2011-09-01

    Prolactin (PRL) is a hormone and a neuromodulator. It sensitizes TRPV1 (transient receptor potential cation channel subfamily V member 1) responses in sensory neurons, but it is not clear whether peripheral inflammation results in the release of endogenous PRL, or whether endogenous PRL is capable of acting as an inflammatory mediator in a sex-dependent manner. To address these questions, we examined inflammation-induced release of endogenous PRL, and its regulation of thermal hyperalgesia in female and male rats. PRL is expressed in several types of peripheral neuronal and non-neuronal cells, including TRPV1-positive nerve fibers, preadipocytes and activated macrophages/monocytes localized in the vicinity of nerves. Evaluation of PRL levels in hindpaws and plasma indicated that complete Freund's adjuvant (CFA) stimulates release of peripheral, but not systemic, PRL within 6-48 h in both ovariectomized females with estradiol replacement (OVX-E) and intact male rats. The time course of release varies in OVX-E and intact male rats. We next employed the prolactin receptor (PRL-R) antagonist Δ1-9-G129R-hPRL to assess the role of locally produced PRL in nociception. Applied at a ratio of 1 : 1 (PRL:Δ1-9-G129R-hPRL; 40 nm each), this antagonist was able to nearly (≈ 80%) reverse PRL-induced sensitization of capsaicin responses in rat sensory neurons. CFA-induced inflammatory thermal hyperalgesia in OVX-E rat hindpaws was significantly reduced in a dose-dependent manner by the PRL-R antagonist at 6 h but not at 24 h. In contrast, PRL contributed to inflammatory thermal hyperalgesia in intact male rats at 24, but not at 6 h. These findings indicate that inflammation leads to accumulation of endogenous PRL in female and male rats. Furthermore, PRL acts as an inflammatory mediator at different time points for female and intact male rats.

  4. Phosphorylation of TRPV1 by cyclin-dependent kinase 5 promotes TRPV1 surface localization, leading to inflammatory thermal hyperalgesia.

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    Liu, Jiao; Du, Junxie; Yang, Yanrui; Wang, Yun

    2015-11-01

    Cyclin-dependent kinase 5 (Cdk5) is an important serine/threonine kinase that plays critical roles in many physiological processes. Recently, Cdk5 has been reported to phosphorylate TRPV1 at threonine 407 (Thr-407) in humans (Thr-406 in rats), which enhances the function of TRPV1 channel and promotes thermal hyperalgesia in the complete Freund's adjuvant (CFA)-induced inflammatory pain rats. However, the underlying mechanisms are still unknown. Here, we demonstrate that Cdk5 phosphorylates TRPV1 at Threonine 406 and promotes the surface localization of TRPV1, leading to inflammatory thermal hyperalgesia. The mutation of Thr-406 of TRPV1 to alanine reduced the interaction of TRPV1 with the cytoskeletal elements and decreased the binding of TRPV1 with the motor protein KIF13B, which led to reduced surface distribution of TRPV1. Disrupting the phosphorylation of TRPV1 at Thr-406 dramatically reduced the surface level of TRPV1 in HEK 293 cells after transient expression and the channel function in cultured dorsal root ganglion (DRG) neurons. Notably, intrathecal administration of the interfering peptide against the phosphorylation of Thr-406 alleviated heat hyperalgesia and reduced the surface level of TRPV1 in inflammatory pain rats. Together, these results demonstrate that Cdk5-mediated phosphorylation of TRPV1 at Thr-406 increases the surface level and the function of TRPV1, while the TAT-T406 peptide can effectively attenuate thermal hyperalgesia. Our studies provide a potential therapy for inflammatory pain.

  5. 5-hydroxyindolacetic acid (5-HIAA, a main metabolite of serotonin, is responsible for complete Freund's adjuvant-induced thermal hyperalgesia in mice

    Directory of Open Access Journals (Sweden)

    Moessner Rainald

    2011-03-01

    Full Text Available Abstract Background The role of serotonin (5-hydroxytrptamine, 5-HT in the modulation of pain has been widely studied. Previous work led to the hypothesis that 5-hydroxyindolacetic acid (5-HIAA, a main metabolite of serotonin, might by itself influence pain thresholds. Results In the present study, we investigated the role of 5-HIAA in inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA into the hind paw of mice. Wild-type mice were compared to mice deficient of the 5-HT transporter (5-HTT-/- mice using behavioral tests for hyperalgesia and high-performance liquid chromatography (HPLC to determine tissue levels of 5-HIAA. Wild-type mice reproducibly developed thermal hyperalgesia and paw edema for 5 days after CFA injection. 5-HTT-/- mice treated with CFA had reduced thermal hyperalgesia on day 1 after CFA injection and normal responses to heat thereafter. The 5-HIAA levels in spinal cord and sciatic nerve as measured with HPLC were lower in 5-HTT-/- mice than in wild-type mice after CFA injection. Pretreatment of wild-type mice with intraperitoneal injection of para-chlorophenylalanine (p-CPA, a serotonin synthesis inhibitor, resulted in depletion of the 5-HIAA content in spinal cord and sciatic nerve and decrease in thermal hyperalgesia in CFA injected mice. The application of exogenous 5-HIAA resulted in potentiation of thermal hyperalgesia induced by CFA in 5-HTT-/- mice and in wild-type mice pretreated with p-CPA, but not in wild-type mice without p-CPA pretreatment. Further, methysergide, a broad-spectrum serotonin receptor antagonist, had no effect on 5-HIAA-induced potentiation of thermal hyperalgesia in CFA-treated wild-type mice. Conclusion Taken together, the present results suggest that 5-HIAA plays an important role in modulating peripheral thermal hyperalgesia in CFA induced inflammation, probably via a non-serotonin receptor mechanism.

  6. Effects of intrathecal administration of nitric oxide synthase inhibitors on carrageenan-induced thermal hyperalgesia

    OpenAIRE

    Osborne, Michael G; Coderre, Terence J

    1999-01-01

    We examined the effects of various nitric oxide synthase (NOS) inhibitors on carrageenan-induced thermal hyperalgesia.First, we determined the time point at which a subcutaneous plantar injection of carrageenan into the rat hindpaw produced maximum thermal hyperalgesia. Subsequently, we demonstrated that intrathecal administration of the non-selective NOS inhibitor L-NG-nitro-arginine methyl ester (L-NAME) produces a dose-dependent reduction of carrageenan-induced thermal hyperalgesia.Four re...

  7. NMDA and AMPA receptors contribute to the maintenance of substance P-induced thermal hyperalgesia.

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    Nakayama, Tomohiro; Naono, Rumi; Ikeda, Tetsuya; Nishimori, Toshikazu

    2010-05-01

    It is well known that intrathecal administration of substance P (SP) induces thermal hyperalgesia, but the mechanisms underlying the maintenance of SP-induced thermal hyperalgesia remain to be clarified. Thus, to clarify the receptors involved in the maintenance of SP-induced thermal hyperalgesia, the effect of administering SP or glutamate receptor agonists, NMDA or AMPA, under SP-induced thermal hyperalgesia was investigated. Also, the effect of pretreatment with protein kinase inhibitors on scratching behavior by NMDA or AMPA under SP-induced thermal hyperalgesia was examined. Under SP-induced thermal hyperalgesia, the number of scratchings following SP administration was time-dependently suppressed, whereas the number of scratchings after NMDA or AMPA administration was markedly enhanced and SP-induced thermal hyperalgesia was attenuated by pretreatment with NMDA or AMPA receptor antagonist. Furthermore, pretreatment with kinase inhibitors significantly attenuated the enhancement of scratching behavior by NMDA or AMPA under SP-induced thermal hyperalgesia. These findings indicate that SP-induced thermal hyperalgesia may be maintained through the enhanced responsiveness of NMDA or AMPA receptors, but not the receptor of SP, mediated by kinases.

  8. Spared nerve injury rats exhibit thermal hyperalgesia on an automated operant dynamic thermal escape Task

    OpenAIRE

    Chialvo Dante R; Calvo Oscar; Baliki Marwan; Apkarian A Vania

    2005-01-01

    Abstract Well-established methods are available to measure thermal and mechanical sensitivity in awake behaving rats. However, they require experimenter manipulations and tend to emphasize reflexive behaviors. Here we introduce a new behavioral test, with which we examine thermal sensitivity of rats with neuropathic injury. We contrast thermal hyperalgesia between spared nerve injury and chronic constriction injury rats. This device is a fully automated thermal sensitivity assessment tool des...

  9. Is heat pain detection threshold associated with the area of secondary hyperalgesia following brief thermal sensitization?

    DEFF Research Database (Denmark)

    Hansen, Morten Sejer; Wetterslev, Jørn; Pipper, Christian Bressen

    2016-01-01

    if HPDT, a known quantitative sensory test, is associated with areas of secondary hyperalgesia following brief thermal sensitization TRIAL REGISTRATION: Clinicaltrials.gov (Identifier: NCT02527395 ). Danish Research Ethics Committee (Identifier: H-8-2014-012). Danish Data Protection Agency (Identifier: 30-1436)....... investigates different aspects of the human pain response. Brief thermal sensitization induces a mild burn injury, resulting in development of primary hyperalgesia at the site of stimulation, and secondary hyperalgesia surrounding the site of stimulation. Central sensitization is believed to play an important...... role in the development of secondary hyperalgesia; however, a possible association of secondary hyperalgesia following brief thermal sensitization and other heat pain models remains unknown. Our aim with this study is to investigate how close the heat pain detection threshold is associated...

  10. The amino-terminal region of hemokinin-1 regulates the induction of thermal hyperalgesia in rats.

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    Sunakawa, N; Naono, R; Ikeda, T; Matsushima, O; Sakoda, S; Nishimori, T

    2010-06-01

    It is known that intrathecal administration of substance P (SP) induces thermal hyperalgesia, whereas hemokinin-1 (HK-1), a member of the same tachykinin family as SP, hardly induces thermal hyperalgesia; however, the underlying mechanism remains to be elucidated. Therefore, we aimed to clarify which amino acid of these peptides contributes to the induction of thermal hyperalgesia. When two chimera peptides between the N-terminal region of SP and the C-terminal region of HK-1, and vice versa, SP (1-5)/HK-1 and HK-1 (1-5)/SP, were intrathecally administered, SP (1-5)/HK-1 induced thermal hyperalgesia whereas HK-1 (1-5)/SP had hardly any effect; furthermore, thermal hyperalgesia was induced by only C-terminal fragments of HK-1 and SP. These findings indicate that the N-terminal region of HK-1 is involved in the non-induction of thermal hyperalgesia. Next, we synthesized and intrathecally administered these chimera peptides in which part of the N-terminal region of HK-1 was replaced with that of SP, and vice versa, and all synthesized peptides induced thermal hyperalgesia. Both SP (1-2)/HK-1 and HK-1 (1-4)/SP certainly induced thermal hyperalgesia, although HK-1 and HK-1 (1-5)/SP had hardly any effect; therefore, it is probable that Ser at the 2nd position and Arg at the 5th position of HK-1 may be involved in the non-induction of thermal hyperalgesia. Furthermore, peptides in which amino acid at the 3rd and/or 4th positions of HK-1 was replaced with that of SP were synthesized. Intrathecal administration of HK-1 (1-2,4-5)/SP, but not HK-1 (1-2,5)/SP and HK-1 (1-3,5)/SP, hardly induced thermal hyperalgesia. These findings indicate that three amino acids, Ser, Thr and Arg at the 2nd, 4th and 5th positions of HK-1, respectively, regulate the induction of thermal hyperalgesia by HK-1.

  11. Differential regulation of peripheral IL-1β-induced mechanical allodynia and thermal hyperalgesia in rats.

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    Kim, Min J; Lee, Sang Y; Yang, Kui Y; Nam, Soon H; Kim, Hyun J; Kim, Young J; Bae, Yong C; Ahn, Dong K

    2014-04-01

    This study examined the differential mechanisms of mechanical allodynia and thermal hyperalgesia after injection of interleukin (IL) 1β into the orofacial area of male Sprague-Dawley rats. The subcutaneous administration of IL-1β produced both mechanical allodynia and thermal hyperalgesia. Although a pretreatment with iodoresiniferatoxin (IRTX), a transient receptor potential vanilloid 1 (TRPV1) antagonist, did not affect IL-1β-induced mechanical allodynia, it significantly abolished IL-1β-induced thermal hyperalgesia. On the other hand, a pretreatment with D-AP5, an N-methyl-d-aspartate (NMDA) receptor antagonist, and NBQX, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, blocked IL-1β-induced mechanical allodynia. Pretreatment with H89, a protein kinase A (PKA) inhibitor, blocked IL-1β-induced mechanical allodynia but not thermal hyperalgesia. In contrast, pretreatment with chelerythrine, a protein kinase C (PKC) inhibitor, inhibited IL-1β-induced thermal hyperalgesia. Subcutaneous injections of 2% lidocaine, a local anesthetic agent, blocked IL-1β-induced thermal hyperalgesia but not IL-1β-induced mechanical allodynia. In the resiniferatoxin (RTX)-pretreated rats, a subcutaneous injection of IL-1β did not produce thermal hyperalgesia due to the depletion of TRPV1 in the primary afferent fibers. Double immunofluorescence revealed the colocalization of PKA with neurofilament 200 (NF200) and of PKC with the calcitonin gene-related peptide (CGRP) in the trigeminal ganglion. Furthermore, NMDA receptor 1 (NR1) and TRPV1 predominantly colocalize with PKA and PKC, respectively, in the trigeminal ganglion. These results suggest that IL-1β-induced mechanical allodynia is mediated by sensitized peripheral NMDA/AMPA receptors through PKA-mediated signaling in the large-diameter primary afferent nerve fibers, whereas IL-1β-induced thermal hyperalgesia is mediated by sensitized peripheral TRPV1 receptors through PKC

  12. Contribution of transient receptor potential vanilloid subfamily 1 to endothelin-1-induced thermal hyperalgesia.

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    Kawamata, T; Ji, W; Yamamoto, J; Niiyama, Y; Furuse, S; Namiki, A

    2008-06-26

    Endothelin-1 (ET-1) plays an important role in peripheral pain processing. However, the mechanisms of the nociceptive action of ET-1 have not been fully elucidated. In this study, we investigated the contribution of transient receptor potential vanilloid subfamily 1 (TRPV1) to ET-1-induced thermal hyperalgesia. Intraplantar ET-1-induced thermal hyperalgesia was examined by assessing the paw withdrawal latency to noxious heat stimuli. In electrophysiological study, whole-cell patch-clamp recordings were performed to investigate the interaction of ET-1 and TRPV1 using human embryonic kidney 293 (HEK293) cells expressing endothelin type A receptor (ET(A)) and TRPV1. Intraplantar ET-1 (3, 10 and 30 pmol) produced thermal hyperalgesia in a dose-dependent manner. Thermal hyperalgesia was attenuated by the inhibition of ET(A) and protein kinase C (PKC) but not that of ET(B). ET-1-induced thermal hyperalgesia was significantly attenuated in TRPV1-deficient mice compared with that in wild-type mice. In voltage-clamp experiments, 10 nM capsaicin evoked small inward currents in HEK293 cells expressing TRPV1 and ET(A). In the presence of ET-1, capsaicin produced much larger current responses (Pthermal hyperalgesia.

  13. Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model

    DEFF Research Database (Denmark)

    Larsen, Malte Selch; Keizer, Ron; Munro, Gordon;

    2016-01-01

    PURPOSE: Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin's effect on mechanical hypersensitivity in a rat model of CFA...... provides further knowledge into the understanding of gabapentin's non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides...

  14. Trigeminal-Rostral Ventromedial Medulla circuitry is involved in orofacial hyperalgesia contralateral to tissue injury

    Directory of Open Access Journals (Sweden)

    Chai Bryan

    2012-10-01

    Full Text Available Abstract Background Our previous studies have shown that complete Freund’s adjuvant (CFA-induced masseter inflammation and microinjection of the pro-inflammatory cytokine interleukin-1β (IL-1β into the subnucleus interpolaris/subnucleus caudalis transition zone of the spinal trigeminal nucleus (Vi/Vc can induce contralateral orofacial hyperalgesia in rat models. We have also shown that contralateral hyperalgesia is attenuated with a lesion of the rostral ventromedial medulla (RVM, a critical site of descending pain modulation. Here we investigated the involvement of the RVM-Vi/Vc circuitry in mediating contralateral orofacial hyperalgesia after an injection of CFA into the masseter muscle. Results Microinjection of the IL-1 receptor antagonist (5 nmol, n=6 into the ipsilateral Vi/Vc attenuated the CFA-induced contralateral hyperalgesia but not the ipsilateral hyperalgesia. Intra-RVM post-treatment injection of the NK1 receptor antagonists, RP67580 (0.5-11.4 nmol and L-733,060 (0.5-11.4 nmol, attenuated CFA-induced bilateral hyperalgesia and IL-1β induced bilateral hyperalgesia. Serotonin depletion in RVM neurons prior to intra-masseter CFA injection prevented the development of contralateral hyperalgesia 1–3 days after CFA injection. Inhibition of 5-HT3 receptors in the contralateral Vi/Vc with direct microinjection of the select 5-HT3 receptor antagonist, Y-25130 (2.6-12.9 nmol, attenuated CFA-induced contralateral hyperalgesia. Lesions to the ipsilateral Vc prevented the development of ipsilateral hyperalgesia but did not prevent the development of contralateral hyperalgesia. Conclusions These results suggest that the development of CFA-induced contralateral orofacial hyperalgesia is mediated through descending facilitatory mechanisms of the RVM-Vi/Vc circuitry.

  15. Pioglitazone attenuates tactile allodynia and thermal hyperalgesia in mice subjected to peripheral nerve injury.

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    Maeda, Takehiko; Kiguchi, Norikazu; Kobayashi, Yuka; Ozaki, Masanobu; Kishioka, Shiroh

    2008-11-01

    To clarify the role of peroxisome proliferator activated receptor gamma (PPARgamma) in neuropathic pain, we examined the effect of pioglitazone, a PPARgamma agonist, on tactile allodynia and thermal hyperalgesia in a neuropathic pain model. Mice were subjected to partial sciatic nerve ligation (PSL) and given pioglitazone (1 - 25 mg/kg, p.o.) once daily. PPARgamma was distributed in the neurons of the dorsal root ganglion and the dorsal horn of the spinal cord and in the adipocytes at the epineurium of the sciatic nerve in naive mice. PSL elicited tactile allodynia and thermal hyperalgesia for two weeks. Administration of pioglitazone for the first week after PSL attenuated thermal hyperalgesia and tactile allodynia, which was dose-dependent and blocked by GW9662 (2 mg/kg, i.p.), a PPARgamma antagonist. Administration of pioglitazone for the second week also relieved tactile allodynia, but administration one week before PSL had no effect. A single administration of pioglitazone to mice on day 7 of PSL did not alter tactile allodynia and thermal hyperalgesia. PSL-induced upregulation of tumor necrosis factor-alpha and interleukin-6, which are essential for neuropathic pain, was suppressed by pioglitazone for the first week. This suggests that pioglitazone alleviates neuropathic pain through attenuation of proinflammatory cytokine upregulation by PPARgamma stimulation.

  16. Dissociable neural activity to self- vs. externally administered thermal hyperalgesia: a parametric fMRI study.

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    Mohr, C; Leyendecker, S; Helmchen, C

    2008-02-01

    Little is known regarding how cognitive strategies help to modulate neural responses of the human brain in ongoing pain syndromes to alleviate pain. Under pathological pain conditions, any self-elicited contact with usually non-painful stimuli may become painful. We examined whether the human brain is capable of dissociating self-controlled from externally administered thermal hyperalgesia in the experimental capsaicin model. Using functional magnetic resonance imaging, 17 male subjects were investigated in a parametric design with heat stimuli at topically capsaicin-sensitized skin. In contrast to external stimulation, self-administered pain was controllable. For both conditions application trials without noticeable thermal stimulation were introduced and used as high-level baseline (HLB) to account for the capsaicin-induced ongoing pain and other covariables. Following subtraction of the HLB, the anterior insula and the anterior cingulate cortex (ACC) but not the somatosensory cortices maintained parametric neural responses to thermal hyperalgesia. A stronger pain-related activity increase during self-administered stimuli was observed in the posterior insula. In contrast, prefrontal cortex showed stronger increases to uncontrollable external heat stimuli. In the state of ongoing pain (capsaicin), pain-intensity-encoding regions (anterior insula, ACC) but not those with sensory discriminative functions (SI, SII) showed graded, pain-intensity-related neural responses in thermal hyperalgesia. Some areas were able to dissociate between self- and externally administered stimuli in thermal hyperalgesia, which might be related to differences in perceived controllability. Thus, neural mechanisms maintain the ability to dissociate external from self-generated states of injury in thermal hyperalgesia. This may help to understand how cognitive strategies potentially alleviate chronic pain syndromes.

  17. Tetrodotoxin suppresses thermal hyperalgesia and mechanical allodynia in a rat full thickness thermal injury pain model.

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    Salas, Margaux M; McIntyre, Matthew K; Petz, Lawrence N; Korz, Walter; Wong, Donald; Clifford, John L

    2015-10-21

    Burn injuries have been identified as the primary cause of injury in 5% of U.S. military personnel evacuated from Operations Iraqi Freedom and Enduring Freedom. Severe burn-associated pain is typically treated with opioids such as fentanyl, morphine, and methadone. Side effects of opioids include respiratory depression, cardiac depression, decrease in motor and cognitive function, as well as the development of hyperalgesia, tolerance and dependence. These effects have led us to search for novel analgesics for the treatment of burn-associated pain in wounded combat service members. Tetrodotoxin (TTX) is a selective voltage-gated sodium channel blocker currently in clinical trials as an analgesic. A phase 3 clinical trial for cancer-related pain has been completed and phase 3 clinical trials on chemotherapy-induced neuropathic pain are planned. It has also been shown in mice to inhibit the development of chemotherapy-induced neuropathic pain. TTX was originally identified as a neurotoxin in marine animals but has now been shown to be safe in humans at therapeutic doses. The antinociceptive effects of TTX are thought to be due to inhibition of Na(+) ion influx required for initiation and conduction of nociceptive impulses. One TTX sensitive sodium channel, Nav1.7, has been shown to be essential in lowering the heat pain threshold after burn injuries. To date, the analgesic effect of TTX has not been tested in burn-associated pain. Male Sprague-Dawley rats were subjected to a full thickness thermal injury on the right hind paw. TTX (8 μg/kg) was administered once a day systemically by subcutaneous injection beginning 3 days post thermal injury and continued through 7 days post thermal injury. Thermal hyperalgesia and mechanical allodynia were assessed 60 and 120 min post injection on each day of TTX treatment. TTX significantly reduced thermal hyperalgesia at all days tested and had a less robust, but statistically significant suppressive effect on mechanical

  18. Blocking TNF-α with infliximab alleviates ovariectomy induced mechanical and thermal hyperalgesia in rats.

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    Chen, Bai Ling; Li, Yi Qiang; Xie, Deng Hui; He, Qiu Lan; Yang, Xiao Xi

    2012-06-01

    Studies have proved an increased expression of tumor necrosis factor alpha (TNF-α) in estrogen deficiency animals, and TNF-α also plays a role in inflammation and neuropathic pain. This study aimed to explore the relationship between TNF-α and ovariectomy induced hyperalgesia. 36 female Sparague-Dawley were included, estrogen depletion models were established by ovariectomy. Then infliximab (a TNF-α blocker) was administrated to the ovariectomized rats for 8 weeks. Pain behavioral tests were performed once a week. The bone mineral density (BMD), serum estradiol and TNF-α level were determined at the 8th week after ovariectomy. The expression of TNF-α in lumbar 5 dorsal root ganglions (L5 DRGs) was examined by immunofluorescence method. Significant hyperalgesia to mechanical and thermal stimuli in groups Ovx-1 and Ovx-2 was observed 1 week after the operation. After treated with infliximab, the pain threshold of Ovx-2 was partially restored, although still lower than the Sham group. The serum TNF-α level of Ovx-1 was significantly higher than Sham and Ovx-2. TNF-α immunofluorescence indicated a significant increase in the expression of TNF-α at L5 DRGs in group Ovx-1 when compared with groups Sham and Ovx-2. The BMD of group Ovx-2 was significantly higher than group Ovx-1 and lower than group Sham. In conclusion, TNF-α plays an important role in estrogen deficiency induced mechanical and thermal hyperalgesia, and DRG may be one site on which TNF-α acts to cause hyperalgesia. Blocking the effect of TNF-α could partially alleviate the estrogen deficiency induced hyperalgesia in rats. Thus, TNF-α may contribute to chronic pain in postmenopausal women.

  19. RhoA/Rho kinase pathway contributes to the pathogenesis of thermal hyperalgesia in diabetic mice.

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    Ohsawa, Masahiro; Aasato, Megumi; Hayashi, Shun-Suke; Kamei, Junzo

    2011-01-01

    Diabetic neuropathy is one of the most common complications of diabetes and causes various problems in daily life. Several investigations have noted that many factors in the spinal cord are involved in the symptoms of painful diabetic neuropathy, and there are very few effective therapeutic regimens. In the present study, we sought to elucidate the role of the RhoA/Rho kinase (ROCK) pathway in thermal hyperalgesia in diabetic mice. The intracellular localization of RhoA and the expression of eNOS were measured by western blotting. Thermal hyperalgesia was assessed by the tail-flick test and mechanical allodynia was assessed by automated von Frey filament test in streptozotocin(STZ)-induced diabetic mice. The spinal cord of STZ-treated diabetic mice showed increased membrane-bound RhoA compared to non-diabetic control. Treatment with the RhoA inhibitor exoenzyme C3, Clostridium botulinum, and the ROCK inhibitor Y27632 attenuated thermal hyperalgesia and mechanical allodynia in diabetic mice. Moreover, daily treatment with simvastatin attenuated all of those changes in diabetic mice. The expression of eNOS and NO metabolite contents in the spinal cord was decreased in diabetic mice, and these changes were normalized by treatment with simvastatin. The present results show that HMG-CoA reductase inhibitors have an inhibitory effect on thermal hyperalgesia in diabetic mice, which is mediated by an increase in NO production through the inhibition of RhoA/ROCK pathways. These results suggest that ROCK inhibitors and HMG-CoA inhibitors may be attractive compounds to relieve the symptoms of painful diabetic neuropathies.

  20. Reduction of spinal PGE2 concentrations prevents swim stress-induced thermal hyperalgesia.

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    Guevara, Coram; Fernandez, Ana Cristina; Cardenas, Ricardo; Suarez-Roca, Heberto

    2015-03-30

    We evaluated the association between spinal PGE2 and thermal hyperalgesia following repeated stress. Thermal nociception was determined in male Sprague-Dawley rats using the hot-plate test, before and after forced-swimming; non-conditioned rats served as controls. Animals were pretreated with ketoprofen or meloxicam, preferential COX-1 and COX-2 inhibitors, respectively. After the second hot-plate test, we measured serum corticosterone (stress marker), and lumbar spinal PGE2 (neuroinflammation marker) under peripheral inflammation (1% formalin plantar injection). Stressed rats displayed response latencies 40% shorter and inflammatory spinal PGE2 levels 95% higher than controls. Pretreatment with ketoprofen or meloxicam prevented hyperalgesia and elevation of spinal PGE2, increasing the escape behavior time during forced swimming 95% respect to saline-treated rats. Corticosterone levels in stressed rats were 97% higher than controls; COX inhibitors reduced them by 84%. PGE2 could participate in stress-induced hyperalgesia, learned helplessness, and corticosterone production, supporting the use of non-steroidal anti-inflammatory drugs (NSAIDs) for persistent pain associated with chronic stress and depression.

  1. Intradermal injection of Botulinum toxin type A alleviates infraorbital nerve constriction-induced thermal hyperalgesia in an operant assay.

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    Kumada, A; Matsuka, Y; Spigelman, I; Maruhama, K; Yamamoto, Y; Neubert, J K; Nolan, T A; Watanabe, K; Maekawa, K; Kamioka, H; Yamashiro, T; Kuboki, T; Oguma, K

    2012-01-01

    Recent studies have shown that infraorbital nerve constriction (IoNC)-induced mechanical allodynia has been attenuated by administration of highly purified 150-kDa Botulinum neurotoxin type A (BoNT/A). Here, we extend these studies to determine whether BoNT/A could attenuate IoNC-induced symptoms of thermal hyperalgesia. Instead of testing head withdrawal thresholds, a thermal operant assay was used to evaluate cortical processing of sensory input following IoNC. In this assay, a fasted rat's desire to obtain a food reward (sweetened condensed milk) is coupled to its ability to tolerate facial contact with a warm (45 °C) thermode. Bilateral IoNC decreased the ratio of thermode contact duration/event, which is an indicative of thermal hyperalgesia. BoNT/A injection intradermally in the area of infraorbital nerve (IoN) innervation 7 days after IoNC resulted in decreased number of facial contacts and increased the ratio of contact duration/event (measured at 14 days after IoNC). The BoNT/A (2-200 pg) effects were dose dependent and statistically significant at 100 and 200 pg (P thermal hyperalgesia symptoms was obtained with a 200-pg dose, without affecting sham rat behaviour. Off-site (neck) injection of BoNT/A did not relieve thermal hyperalgesia, while co-injection of BoNT/A with a neutralising antibody in the area of IoN innervation prevented relief of thermal hyperalgesia. Neither IoNC nor BoNT/A injection affected operant assay parameters with a 24 °C thermode, indicating selectivity of thermal hyperalgesia measurements. These results strongly suggest that intradermal injection of BoNT/A in the area of IoN innervation alleviates IoNC-induced thermal hyperalgesia in an operant assay.

  2. 5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice.

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    Ulugol, Ahmet; Oltulu, Cagatay; Gunduz, Ozgur; Citak, Cihad; Carrara, Roberto; Shaqaqi, Mohammad Reza; Sanchez, Alicia Mansilla; Dogrul, Ahmet

    2012-08-01

    The role of 5-HT7 receptors in the nociceptive processing received most attention during the last few years. The involvement of 5-HT₇ receptors in nerve injury-induced neuropathic pain states have been reported only recently; however, there are no reports on its contribution in diabetic neuropathic pain. We therefore planned to investigate the effect of 5-HT₇ receptor activation on the changes of nociceptive threshold in diabetic mice. Diabetes was induced by a single intraperitoneal injection of streptozocin (150 mg/kg, i.p.). The nociceptive responses in normal and diabetic animals were tested in the hot-plate and tail-flick assays. Both hot-plate and tail-flick latencies significantly shortened at 1-3/4 weeks (thermal hyperalgesia) and prolonged at 6-7 weeks (thermal hypoalgesia) after streptozocin administration. At the dose of 10 mg/kg, systemic injections of AS-19, a selective 5-HT₇ receptor agonist, reduced thermal hyperalgesia at early stage of diabetes, but did not influence thermal hypoalgesia at late stage. Co-administration of SB-258719, a selective 5-HT₇ receptor antagonist, at a dose that had no effect on its own (10 mg/kg), reversed the anti-hyperalgesic effect of AS-19. Our results indicate that systemic administration of 5-HT₇ receptor agonists may have clinical utility in treating diabetic neuropathic pain.

  3. Acid-sensing ion channel 3 mediates peripheral anti-hyperalgesia effects of acupuncture in mice inflammatory pain

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    Chen Wei-Hsin

    2011-11-01

    Full Text Available Abstract Background Peripheral tissue inflammation initiates hyperalgesia accompanied by tissue acidosis, nociceptor activation, and inflammation mediators. Recent studies have suggested a significantly increased expression of acid-sensing ion channel 3 (ASIC3 in both carrageenan- and complete Freund's adjuvant (CFA-induced inflammation. This study tested the hypothesis that acupuncture is curative for mechanical hyperalgesia induced by peripheral inflammation. Methods Here we used mechanical stimuli to assess behavioral responses in paw and muscle inflammation induced by carrageenan or CFA. We also used immunohistochemistry staining and western blot methodology to evaluate the expression of ASIC3 in dorsal root ganglion (DRG neurons. Results In comparison with the control, the inflammation group showed significant mechanical hyperalgesia with both intraplantar carrageenan and CFA-induced inflammation. Interestingly, both carrageenan- and CFA-induced hyperalgesia were accompanied by ASIC3 up-regulation in DRG neurons. Furthermore, electroacupuncture (EA at the ST36 rescued mechanical hyperalgesia through down-regulation of ASIC3 overexpression in both carrageenan- and CFA-induced inflammation. Conclusions In addition, electrical stimulation at the ST36 acupoint can relieve mechanical hyperalgesia by attenuating ASIC3 overexpression.

  4. Spinal interleukin-17 promotes thermal hyperalgesia and NMDA NR1 phosphorylation in an inflammatory pain rat model.

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    Meng, Xianze; Zhang, Yu; Lao, Lixing; Saito, Rikka; Li, Aihui; Bäckman, Cristina M; Berman, Brian M; Ren, Ke; Wei, Pin-Kang; Zhang, Rui-Xin

    2013-02-01

    It is known that interleukin-17 (IL-17) is associated with autoimmune disorders and that peripheral IL-17 plays a role in arthritis and neuropathic pain. The present study investigated the possibility of spinal cell expression of IL-17 during inflammatory pain and possible IL-17 involvement in such pain. Hyperalgesia was induced by injecting complete Freund adjuvant (CFA, 0.08mL, 40μg Mycobacterium tuberculosis) into one hind paw of the rat. Paw withdrawal latency (PWL) was tested before (-48h) and 2 and 24h after CFA injection to assess hyperalgesia. IL-17 antibody (0.2-2μg/rat) was given intrathecally (i.t.) 24h before CFA to block the action of basal IL-17 and 2h before each of 2 PWL tests to block CFA-induced IL-17. I.t. recombinant IL-17 (10-400ng per rat) was administered to naive rats to determine its effects on PWL and phosphorylated NR1 (p-NR1). p-NR1 modulates N-methyl-d-aspartate receptor (NMDAR) activity to facilitate pain. Spinal cords were removed for IL-17 immunostaining, double immunostaining of IL-17/cell markers and IL-17 receptor A (IL-17RA)/NR1, for Western blot testing of IL-17, p-NR1, IL-17RA, and GFAP, for in situ IL-17RA hybridization, and for real time polymerase chain reaction of IL-17RA. The data reveal that IL-17 is up-regulated in activated and nonactivated astrocytes; that IL-17RA is localized in NR1-immunoreactive neurons and up-regulated; and that IL-17 antibody at 2μg/rat significantly increased PWL (P<.05) and decreased p-NR1 and IL-17RA compared to control in CFA- and IL-17-injected rats. The results suggest that spinal IL-17 is produced by astrocytes and enhances p-NR1 to facilitate pain.

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

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    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

  6. 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.

  7. Local loperamide inhibits thermal hyperalgesia but not mechanical allodynia induced by intratibial inoculation of melanoma cells in mice.

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    Curto-Reyes, Verdad; Juárez, Lucía; García-Pérez, Eva; Fresno, Manuel Florentino; Hidalgo, Agustín; Menéndez, Luis; Baamonde, Ana

    2008-11-01

    The stimulation of peripheral opioid receptors counteracts thermal hyperalgesia produced by the intratibial inoculation of NCTC 2472 cells in mice, through the activation of the nitric oxide/cGMP/ATP-sensitive K+-channels (NO/cGMP/K(+) (ATP)) cascade (Menéndez et al. 2007, Neuropharmacology 53:71-80). We aimed to elucidate whether this peripheral opioid antihyperalgesic effect is exclusive to this model or might also occur in other types of bone neoplastic processes. In C57BL/6 mice intratibially inoculated with B16-F10 melanoma cells, the progressive tumoral damage was accompanied by the establishment of thermal hyperalgesia (unilateral hot plate test) and mechanical allodynia (von Frey test). Intraplantar administration of loperamide (15 microg, 30 min before) inhibited thermal hyperalgesia, but did not modify the intense mechanical allodynia. The fact that the coadministration of naloxone-methiodide (5 microg) completely suppressed the thermal antihyperalgesic effect induced by loperamide indicates its production through the stimulation of peripheral opioid receptors. Furthermore, its prevention by the coadministration of the non-selective inhibitor of the NO synthase, N(G)-monomethyl-L-arginine (L-NMMA, 10 microg), the selective inhibitor of neural NOS, N-omega-propyl-L-arginine (1-10 microg), or the K+ (ATP) channel blocker, glibenclamide (10 microg) demonstrated the involvement of the NO/cGMP/K(+) (ATP) pathway in the antihyperalgesic effect induced by loperamide. Overall, the present results show that the intratibial inoculation of B16-F10 cells to C57BL/6 mice evokes thermal hyperalgesia and mechanical allodynia and that, as occurred in the osteosarcoma model, the stimulation of peripheral opioid receptors is not effective in modifying neoplastic allodynia but completely inhibits thermal hyperalgesia through the activation of the NO/cGMP/K+ (ATP) cascade.

  8. Bilateral mechanical and thermal hyperalgesia and tactile allodynia after chronic compression of dorsal root ganglion in mice.

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    Chen, Rong-Gui; Kong, Wei-Wei; Ge, Da-Long; Luo, Ceng; Hu, San-Jue

    2011-08-01

    OBJECTIVE Low back pain is one of the most inextricable problems encountered in clinics. Animal models that imitate symptoms in humans are valuable tools for investigating low back pain mechanisms and the possible therapeutic applications. With the development of genetic technology in pain field, the possibility of mutating specific genes in mice has provided a potent tool for investigating the specific mechanisms of pain. The aim of the present study was to develop a mouse model of chronic compression of dorsal root ganglion (CCD), in which gene mutation can be applied to facilitate the studies of chronic pain. METHODS Chronic compression of L4 and L5 dorsal root ganglia was conducted in mice by inserting fine stainless steel rods into the intervertebral foramina, one at L4 and the other at L5. Mechanical allodynia and thermal hyperalgesia were examined with von Frey filaments and radiating heat stimulator, respectively. RESULTS The CCD mice displayed dramatic mechanical and thermal hyperalgesia as well as tactile allodynia in the hindpaw ipsilateral to CCD. In addition, this mechanical and thermal hyperalgesia as well as tactile allodynia was also found to spread to the contralateral hindpaw. CONCLUSION This model, combined with the possible genetic modification, will strengthen our knowledge of the underlying mechanisms of low back pain. It also favors the development of new treatment strategies for pain and hyperalgesia after spinal injury and other disorders which affect the dorsal root ganglion in humans.

  9. Pharmacology of intracisternal or intrathecal glycine, muscimol, and baclofen in strychnine-induced thermal hyperalgesia of mice.

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    Lee, Il Ok; Son, Jin Kook; Lim, Eui-Sung; Kim, Yeon-Soo

    2011-10-01

    Glycine and γ-aminobutyric acid (GABA) are localized and released by the same interneurons in the spinal cord. Although the effects of glycine and GABA on analgesia are well known, little is known about the effect of GABA in strychnine-induced hyperalgesia. To investigate the effect of GABA and the role of the glycine receptor in thermal hyperalgesia, we designed an experiment involving the injection of muscimol (a GABA(A) receptor agonist), baclofen (a GABA(B) receptor agonist) or glycine with strychnine (strychnine sensitive glycine receptor antagonist). Glycine, muscimol, or baclofen with strychnine was injected into the cisterna magna or lumbar subarachnoidal spaces of mice. The effects of treatment on strychnine-induced heat hyperalgesia were observed using the pain threshold index via the hot plate test. The dosages of experimental drugs and strychnine we chose had no effects on motor behavior in conscious mice. Intracisternal or intrathecal administration of strychnine produced thermal hyperalgesia in mice. Glycine antagonize the effects of strychnine, whereas, muscimol or baclofen does not. Our results indicate that glycine has anti-thermal hyperalgesic properties in vivo; and GABA receptor agonists may lack the binding abilities of glycine receptor antagonists with their sites in the central nervous system.

  10. Posttranslational nitration of tyrosine residues modulates glutamate transmission and contributes to N-methyl-D-aspartate-mediated thermal hyperalgesia.

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    Muscoli, Carolina; Dagostino, Concetta; Ilari, Sara; Lauro, Filomena; Gliozzi, Micaela; Bardhi, Erlisa; Palma, Ernesto; Mollace, Vincenzo; Salvemini, Daniela

    2013-01-01

    Activation of the N-methyl-D-aspartate receptor (NMDAR) is fundamental in the development of hyperalgesia. Overactivation of this receptor releases superoxide and nitric oxide that, in turn, forms peroxynitrite (PN). All of these events have been linked to neurotoxicity. The receptors and enzymes involved in the handling of glutamate pathway--specifically NMDARs, glutamate transporter, and glutamine synthase (GS)--have key tyrosine residues which are targets of the nitration process causing subsequent function modification. Our results demonstrate that the thermal hyperalgesia induced by intrathecal administration of NMDA is associated with spinal nitration of GluN1 and GluN2B receptor subunits, GS, that normally convert glutamate into nontoxic glutamine, and glutamate transporter GLT1. Intrathecal injection of PN decomposition catalyst FeTM-4-PyP(5+) prevents nitration and overall inhibits NMDA-mediated thermal hyperalgesia. Our study supports the hypothesis that nitration of key proteins involved in the regulation of glutamate transmission is a crucial pathway used by PN to mediate the development and maintenance of NMDA-mediated thermal hyperalgesia. The broader implication of our findings reinforces the notion that free radicals may contribute to various forms of pain events and the importance of the development of new pharmacological tool that can modulate the glutamate transmission without blocking its actions directly.

  11. Mechanical and thermal hyperalgesia and ectopic neuronal discharge after chronic compression of dorsal root ganglia.

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    Song, X J; Hu, S J; Greenquist, K W; Zhang, J M; LaMotte, R H

    1999-12-01

    Chronic compression of the dorsal root ganglion (CCD) was produced in adult rats by implanting a stainless steel rod unilaterally into the intervertebral foramen, one rod at L(4) and another at L(5). Two additional groups of rats received either a sham surgery or an acute injury consisting of a transient compression of the ganglion. Withdrawal of the hindpaw was used as evidence of a nocifensive response to mechanical and thermal stimulation of the plantar surface. In addition, extracellular electrophysiological recordings of spontaneous discharges were obtained from dorsal root fibers of formerly compressed ganglia using an in vitro nerve-DRG-dorsal root preparation. The mean threshold force of punctate indentation and the mean threshold temperature of heating required to elicit a 50% incidence of foot withdrawal ipsilateral to the CCD were significantly lower than preoperative values throughout the 35 days of postoperative testing. The number of foot withdrawals ipsilateral to the CCD during a 20-min contact with a temperature-controlled floor was significantly increased over preoperative values throughout postoperative testing when the floor was 4 degrees C (hyperalgesia) and, to a lesser extent, when it was 30 degrees C (spontaneous pain). Stroking the foot with a cotton wisp never elicited a reflex withdrawal before surgery but did so in most rats tested ipsilateral to the CCD during the first 2 postoperative weeks. In contrast, the CCD produced no changes in responses to mechanical or thermal stimuli on the contralateral foot. The sham operation and acute injury produced no change in behavior other than slight, mechanical hyperalgesia for approximately 1 day, ipsilateral to the acute injury. Ectopic spontaneous discharges generated within the chronically compressed ganglion and, occurring in the absence of blood-borne chemicals and without an intact sympathetic nervous system, were recorded from neurons with intact, conducting, myelinated or unmyelinated

  12. Heat pain detection threshold is associated with the area of secondary hyperalgesia following brief thermal sensitization: a study of healthy male volunteers

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    Hansen, Morten Sejer; Wetterslev, Jørn; Pipper, Christian Bressen; Asghar, Mohammad Sohail; Dahl, Jørgen Berg

    2017-01-01

    Introduction The area of secondary hyperalgesia following brief thermal sensitization (BTS) of the skin and heat pain detection thresholds (HPDT) may both have predictive abilities in regards to pain sensitivity and clinical pain states. The association between HPDT and secondary hyperalgesia, however, remains unsettled, and the dissimilarities in physiologic properties suggest that they may represent 2 distinctively different pain entities. The aim of this study was to investigate the association between HPDT and BTS-induced secondary hyperalgesia. Methods A sample of 121 healthy male participants was included and tested on 2 separate study days with BTS (45°C, 3 minutes), HPDT, and pain during thermal stimulation (45°C, 1 minute). Areas of secondary hyperalgesia were quantified after monofilament pinprick stimulation. The pain catastrophizing scale (PCS) and hospital anxiety and depression scale (HADS) were also applied. Results A significant association between HPDT and the size of the area of secondary hyperalgesia (p<0.0001) was found. The expected change in area of secondary hyperalgesia due to a 1-degree increase in HPDT was estimated to be −27.38 cm2, 95% confidence interval (CI) of −37.77 to −16.98 cm2, with an R2 of 0.19. Likewise, a significant association between HADS-depression subscore and area of secondary hyperalgesia (p=0.046) was found, with an estimated expected change in secondary hyperalgesia to a 1-point increase in HADS-depression subscore of 11 cm2, 95% CI (0.19–21.82), and with R2 of 0.03. We found no significant associations between secondary hyperalgesia area and PCS score or pain during thermal stimulation. Conclusion HPDT and the area of secondary hyperalgesia after BTS are significantly associated; however, with an R2 of only 19%, HPDT only offers a modest explanation of the inter-participant variation in the size of the secondary hyperalgesia area elicited by BTS. PMID:28184167

  13. Anti-hyperalgesic effects of anti-serotonergic compounds on serotonin- and capsaicin-evoked thermal hyperalgesia in the rat.

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    Loyd, D R; Chen, P B; Hargreaves, K M

    2012-02-17

    The peripheral serotonergic system has been implicated in the modulation of an array of pain states, from migraine to fibromyalgia; however, the mechanism by which serotonin (5HT) induces pain is unclear. Peripherally released 5HT induces thermal hyperalgesia, possibly via modulation of the transient receptor potential V1 (TRPV1) channel, which is gated by various noxious stimuli, including capsaicin. We previously reported in vitro that 5HT increases calcium accumulation in the capsaicin-sensitive population of sensory neurons with a corresponding increase in proinflammatory neuropeptide release, and both are antagonized by pretreatment with 5HT(2A) and 5HT(3) antagonists, as well as the anti-migraine drug sumatriptan. In the current study, we extended these findings in vivo using the rat hind paw thermal assay to test the hypothesis that peripheral 5HT enhances TRPV1-evoked thermal hyperalgesia that can be attenuated with 5HT(2A) and 5HT(3) receptor antagonists, as well as sumatriptan. Thermal hyperalgesia and edema were established by 5HT injection (0.1-10 nmol/100 μl) into the rat hind paw, and the latency to paw withdrawal (PWL) from noxious heat was determined. Rats were then pretreated with either 5HT before capsaicin (3 nmol/10 μl), the 5HT(2A) receptor antagonist ketanserin or the 5HT(3) receptor antagonist granisetron (0.0001-0.1 nmol/100 μl) before 5HT and/or capsaicin, or the 5HT(1B/1D) receptor agonist sumatriptan (0.01-1 nmol/100 μl) before capsaicin, and PWL was determined. We report that 5HT pretreatment enhances TRPV1-evoked thermal hyperalgesia, which is attenuated with local pretreatment with ketanserin, granisetron, or sumatriptan. We also report that peripheral 5HT induced a similar magnitude of thermal hyperalgesia in male and female rats. Overall, our results provide in vivo evidence supporting an enhancing role of 5HT on TRPV1-evoked thermal hyperalgesia, which can be attenuated by peripheral serotonergic intervention.

  14. Thermal hyperalgesia after sciatic nerve block in rat is transient and clinically insignificant.

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    Janda, Allison; Lydic, Ralph; Welch, Kathleen B; Brummett, Chad M

    2013-01-01

    Ropivacaine has been associated with transient heat hyperalgesia in sciatic nerve blocks in rat. The goal of the present study was to evaluate the hypothesized presence of transient heat hyperalgesia after perineural injection of ropivacaine with a secondary subanalysis of 2 published studies. Paw withdrawal latency was used to assess the duration of sensory blockade and presence of heat hyperalgesia at 210, 240, 270, and 300 minutes and 24 hours after injection. The analysis revealed hyperalgesia at a single time point (240 minutes after injection; mean difference, -0.60 seconds; P = 0.012) that resolved within 30 minutes, and there was no other significant hyperalgesia at other time points. Although statistically significant, the single time point measurement represented only an 11% change from baseline and was no longer present 30 minutes later. These data support the need for a reevaluation of the interpretation that pain can be worsened by perineural ropivacaine injection.

  15. Minocycline injection in the ventral posterolateral thalamus reverses microglial reactivity and thermal hyperalgesia secondary to sciatic neuropathy.

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    LeBlanc, Brian W; Zerah, Michele L; Kadasi, Laith M; Chai, Noori; Saab, Carl Y

    2011-07-08

    We hypothesized that microglia in the ventral posterolateral (VPL) nucleus of the thalamus are reactive following peripheral nerve injury, and that inhibition of microglia by minocycline injection in the VPL attenuates thermal hyperalgesia. Our results show increased expression of OX-42 co-localized with phosphorylated p38MAPK (P-p38) in the VPL seven days after chronic constriction injury (CCI) of the sciatic nerve. However, astrocytic GFAP expression in the VPL is unchanged 7 and 14 days after CCI. Microinjection of minocycline into the VPL contralateral to CCI reverses thermal hyperalgesia, whereas vehicle injection has no effect on paw withdrawal latency. Minocycline abrogates the increased expression of OX-42 in the VPL after CCI. Therefore, peripheral nerve injury favors a hyperactive microglial phenotype in the VPL, suggesting remote neuroimmune signaling from the damaged nerve to the brain, concomitant with neuropathic behavior that is reversed by local intervention in the VPL to inhibit microglia.

  16. The effect of intrathecal gabapentin on mechanical and thermal hyperalgesia in neuropathic rats induced by spinal nerve ligation.

    OpenAIRE

    Cho, Hyun Sung; Kim, Myung Hee; Choi, Duck Hwan; LEE, JUNG IL; Gwak, Mi Sook; Hahm, Tae Soo

    2002-01-01

    Gabapentin decreases the level of glutamate and elevates that of alpha-amino-butyric acid in the central nervous system. Gabapentin was shown to have antinociceptive effects in several facilitated pain models. Intrathecal gabapentin was also known to be effective in reducing mechanical allodynia in animals with neuropathic pain. In this study, we investigated to see whether intrathecal gabapentin produces antihyperalgesic effects on thermal and mechanical hyperalgesia in neuropathic rats and ...

  17. Different analgesic effects of intrathecal endomorphin-2 on thermal hyperalgesia and evoked inflammatory pain in ovariectomized rats.

    Science.gov (United States)

    Zhao, Xiao-Hui; Zhao, Ya-Qun; Zhu, Chao; Chen, Lei; Hu, Wei; Zhang, Ting; Dong, Yu-Lin; Wu, Sheng-Xi; Kaye, Alan David; Wang, Wen; Li, Yun-Qing

    2015-01-01

    Hormone replacement remains one of the common therapies for menopause-related pain but is associated with risk of orofacial or back pain. Spinal endomorphin-2 (EM-2) is involved in varied pain and its release is steroid-dependent, but whether increasing spinal EM-2 can inhibit thermal hyperalgesia and inflammatory pain in ovariectomized (OVX) female rats, an animal model mimicking menopause, is not clear, nor is the potential involvement of spinal mu-opioid receptor (MOR). In the current study, we revealed that the temporal decrease of spinal EM-2 is accompanied with OVX-induced thermal hyperalgesia that was dose-dependently attenuated by intrathecal (IT) delivery of EM-2. The subcutaneous injection of formalin-induced inflammatory pain in OVX rats was exacerbated and IT delivery of EM-2 dose-dependently inhibited the inflammatory pain. However, the ED50 for IT delivery of EM-2 on thermal hyperalgesia is smaller than that on inflammatory pain in OVX rats, suggesting different contributions of the EM-2 system to these 2 pain modalities in OVX rats. IT pretreatment with MOR antagonist, beta-funaltrexamine (β-FNA), attenuated IT EM-2 analgesia on both thermal hyperalgesia and inflammatory pain in OVX rats. Furthermore, IT delivery of EM-2 did not affect the animals' locomotion or anxiety status. Our findings suggested that IT EM-2 might be a safer analgesia strategy than hormone replacement therapy in reducing risk of orofacial or back pain. However, a long-lasting form of EM-2 with less tolerance is needed to induce sustained analgesia.

  18. Coadministration of indomethacin and minocycline attenuates established paclitaxel-induced neuropathic thermal hyperalgesia: Involvement of cannabinoid CB1 receptors.

    Science.gov (United States)

    Parvathy, Subramanian S; Masocha, Willias

    2015-06-18

    Taxanes such as paclitaxel, which are chemotherapeutic drugs, cause dose-dependent painful neuropathy in some patients. We investigated whether coadministration of minocycline and indomethacin produces antinociceptive effects in mice with paclitaxel-induced neuropathic thermal hyperalgesia and if the cannabinoid system is involved. Previously, we reported that coadministration of these two drugs results in antinociception against inflammatory pain at doses where either drug alone lack significant activity. In the current study, we observed that treatment of female mice with indomethacin or minocycline alone did not affect established paclitaxel-induced thermal hyperalgesia, whereas coadministration of the two drugs attenuated it. In male mice indomethacin had some antihyperalgesic activity, whilst minocycline did not. Coadministration of the two drugs had supraadditive antihyperalgesic activity in male mice. Administration of a cannabinoid CB1 receptor antagonist AM 251 blocked the antihyperalgesic effects of the combination of minocycline and indomethacin in both male and female mice. In conclusion our results indicate that coadministration of minocycline and indomethacin abrogates established paclitaxel-induced neuropathic thermal hyperalgesia in mice, and the potentiation of the antinociceptive effects of this combination involves the cannabinoid system.

  19. A rat model of full thickness thermal injury characterized by thermal hyperalgesia, mechanical allodynia, pronociceptive peptide release and tramadol analgesia.

    Science.gov (United States)

    Fowler, Marcie; Clifford, John L; Garza, Thomas H; Slater, Terry M; Arizpe, Helen M; Novak, Joseph; Petz, Lawrence N; Loyd, Dayna R

    2014-06-01

    Opioid-related side effects are problematic for burn patients. Dual mechanism therapeutics targeting opioid and non-opioid mechanisms may have reduced side effects with similar analgesic efficacy. Tramadol combines mu opioid receptor agonism with norepinephrine reuptake inhibition and has been effective in treating some types of pain. The effectiveness of tramadol in treating pain associated with burns is unclear. We hypothesized that tramadol is effective in reducing thermal injury-evoked pain behaviors in a rat model. Rats were anesthetized and a 100°C metal probe was placed on the hindpaw for 30 s to induce a full thickness thermal injury. A subset of rats was perfusion fixed and hindpaw tissue and spinal cord collected for anatomical analysis. Rats received morphine (5 mg/kg; i.p.), tramadol (10-30 mg/kg; i.p.) or vehicle and latency to paw withdrawal from a noxious thermal or non-noxious mechanical stimulus was recorded every 10 min over 70 min and again at 2 h. We report that pain behaviors developed within 48 h and peaked at 1 week; paralleled by enhanced expression of pronociceptive neuropeptides in the spinal cord. Morphine and tramadol significantly attenuated hyperalgesia and allodynia, while not significantly altering motor coordination/sedation. These data indicate dual mechanism therapeutics may be effective for treating pain associated with burns.

  20. Role of spinal GABAA receptor reduction induced by stress in rat thermal hyperalgesia.

    Science.gov (United States)

    Ma, Xuelian; Bao, Weiying; Wang, Xiujun; Wang, Zhilong; Liu, Qiaoran; Yao, Zhenyu; Zhang, Di; Jiang, Hong; Cui, Shuang

    2014-11-01

    The mechanisms underlying stress-induced hyperalgesia (SIH) remain poorly understood. Recent findings have provided strong evidence indicating that SIH could be related, at least in part, to alterations in spinal cord GABA activity. In the present study, we first investigated how acute restraint stress impacted pain responses as assessed using the tail flick immersion test. These results showed that rats developed hyperalgesia at 6 h after being subjected to 1-h acute restraint stress. Second, we measured the activation of spinal neurons and alterations in expression of GABAA receptor β2 and β3 subunits as related to stress-induced hyperalgesia. Results from Western blot and immunofluorescence assays showed that c-fos protein increased in the dorsal horn of the lumbar spinal cord and GABAA receptor β2 and β3 subunit proteins decreased significantly at 6 h after exposure to 1 h of acute restraint stress. Finally, the effects of spinal GABAA receptor alteration on SIH were evaluated. These results showed that intrathecal administration of muscimol inhibited hyperalgesia induced by stress while bicuculline enhanced hyperalgesia in the control groups. Taken together, the present data reveal that GABAA receptor β2 and β3 decrease following 1 h of acute restraint stress and may play a critical role in SIH.

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

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    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.

  2. Increases in PKC gamma expression in trigeminal spinal nucleus is associated with orofacial thermal hyperalgesia in streptozotocin-induced diabetic mice.

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    Xie, Hong-Ying; Xu, Fei; Li, Yue; Zeng, Zhao-Bin; Zhang, Ran; Xu, Hui-Jun; Qian, Nian-Song; Zhang, Yi-Guan

    2015-01-01

    Painful diabetic polyneuropathy (PDN) at the early phrase of diabetes frequently exhibits increased responsiveness to nociception. In diabetic patients and animal models, alterations in the transmission of orofacial sensory information have been demonstrated in trigeminal system. Herein, we examined the changes of protein kinase Cγ subunit (PKCγ) in trigeminal spinal nucleus (Sp5C) and observed the development of orofacial thermal sensitivity in streptozotocin (STZ)-induced type 1 diabetic mice. With hyperglycemia and body weight loss, STZ mice exhibited orofacial thermal hyperalgesia, along with increased PKCγ expression in Sp5C. Insulin treatment at the early stage of diabetes could alleviate the orofacial thermal hyperalgesia and impaired increased PKCγ in Sp5C in diabetic mice. In summary, our results demonstrate that PKCγ might be involved in orofacial thermal hyperalgesia of diabetes, and early insulin treatment might be effective way to treat orofacial PDN.

  3. Impaired nocifensive behaviours and mechanical hyperalgesia, but enhanced thermal allodynia in pituitary adenylate cyclase-activating polypeptide deficient mice.

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    Sándor, K; Kormos, V; Botz, B; Imreh, A; Bölcskei, K; Gaszner, B; Markovics, A; Szolcsányi, J; Shintani, N; Hashimoto, H; Baba, A; Reglodi, D; Helyes, Z

    2010-10-01

    Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and its receptors (PAC1 and VPAC) have been shown in the spinal dorsal horn, dorsal root ganglia and sensory nerve terminals. Data concerning the role of PACAP in central pain transmission are controversial and we have recently published its divergent peripheral effects on nociceptive processes. The aim of the present study was to investigate acute somatic and visceral nocifensive behaviours, partial sciatic nerve ligation-evoked chronic neuropathic, as well as resiniferatoxin-induced inflammatory thermal and mechanical hyperalgesia in PACAP deficient (PACAP(-/-)) mice to elucidate its overall function in pain transmission. Neuronal activation was investigated with c-Fos immunohistochemistry. Paw lickings in the early (0-5 min) and late (20-45 min) phases of the formalin test were markedly reduced in PACAP(-/-) mice. Acetic acid-evoked abdominal contractions referring to acute visceral chemonociception was also significantly attenuated in PACAP knockout animals. In both models, the excitatory role of PACAP was supported by markedly greater c-Fos expression in the periaqueductal grey and the somatosensory cortex. In PACAP-deficient animals neuropathic mechanical hyperalgesia was absent, while c-Fos immunopositivity 20 days after the operation was significantly higher. In this chronic model, these neurons are likely to indicate the activation of secondary inhibitory pathways. Intraplantarly injected resiniferatoxin-evoked mechanical hyperalgesia involving both peripheral and central processes was decreased, but thermal allodynia mediated by only peripheral mechanisms was increased in PACAP(-/-) mice. These data clearly demonstrate an overall excitatory role of PACAP in pain transmission originating from both exteroceptive and interoceptive areas, it is also involved in central sensitization. This can be explained by the signal transduction mechanisms of its identified receptors, both PAC1 and VPAC

  4. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition

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    Huynh Truc

    2007-12-01

    Full Text Available Abstract Mechanical hyperalgesia is a clinically-relevant form of pain sensitization that develops through largely unknown mechanisms. TRPA1, a Transient Receptor Potential ion channel, is a sensor of pungent chemicals that may play a role in acute noxious mechanosensation and cold thermosensation. We have developed a specific small molecule TRPA1 inhibitor (AP18 that can reduce cinnameldehyde-induced nociception in vivo. Interestingly, AP18 is capable of reversing CFA-induced mechanical hyperalgesia in mice. Although TRPA1-deficient mice develop normal CFA-induced hyperalgeisa, AP18 is ineffective in the knockout mice, consistent with an on-target mechanism. Therefore, TRPA1 plays a role in sensitization of nociception, and that compensation in TRPA1-deficient mice masks this requirement.

  5. Evodiamine suppresses capsaicin-induced thermal hyperalgesia through activation and subsequent desensitization of the transient receptor potential V1 channels.

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    Iwaoka, Emiko; Wang, Shenglan; Matsuyoshi, Nobuyuki; Kogure, Yoko; Aoki, Shunji; Yamamoto, Satoshi; Noguchi, Koichi; Dai, Yi

    2016-01-01

    Evodiae fructus (EF), a fruit of Evodia rutaecarpa Bentham, has long been used as an analgesic drug in traditional Chinese and Japanese medicine. However, the underlying molecular mechanism of its pharmacological action is unclear. Here, using calcium imaging, whole-cell patch-clamp recording, and behavioral analysis, we investigated the pharmacological action of EF and its principal compound, evodiamine, on the transient receptor potential (TRP) V1 channels. Dorsal root ganglion (DRG) neurons and TRPV1- or TRPA1-transfected human embryonic kidney-derived (HEK) 293 cells were used for calcium imaging or whole-cell patch-clamp recording. Twenty male adult Sprague-Dawley rats were used for the capsaicin-induced thermal hyperalgesia behavioral analyses. We found that evodiamine induced significant increases in intracellular calcium and robust inward currents in a subpopulation of isolated rat DRG neurons, most of which were also sensitive to capsaicin. The effect of evodiamine was completely blocked by capsazepine, a competitive antagonist of TRPV1. Evodiamine induced significant inward currents in TRPV1-, but not TRPA1-transfected HEK293 cells. Pretreatment with evodiamine reduced capsaicin-induced currents significantly. Furthermore, the in vivo pre-treatment of evodiamine suppressed thermal hyperalgesia induced by intraplantar injection of capsaicin in rats. These results identify that the analgesic effect of EF and evodiamine may be due to the activation and subsequent desensitization of TRPV1 in sensory neurons.

  6. Effects of Se-phenyl thiazolidine-4-carboselenoate on mechanical and thermal hyperalgesia in brachial plexus avulsion in mice: mediation by cannabinoid CB1 and CB2 receptors.

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    Del Fabbro, Lucian; Borges Filho, Carlos; Cattelan Souza, Leandro; Savegnago, Lucielli; Alves, Diego; Henrique Schneider, Paulo; de Salles, Helena Domingues; Jesse, Cristiano R

    2012-09-26

    In this study, we investigated the therapeutic effects of treatment with (R)-Se-phenyl thiazolidine-4-carboselenoate (Se-PTC), an organic selenium compound with antinociceptive properties, against mechanical and thermal hyperalgesia induced by brachial plexus avulsion (BPA), a neuropathic model in mice. The involvement of cannabinoid CB(1) and CB(2) receptors in the Se-PTC anti-hyperalgesic effect was also investigated. Se-PTC treatment at (25 and 50mg/kg, per oral, p.o.) lowered (BPA model) induced mechanical and thermal hyperalgesia in mice. Pretreatment with cannabinoid CB(1) (AM251; 1mg/kg, intraperitoneally, i.p.), or CB(2) (AM630; 3mg/kg, i.p.) receptor antagonists reverted the mechanical and thermal anti-hyperalgesic effect of Se-PTC (25mg/kg) in the BPA model. Selective CB(1) (ACEA, 10mg/kg, i.p.) and CB(2) (JWH-133, 10mg/kg, i.p.) receptor agonists lowered mechanical and thermal hyperalgesia in the BPA model, and this effect was prevented by selective CB(1) and CB(2) receptor antagonists. Gabapentin (70mg/kg, p.o.), positive control administration also lowered mechanical and thermal hyperalgesia in the BPA model. The results suggest that the mechanical and thermal hyperalgesia observed following BPA in mice is dependent on cannabinoid receptors. The results indicate that modulating cannabinoid receptors represent a valuable approach for the treatment of neuropathic pain. In conclusion, the results suggested that Se-PTC produces pronounced mechanical and thermal anti-hyperalgesic effects in neuropathic models in mice by modulating CB(1) and CB(2) receptors.

  7. Inhibition of osteosarcoma-induced thermal hyperalgesia in mice by the orally active dual enkephalinase inhibitor PL37. Potentiation by gabapentin.

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    Menéndez, Luis; Hidalgo, Agustín; Meana, Alvaro; Poras, Hervé; Fournié-Zaluski, Marie-Claude; Roques, Bernard P; Baamonde, Ana

    2008-10-31

    We have previously shown that stimulation of peripheral opioid receptors by exogenous opiates counteracts the thermal hyperalgesia elicited by a tibial osteosarcoma due to intraosteal inoculation of NCTC 2472 cells to mice. Aiming to study whether pheripheral endogenous enkephalins could also counteract this painful symptom, we assayed in this model the effects of PL37, an orally active dual inhibitor of enkephalin inactivating enzymes. Oral administration of PL37 (25 mg/kg) completely supressed osteosarcoma-induced thermal hyperalgesia through the activation of micro-opioid receptors, since the administration of cyprodime (1 mg/kg) inhibited its antihyperalgesic effect. Neither naltrindole (0.1 mg/kg) nor nor-binaltorphimine (10 mg/kg) modified this PL37-induced antihyperalgesic effect. Moreover, the inhibition of the antihyperalgesic effect induced by PL37 after the administration of naloxone-methiodide (2 mg/kg), a non selective opioid antagonist that does not cross the blood-brain barrier, demonstrates the involvement of peripheral opioid receptors. In contrast, centrally mediated effects may be detected when assaying a higher dose of PL37 (50 mg/kg). Besides, the administration of gabapentin (6.25-25 mg/kg, i.p.) dose-dependently inhibited osteosarcoma-induced thermal hyperalgesia. Interestingly, the combined administration of subeffective doses of PL37 and gabapentin completely prevented this type of thermal hyperalgesia. An isobolographic analysis of this interaction demonstrated a synergistic interaction between both drugs.

  8. Involvement of TRPV4-NO-cGMP-PKG pathways in the development of thermal hyperalgesia following chronic compression of the dorsal root ganglion in rats.

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    Ding, Xin-Li; Wang, Yong-Hui; Ning, Li-Ping; Zhang, Yang; Ge, Hong-You; Jiang, Hong; Wang, Rong; Yue, Shou-Wei

    2010-03-17

    The aim of the present study was to test the hypothesis that the TRPV4-NO-cGMP-PKG cascade is involved in the maintenance of thermal hyperalgesia following chronic compression of the dorsal root ganglion (DRG) (the procedure hereafter termed CCD) in rats. CCD rats showed thermal hyperalgesia and increased nitrite production. Intrathecal administration of ruthenium red (TRPV4 antagonist, 0.1-1 nmol), TRPV4 antisense ODN (TRPV4 AS, 40 microg, daily for 7 days), N(G)-L-nitro-arginine methyl ester (l-NAME, inhibitor of NO synthase, 30-300 nmol), 1H-[1,2,4]-oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, a soluble guanylate cyclase inhibitor, 50-100 nmol) or 8-(4-Chlorophenylthio) guanosine 3',5'-cyclic Monophosphothioate, Rp-Isomer sodium salt (Rp-8-pCPT-cGMPS, a PKG inhibitor, 25-50 nmol) induced a significant (Pthermal hyperalgesia and nitrite production. Our data suggested that the TRPV4-NO-cGMP-PKG pathway could be involved in CCD-induced thermal hyperalgesia.

  9. Impaired inflammatory pain and thermal hyperalgesia in mice expressing neuron-specific dominant negative mitogen activated protein kinase kinase (MEK

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    Kaplan David

    2006-01-01

    Full Text Available Abstract Background Numerous studies have implicated spinal extracellular signal-regulated kinases (ERKs as mediators of nociceptive plasticity. These studies have utilized pharmacological inhibition of MEK to demonstrate a role for ERK signaling in pain, but this approach cannot distinguish between effects of ERK in neuronal and non-neuronal cells. The present studies were undertaken to test the specific role of neuronal ERK in formalin-induced inflammatory pain. Dominant negative MEK (DN MEK mutant mice in which MEK function is suppressed exclusively in neurons were tested in the formalin model of inflammatory pain. Results Formalin-induced second phase spontaneous pain behaviors as well as thermal hyperalgesia measured 1 – 3 hours post-formalin were significantly reduced in the DN MEK mice when compared to their wild type littermate controls. In addition, spinal ERK phosphorylation following formalin injection was significantly reduced in the DN MEK mice. This was not due to a reduction of the number of unmyelinated fibers in the periphery, since these were almost double the number observed in wild type controls. Further examination of the effects of suppression of MEK function on a downstream target of ERK phosphorylation, the A-type potassium channel, showed that the ERK-dependent modulation of the A-type currents is significantly reduced in neurons from DN MEK mice compared to littermate wild type controls. Conclusion Our results demonstrate that the neuronal MEK-ERK pathway is indeed an important intracellular cascade that is associated with formalin-induced inflammatory pain and thermal hyperalgesia.

  10. Exogenous melatonin abolishes mechanical allodynia but not thermal hyperalgesia in neuropathic pain. The role of the opioid system and benzodiazepine-gabaergic mechanism.

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    Zurowski, D; Nowak, L; Machowska, A; Wordliczek, J; Thor, P J

    2012-12-01

    Melatonin (MT) is a neurohormone synthesized and secreted by the pineal gland. MT plays an important role in the regulation of physiological and neuroendocrine functions. The purpose of this study was to assess the overall effect of melatonin on neuropathic pain, the type of melatonin receptor involved, and potential role of the opioid system and GABA(A) receptors. The experiments were conducted by using the animal neuropathic pain model (CCI). The rats with CCI showed the characteristic for the mechanical allodynia and thermal hyperalgesia signs that were calculated by using the von Frey's and Hargreaves' tests. The conducted studies measured the effects of intraperitoneal administration of naloxone (opioid antagonist), prazosin (MT3 antagonist), luzindole (MT1/MT2 receptor antagonist), picrotoxin (GABA(A) antagonist) and flumazenil (benzodiazepine antagonist) on the antinociceptive effects caused by melatonin. Melatonin caused the increase in the pain threshold of the mechanical allodynia and the slight increase in the threshold of the thermal hyperalgesia. The pre-treatment with naloxone completely abolished the antinociceptive effects of melatonin in von Frey's test, but not thermal sensation in the Hargreaves's test. Prazosin did not have any effects, while administration of luzindole significantly suppressed the antinociceptive effect of melatonin. The antiallodynic effect of MT was also abolished by flumazenil and picrotoxin. Melatonin influences the mechanical allodynia but not thermal hyperalgesia via activation of opioid system and benzodiazepine-GABAergic pathway. Antinociceptive effects of melatonin are mostly related to the MT1/MT2 receptors interaction.

  11. Nuclear factor-kappa B mediates TRPV4-NO pathway involved in thermal hyperalgesia following chronic compression of the dorsal root ganglion in rats.

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    Wang, Chao; Ning, Li-Ping; Wang, Yong-Hui; Zhang, Yang; Ding, Xin-Li; Ge, Hong-You; Arendt-Nielsen, Lars; Yue, Shou-Wei

    2011-08-01

    The aim of this study was to test the hypothesis that nuclear factor-kappa B (NF-κB) is involved in TRPV4-NO pathway in thermal hyperalgesia following chronic compression of the dorsal root ganglion (DRG) (the procedure hereafter termed CCD) in rat. Intrathecal administration of two NF-κB inhibitors, pyrrolidine dithiocarbamate (PDTC; 10(-1) to 10(-2)M) and BAY (100-50 μM), both induced significantly dose-dependent increase in the paw withdrawal latency (PWL) and decrease in nitric oxide (NO) content in DRG when compared with control rats. Pretreatment with 4α-phorbol 12,13-didecanoate (4α-PDD, transient receptor potential vanilloid 4 (TRPV4) synthetic activator, 1 nm) attenuated the suppressive effects of PDTC (10(-1)M) and BAY (100 μM) on CCD-induced thermal hyperalgesia and NO production. In addition, Western blot analysis indicated that CCD rats exhibited nuclear NF-κB protein expression and low levels of cytoplasmic inhibitory-kappa B (I-κB) expression; the increase in NF-κB expression and decrease in I-κB expression were reversed after intrathecal injection of PDTC. In conclusion, our data suggested that NF-κB could be involved in TRPV4-NO pathway in CCD-induced thermal hyperalgesia.

  12. Tumour necrosis factor alpha mediates transient receptor potential vanilloid 1-dependent bilateral thermal hyperalgesia with distinct peripheral roles of interleukin-1beta, protein kinase C and cyclooxygenase-2 signalling.

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    Russell, Fiona A; Fernandes, Elizabeth S; Courade, Jean-Philippe; Keeble, Julie E; Brain, Susan D

    2009-04-01

    TNFalpha plays a pivotal role in rheumatoid arthritis (RA) but little is known of the mechanisms that link the inflammatory and nociceptive effects of TNFalpha. We have established a murine model of TNFalpha-induced TRPV1-dependent bilateral thermal hyperalgesia that then allowed us to identify distinct peripheral mechanisms involved in mediating TNFalpha-induced ipsilateral and contralateral hyperalgesia. Thermal hyperalgesia and inflammation were assessed in both hindpaws following unilateral intraplantar (i.pl.) TNFalpha. The hyperalgesic mechanisms were analysed through pharmacogenetic approaches involving TRPV1(-/-) mice and TRPV1 antagonists. To study the mediators downstream of TNFalpha, cyclooxygenase (COX) and PKC inhibitors were utilised and cytokine and prostaglandin levels assessed. The role of neutrophils was determined through use of the selectin inhibitor, fucoidan. We show that TNFalpha (10pmol) causes thermal hyperalgesia (1-4h) in the ipsilateral inflamed and contralateral uninjured hindpaws, which is TRPV1-dependent. GF109203X, a PKC inhibitor, suppressed the hyperalgesia indicating that PKC is involved in TRPV1 sensitisation. Ipsilateral COX-2-derived prostaglandins were also crucial to the development of the bilateral hyperalgesia. The prevention of neutrophil accumulation with fucoidan attenuated hyperalgesia at 4 but not at 1h, indicating a role in the maintenance but not in the induction of bilateral hyperalgesia. However, TNFalpha-induced IL-1beta generation in both paws and the presence of local IL-1beta in the contralateral paw were essential for the development of bilateral hyperalgesia. These results identify a series of peripheral events through which TNFalpha triggers and maintains bilateral inflammatory pain. This potentially allows a better understanding of mechanisms involved in TNFalpha-dependent pain pathways in symmetrical diseases such as arthritis.

  13. LVV-hemorphin 7 and angiotensin IV in correlation with antinociception and anti-thermal hyperalgesia in rats.

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    Cheng, Bor-Chih; Tao, Pao-Luh; Cheng, Ya-Yun; Huang, Eagle Yi-Kung

    2012-07-01

    Hemorphins, a family of atypical endogenous opioid peptides, are produced by the cleavage of hemoglobin β-chain. Hemorphins were proved to bind to the μ-opioid receptors (agonist) and angiotensin IV receptors (insulin-regulated aminopeptidase; IRAP) (inhibitor). Among the hemorphins, LVV-hemorphin-7 (LVV-H7) was found to be abundant and with a longer half life in the CNS. Using intrathecal and intracerebroventricular injections, LVV-H7 and angiotensin IV were given to the rats, which were then subjected to the plantar test and the tail-flick test. Our results showed that LVV-H7 attenuated carrageenan-induced hyperalgesia at the spinal level, which could not be reversed by the co-administration of naloxone. At the supraspinal level, LVV-H7 also produced a significant anti-hyperalgesia effect but with a lower extent. Angiotensin IV showed a similar anti-hyperalgesia effect at the spinal level, but had no effect at the supraspinal level. In the tail-flick test and paw edema test, both peptides showed no effect. These results suggest that LVV-H7 mainly exert the anti-hyperalgesia effect at the spinal level, possibly through IRAP but not μ-opioid receptors. In addition, we observed the expression of IRAP in the CNS of animals with/without carrageenan-induced hyperalgesia. Our results showed a significant expression of IRAP in the spinal cord of rats. However, there was no significant quantitative change of IRAP after the development of hyperalgesia. The serum level of LVV-H7 was also found to be with no change caused by hyperalgesia. These results indicated that the endogenous LVV-H7 and IRAP may not regulate the severity of hyperalgesia through a quantitative change.

  14. Repeated forced swim stress enhances CFA-evoked thermal hyperalgesia and affects the expressions of pCREB and c-Fos in the insular cortex.

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    Imbe, H; Kimura, A; Donishi, T; Kaneoke, Y

    2014-02-14

    Stress affects brain activity and promotes long-term changes in multiple neural systems. Exposure to stressors causes substantial effects on the perception and response to pain. In several animal models, chronic stress produces lasting hyperalgesia. The insular (IC) and anterior cingulate cortices (ACC) are the regions exhibiting most reliable pain-related activity. And the IC and ACC play an important role in pain modulation via the descending pain modulatory system. In the present study we examined the expression of phospho-cAMP response element-binding protein (pCREB) and c-Fos in the IC and ACC after forced swim stress (FS) and complete Freund's adjuvant (CFA) injection to clarify changes in the cerebral cortices that affect the activity of the descending pain modulatory system in the rats with stress-induced hyperalgesia. FS (day 1, 10min; days 2-3, 20min) induced an increase in the expression of pCREB and c-Fos in the anterior IC (AIC). CFA injection into the hindpaw after the FS shows significantly enhanced thermal hyperalgesia and induced a decrease in the expression of c-Fos in the AIC and the posterior IC (PIC). Quantitative image analysis showed that the numbers of c-Fos-immunoreactive neurons in the left AIC and PIC were significantly lower in the FS+CFA group (L AIC, 95.9±6.8; L PIC, 181.9±23.1) than those in the naive group (L AIC, 151.1±19.3, pthermal hyperalgesia through dysfunction of the descending pain modulatory system.

  15. Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia.

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    Segond von Banchet, Gisela; Boettger, Michael K; König, Christian; Iwakura, Yoichiro; Bräuer, Rolf; Schaible, Hans-Georg

    2013-01-01

    In addition to the proinflammatory cytokines tumor necrosis factor-α, interleukin-6 and interleukin-1ß, the cytokine interleukin-17 (IL-17) is considered an important mediator of autoimmune diseases such as rheumatoid arthritis. Because tumor necrosis factor-α and interleukin-1ß have the potential to influence the expression of transduction molecules such as transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion (DRG) neurons and thus to contribute to pain we explored in the present study whether IL-17A activates DRG neurons and influences the expression of TRPV1. The IL-17A receptor was visualized in most neurons in dorsal root ganglion (DRG) sections as well as in cultured DRG neurons. Upon long-term exposure to IL-17A, isolated and cultured rat DRG neurons showed a significant upregulation of extracellular-regulated kinase (ERK) and nuclear factor κB (NFκB). Long-term exposure of neurons to IL-17A did not upregulate the expression of TRPV1. However, we found a pronounced upregulation of transient receptor potential vanilloid 4 (TRPV4) which is considered a candidate transduction molecule for mechanical hyperalgesia. Upon the injection of zymosan into the paw, IL-17A-deficient mice showed less mechanical hyperalgesia than wild type mice but thermal hyperalgesia was not attenuated in IL-17A-deficient mice. These data show, therefore, a particular role of IL-17 in mechanical hyperalgesia, and they suggest that this effect is linked to an activation and upregulation of TRPV4.

  16. Activation of JNK pathway in spinal astrocytes contributes to acute ultra-low-dose morphine thermal hyperalgesia.

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    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.

  17. Disruption of δ-opioid receptor phosphorylation at Threonine 161 attenuates morphine tolerance in rats with CFA-induced inflammatory hypersensitivity

    Institute of Scientific and Technical Information of China (English)

    Hai-Jing Chen; Wei-Yan Xie; Fang Hu; Ying Zhang; Jun Wang; Yun Wang

    2012-01-01

    Objective Our previous study identified Threonine 161 (Thr-161),located in the second intracellular loop of the δ-opioid receptor (DOR),as the only consensus phosphorylation site for cyclin-dependent kinase 5 (Cdk5).The aim of this study was to assess the function of DOR phosphorylation by Cdk5 in complete Freund's adjuvant (CFA)-induced inflammatory pain and morphine tolerance.Methods Dorsal root ganglion (DRG) neurons of rats with CFA-induced inflammatory pain were acutely dissociated and the biotinylation method was used to explore the membrane localization of phosphorylated DOR at Thr-161 (pThr-161-DOR),and paw withdrawal latency was measured after intrathecal delivery of drugs or Tat-peptide,using a radiant heat stimulator in rats with CFA-induced inflammatory pain.Results Both the total amount and the surface localization of pThr-161-DOR were significantly enhanced in the ipsilateral DRG following CFA injection.Intrathecal delivery of the engineered Tat fusion-interefering peptide corresponding to the second intracellular loop of DOR (Tat-DOR-2L) increased inflammatory hypersensitivity,and inhibited DOR-but not μ-opioid receptor-mediated spinal analgesia in CFA-treated rats.However,intrathecal delivery of Tat-DOR-2L postponed morphine antinociceptive tolerance in rats with CFA-induced inflammatory pain.Conclusion Phosphorylation of DOR at Thr-161 by Cdk5 attenuates hypersensitivity and potentiates morphine tolerance in rats with CFA-induced inflammatory pain,while disruption of the phosphorylation of DOR at Thr-161 attenuates morphine tolerance.

  18. Nuclear factor-kappa B decoy suppresses nerve injury and improves mechanical allodynia and thermal hyperalgesia in a rat lumbar disc herniation model.

    Science.gov (United States)

    Suzuki, Munetaka; Inoue, Gen; Gemba, Takefumi; Watanabe, Tomoko; Ito, Toshinori; Koshi, Takana; Yamauchi, Kazuyo; Yamashita, Masaomi; Orita, Sumihisa; Eguchi, Yawara; Ochiai, Nobuyasu; Kishida, Shunji; Takaso, Masashi; Aoki, Yasuchika; Takahashi, Kazuhisa; Ohtori, Seiji

    2009-07-01

    Nuclear factor-kappa B (NF-kappaB) is a gene transcriptional regulator of inflammatory cytokines. We investigated the transduction efficiency of NF-kappaB decoy to dorsal root ganglion (DRG), as well as the decrease in nerve injury, mechanical allodynia, and thermal hyperalgesia in a rat lumbar disc herniation model. Forty rats were used in this study. NF-kappaB decoy-fluorescein isothiocyanate (FITC) was injected intrathecally at the L5 level in five rats, and its transduction efficiency into DRG measured. In another 30 rats, mechanical pressure was placed on the DRG at the L5 level and nucleus pulposus harvested from the rat coccygeal disc was transplanted on the DRG. Rats were classified into three groups of ten animals each: a herniation + decoy group, a herniation + oligo group, and a herniation only group. For behavioral testing, mechanical allodynia and thermal hyperalgesia were evaluated. In 15 of the herniation rats, their left L5 DRGs were resected, and the expression of activating transcription factor 3 (ATF-3) and calcitonin gene-related peptide (CGRP) was evaluated immunohistochemically compared to five controls. The total transduction efficiency of NF-kappaB decoy-FITC in DRG neurons was 10.8% in vivo. The expression of CGRP and ATF-3 was significantly lower in the herniation + decoy group than in the other herniation groups. Mechanical allodynia and thermal hyperalgesia were significantly suppressed in the herniation + decoy group. NF-kappaB decoy was transduced into DRGs in vivo. NF-kappaB decoy may be useful as a target for clarifying the mechanism of sciatica caused by lumbar disc herniation.

  19. The pain pathway in the rat following noxious thermal stimulation: effect of morphine on pERK1/2 and TRPV1 at the dorsal horn level, and on hyperalgesia.

    Science.gov (United States)

    Donnerer, Josef; Liebmann, Ingrid

    2013-01-01

    The aim of the present study was to investigate the phosphorylation of ERK1/2 in the lumbar dorsal horn of the rat by fluorescence immunohistochemistry following a noxious thermal stimulation of the hind paw. The protein level of TRPV1 in the dorsal spinal cord and the development of a heat hyperalgesia after the acute noxious thermal stimulation were also measured. The protein content of TRPV1 was determined by Western blot and heat hyperalgesia by the plantar test. At 2 and 10 min after the thermal stimulation a 4-fold increase in pERK1/2 immunoreactivity was observed in cells of lamina I/II of the L3-L5 dorsal horn. A pretreatment with the opioid analgesic morphine markedly attenuated ERK1/2 phosphorylation. The protein content of TRPV1 in the lumbar dorsal spinal cord was not significantly altered at 1 and 4 h after the thermal hind paw stimulation and by the morphine pretreatment. Heat hyperalgesia in the plantar test was observed at 8 h, but not at 24 h after the noxious stimulation. This temporary hyperalgesia was prevented by the morphine pretreatment. The present findings indicate that ERK1/2 activation in dorsal horn nociceptive neurons may be linked to the development of hyperalgesia, and that opioid analgesics are effective agents to prevent sensitization in the pain pathway at spinal level.

  20. Docosahexaenoic acid inhibits mechanical allodynia and thermal hyperalgesia in diabetic rats by decreasing the excitability of DRG neurons.

    Science.gov (United States)

    Heng, Li-Jun; Qi, Rui; Yang, Rui-Hua; Xu, Guo-Zheng

    2015-09-01

    Diabetes mellitus is a common metabolic disease in human beings with characteristic symptoms of hyperglycemia, chronic inflammation and insulin resistance. One of the most common complications of early-onset diabetes mellitus is peripheral diabetic neuropathy, which is manifested either by loss of nociception or by allodynia and hyperalgesia. Dietary fatty acids, especially polyunsaturated fatty acids, have been shown the potential of anti-inflammation and modulating neuron excitability. The present study investigated the effects of docosahexaenoic acid (DHA) on the excitability of dorsal root ganglion (DRG) neurons in streptozotocin (STZ)-induced diabetes rats. The effects of DHA on the allodynia and hyperalgesia of diabetic rats were also evaluated. Dietary DHA supplementation effectively attenuated both allodynia and hyperalgesia induced by STZ injection. DHA supplementation decreased the excitability of DRG neurons by decreasing the sodium currents and increasing potassium currents, which may contribute to the effect of alleviating allodynia and hyperalgesia in diabetic rats. The results suggested that DHA might be useful as an adjuvant therapy for the prevention and treatment of painful diabetic neuropathy.

  1. Intrathecal neurosteroids and a neurosteroid antagonist: effects on inflammation-evoked thermal hyperalgesia and tactile allodynia.

    Science.gov (United States)

    Svensson, Elin; Persson, Josefin; Fitzsimmons, Bethany; Yaksh, Tony L

    2013-08-26

    Neurosteroids regulate neuronal excitability though binding sites associated with the ionotropic γ-aminobutyric acid (GABAA) receptor. We sought to characterize the spinal analgesic actions in rats of two 5α-reduced neurosteroids, allopregnanolone and alphaxalone, on nociceptive processing and to determine whether a putative neurosteroid antagonist attenuates this effect: (3α,5α)-17-phenylandrost-16-en-3-ol (17PA). Intrathecal (IT) injection of allopregnanolone (1-30 μg/10 μL in 20% cyclodextrin) delivered through lumbar catheters produced a dose-dependent analgesia in rats as measured by thermal thresholds in the ipsilateral (inflamed by intraplantar carrageenan) and in the contralateral (un-inflamed paws). Similar observations were made with alphaxalone (30-60 μg in 20% cyclodextrin). Effective doses were not associated with suppressive effects on pinnae, blink or placing and stepping reflex. Effects of allopregnanolone (30 μg) on the normal and hyperalgesic paw were completely prevented by IT 17PA (30 μg). Reversal by IT 17PA of an equi-analgesic dose of alphaxalone occurred only at higher antagonist dosing. These results suggest that a spinal neurosteroid-binding site with which 17PA interacts may regulate spinal nociceptive processing in normal and inflamed tissue.

  2. A subset of μ-opioid receptor-expressing cells in the rostral ventromedial medulla contribute to thermal hyperalgesia in experimental neuropathic pain.

    Science.gov (United States)

    Mase, Hiroshi; Sakai, Atsushi; Sakamoto, Atsuhiro; Suzuki, Hidenori

    2011-05-01

    The rostral ventromedial medulla (RVM) is a major region for the descending modulation of pain at the spinal cord level, and neurons in the RVM have been implicated in the inhibition and facilitation of spinal nociceptive transmission. Although recent studies have established that the RVM facilitation of nociceptive transmission in the spinal cord contributes to neuropathic pain, the underlying mechanisms remain largely unknown. In the present study, we investigated the effects of kainic acid (KA)-induced RVM damage on neuropathic pain behavior and the expression of molecules implicated in pain modulation. KA was injected into the RVM midline region after neuropathic pain was established by chronic constrictive injury of the left sciatic nerve. Thermal hyperalgesia, but not mechanical allodynia, was persistently suppressed in the ipsilateral paw by a single KA injection into the RVM for at least the next 7 days in a rat neuropathic pain model. KA injection alone did not affect the nocifensive responses to mechanical and thermal stimuli on the intact side. Immunohistochemical analysis revealed that KA injection into the RVM significantly reduced the number of immunoreactive neurons for μ-opioid receptors, but not tryptophan hydroxylase, in association with the analgesic effect. These results suggest that a subset of RVM neurons expressing μ-opioid receptors contribute to the maintenance of thermal hyperalgesia in neuropathic pain.

  3. Sex differences in hypothalamic-mediated tonic norepinephrine release for thermal hyperalgesia in rats.

    Science.gov (United States)

    Wagner, M; Banerjee, T; Jeong, Y; Holden, J E

    2016-06-02

    Neuropathic pain is treated using serotonin norepinephrine reuptake inhibitors with mixed results. Pain facilitation mediated by α1-adrenoceptors may be involved, but whether norepinephrine (NE) is tonically released is unclear. The aim of this study was to determine whether NE is tonically released from A7 cells following chronic constriction injury (CCI), and if the lateral hypothalamus (LH) plays a role in this release in male and female rats with nociceptive and neuropathic pain types. Neuropathic groups received left CCI while nociceptive groups remained naïve to injury. Fourteen days later, rats were given intrathecal infusion of either the α1-adrenoceptor antagonist WB4101, the α2-adrenoceptor antagonist yohimbine (74 μg), or normal saline for control. Paw withdrawal latency (PWL) from a thermal stimulus was measured. The generalized estimated equation method was used for statistical analysis. Nociceptive rats given WB4101 had a PWL significantly longer than saline control (7.89 ± 0.63 vs. 5.87 ± 0.52 s), while the PWL of neuropathic rats given WB4101 was 13.20 ± 0.52 s compared to 6.78 ± 0.52 s for the saline control rats. Yohimbine had no significant effect. Microinjection of cobalt chloride (CoCl) in the A7 catecholamine cell group to prevent synaptic transmission blocked the effect of WB4101 in all groups, supporting the notion that spinally descending A7 cells tonically release NE that contributes to α1-mediated nociceptive facilitation. Microinjection of CoCl into the left LH blocked the effect of WB4101 in nociceptive and neuropathic male rats, but had no effect in female rats of either pain type, suggesting differential innervation. These findings indicate that tonic release of NE acts at pronociceptive α1-adrenoceptors, that this effect is greater in rats with nerve damage, and that, while NE comes primarily from the A7 cell group, LH innervation of the A7 cell group is different between the sexes.

  4. Relation cellular- molecular between serum IL10 levels and hyperalgesia variation in adjuvant- induced arthritis

    Directory of Open Access Journals (Sweden)

    Zenab Akhtari

    2015-01-01

    Full Text Available Background: Regarding to the important anti-inflammatory role of IL10 during inflammation process and hyperalgesia and edema variation during CFA-induced arthritis and also the increase of Spinal mu opioid receptor (mOR expression, in this study researchers investigate the role of serum IL10 level on mOR expression and edema and hyperalgesia variation during different stages of Complete Freund`s Adjuvant (CFA - induced arthritis in male Wistar rats. Materials and Methods: Mono-arthritis was induced by CFA and inflammatory symptoms (hyperalgesia and edema were assessed on 0, 3, 7, 14th and 21st days of study. Anti-IL10 was administered during the 21 days of study in different experimental groups. mOR expression were detected by western blotting on 0, 3,7, 14th and 21st days of study. Data was analyzed by SPSS statistical software version 19 with using one way ANOVA (post hoc Tokey's. Results: Our results showed that anti-IL10 administration in AA group (Adjuvant Arthritis caused an increase in the paw volume and hyperalgesia until 21st of study. Our study stated that there were no significant differences in spinal mOR expression between AA and AA+anti-IL10rats. Conclusion: Our study confirmed that anti-IL10administration caused to hyperalgesia and edema during AA inflammation. Also these findings suggested that mOR expression increased in chronic phase of AA inflammation, however an increase in the level of spinal mu opioid receptor (mOR expression during AA inflammation is not mediated directly via the effect of serum IL-10.

  5. Electroacupuncture Attenuates CFA-induced Inflammatory Pain by suppressing Nav1.8 through S100B, TRPV1, Opioid, and Adenosine Pathways in Mice

    Science.gov (United States)

    Liao, Hsien-Yin; Hsieh, Ching-Liang; Huang, Chun-Ping; Lin, Yi-Wen

    2017-01-01

    Pain is associated with several conditions, such as inflammation, that result from altered peripheral nerve properties. Electroacupuncture (EA) is a common Chinese clinical medical technology used for pain management. Using an inflammatory pain mouse model, we investigated the effects of EA on the regulation of neurons, microglia, and related molecules. Complete Freund’s adjuvant (CFA) injections produced a significant mechanical and thermal hyperalgesia that was reversed by EA or a transient receptor potential V1 (TRPV1) gene deletion. The expression of the astrocytic marker glial fibrillary acidic protein (GFAP), the microglial marker Iba-1, S100B, receptor for advanced glycation end-products (RAGE), TRPV1, and other related molecules was dramatically increased in the dorsal root ganglion (DRG) and spinal cord dorsal horn (SCDH) of CFA-treated mice. This effect was reversed by EA and TRPV1 gene deletion. In addition, endomorphin (EM) and N6-cyclopentyladenosine (CPA) administration reliably reduced mechanical and thermal hyperalgesia, thereby suggesting the involvement of opioid and adenosine receptors. Furthermore, blocking of opioid and adenosine A1 receptors reversed the analgesic effects of EA. Our study illustrates the substantial therapeutic effects of EA against inflammatory pain and provides a novel and detailed mechanism underlying EA-mediated analgesia via neuronal and non-neuronal pathways. PMID:28211895

  6. The RhoA GTPase-activating protein DLC2 modulates RhoA activity and hyperalgesia to noxious thermal and inflammatory stimuli.

    Science.gov (United States)

    Chan, Fred K C; Chung, Stephen S M; Ng, Irene O; Chung, Sookja K

    2012-01-01

    Deleted in liver cancer 2 (DLC2) is a novel Rho GTPase-activating protein that regulates RhoA activity. DLC2 is ubiquitously expressed in most tissues, including the brain, spinal cord and peripheral nerves, and is thought to be involved in actin cytoskeletal reorganization. Unlike DLC1-deficient mice, DLC2-deficient mice (DLC2(-/-)) are viable and without gross anatomical abnormalities. Interestingly, DLC2(-/-) mice exhibit hyperalgesia to noxious thermal stimuli and inflammation-inducing chemicals, such as formalin and acetic acid. There was no difference in the structure or morphology of cutaneous or sural nerves between DLC2(+/+) and DLC2(-/-) mice. However, sensory nerve conduction velocity in DLC2(-/-) mice was significantly higher than that in DLC2(+/+) mice, whereas motor nerve conduction velocity was not affected. After formalin injection, DLC2(-/-) mice showed increased RhoA activity in the spinal cord and an increased number of phosphorylated ERK1/2-positive cells. The inflammatory hyperalgesia in DLC2(-/-) mice appeared to be mediated through the activation of RhoA and ERK1/2. Taken together, DLC2 plays a key role in pain modulation during inflammation by suppressing the activation of RhoA and ERK to prevent an exaggerated pain response, and DLC2(-/-) mice provide a valuable tool for further understanding the regulation of inflammatory pain.

  7. Cutaneous C-polymodal fibers lacking TRPV1 are sensitized to heat following inflammation, but fail to drive heat hyperalgesia in the absence of TPV1 containing C-heat fibers

    Directory of Open Access Journals (Sweden)

    Koerber H Richard

    2010-09-01

    Full Text Available Abstract Background Previous studies have shown that the TRPV1 ion channel plays a critical role in the development of heat hyperalgesia after inflammation, as inflamed TRPV1-/- mice develop mechanical allodynia but fail to develop thermal hyperalgesia. In order to further investigate the role of TRPV1, we have used an ex vivo skin/nerve/DRG preparation to examine the effects of CFA-induced-inflammation on the response properties of TRPV1-positive and TRPV1-negative cutaneous nociceptors. Results In wildtype mice we found that polymodal C-fibers (CPMs lacking TRPV1 were sensitized to heat within a day after CFA injection. This sensitization included both a drop in average heat threshold and an increase in firing rate to a heat ramp applied to the skin. No changes were observed in the mechanical response properties of these cells. Conversely, TRPV1-positive mechanically insensitive, heat sensitive fibers (CHs were not sensitized following inflammation. However, results suggested that some of these fibers may have gained mechanical sensitivity and that some previous silent fibers gained heat sensitivity. In mice lacking TRPV1, inflammation only decreased heat threshold of CPMs but did not sensitize their responses to the heat ramp. No CH-fibers could be identified in naïve nor inflamed TRPV1-/- mice. Conclusions Results obtained here suggest that increased heat sensitivity in TRPV1-negative CPM fibers alone following inflammation is insufficient for the induction of heat hyperalgesia. On the other hand, TRPV1-positive CH fibers appear to play an essential role in this process that may include both afferent and efferent functions.

  8. Effects of target-controlled infusion of high-dose naloxone on pain and hyperalgesia in a human thermal injury model: a study protocol

    Science.gov (United States)

    Springborg, Anders D.; Jensen, Elisabeth K.; Taylor, Bradley K.; Werner, Mads U.

    2016-01-01

    Abstract Mu-opioid-receptor antagonists have been extensively studied in experimental research as pharmacological tools uncovering mechanisms of pain modulation by the endogenous opioid system. In rodents, administration of high doses of mu-opioid-receptor antagonists after the resolution of an inflammatory injury has demonstrated reinstatement of nociceptive hypersensitivity indicating unmasking of latent sensitization. In a recent human study, pain hypersensitivity assessed as secondary hyperalgesia area (SHA), was reinstated 7 days after a mild thermal injury, in 4 out of 12 subjects after a naloxone infusion. The aims of the present study are first, to replicate our previous findings in a larger-sized study; second, to examine if high sensitizers (subjects presenting with large SHA after a thermal injury) develop a higher degree of hypersensitivity after naloxone challenge than low sensitizers (subjects presenting with restricted SHA after a thermal injury); and third to examine a dose–response relationship between 3 stable naloxone concentrations controlled by target-controlled infusion, and the unmasking of latent sensitization. Healthy participants (n = 80) underwent a screening day (day 0) with induction of a thermal skin injury (47°C, 420 seconds, 12.5 cm2). Assessment of SHA was performed 1 and 2 hours after the injury. Using an enriched design, only participants belonging to the upper quartile of SHA (Q4, high sensitizers; n = 20) and the lower quartile of SHA (Q1, low sensitizers; n = 20) continued the study, comprising 4 consecutive days—days 1 to 4. Thermal skin injuries were repeated on day 1 and day 3, whereas day 2 and day 4 (7 days after day 1 and day 3, respectively) were target-controlled infusion days in which the subjects were randomly allocated to receive either naloxone (3.25 mg/kg, 4 mg/mL) or placebo (normal saline) intravenous. The primary outcome was SHA assessed by weighted-pin instrument (128 mN) 0, 1, 2

  9. KYNA analogue SZR72 modifies CFA-induced dural inflammation- regarding expression of pERK1/2 and IL-1β in the rat trigeminal ganglion

    DEFF Research Database (Denmark)

    Lukács, M; Warfvinge, K; Kruse, L S

    2016-01-01

    modify the neurogenic inflammatory response in the trigeminal ganglion. METHODS: Inflammation in the trigeminal ganglion was induced by local dural application of Complete Freunds Adjuvant (CFA). Levels of phosphorylated MAP kinase pERK1/2 and IL-1β expression in V1 region of the trigeminal ganglion were...... investigated using immunohistochemistry and Western blot. FINDINGS: Pretreatment with one dose of SZR72 abolished the CFA-induced pERK1/2 and IL-1β activation in the trigeminal ganglion. No significant change was noted in case of repeated treatment with SZR72 as compared to a single dose. CONCLUSIONS...

  10. Supraspinal contributions to hyperalgesia

    OpenAIRE

    Urban, M. O.; Gebhart, G. F.

    1999-01-01

    Tissue injury is associated with sensitization of nociceptors and subsequent changes in the excitability of central (spinal) neurons, termed central sensitization. Nociceptor sensitization and central sensitization are considered to underlie, respectively, development of primary hyperalgesia and secondary hyperalgesia. Because central sensitization is considered to reflect plasticity at spinal synapses, the spinal cord has been the principal focus of studies of mechani...

  11. Forebrain overexpression of CaMKII abolishes cingulate long term depression and reduces mechanical allodynia and thermal hyperalgesia

    Directory of Open Access Journals (Sweden)

    Tsien Joe Z

    2006-06-01

    Full Text Available Abstract Activity-dependent synaptic plasticity is known to be important in learning and memory, persistent pain and drug addiction. Glutamate NMDA receptor activation stimulates several protein kinases, which then trigger biochemical cascades that lead to modifications in synaptic efficacy. Genetic and pharmacological techniques have been used to show a role for Ca2+/calmodulin-dependent kinase II (CaMKII in synaptic plasticity and memory formation. However, it is not known if increasing CaMKII activity in forebrain areas affects behavioral responses to tissue injury. Using genetic and pharmacological techniques, we were able to temporally and spatially restrict the over expression of CaMKII in forebrain areas. Here we show that genetic overexpression of CaMKII in the mouse forebrain selectively inhibits tissue injury-induced behavioral sensitization, including allodynia and hyperalgesia, while behavioral responses to acute noxious stimuli remain intact. CaMKII overexpression also inhibited synaptic depression induced by a prolonged repetitive stimulation in the ACC, suggesting an important role for CaMKII in the regulation of cingulate neurons. Our results suggest that neuronal CaMKII activity in the forebrain plays a role in persistent pain.

  12. Intrathecal administration of Cav3.2 and Cav3.3 antisense oligonucleotide reverses tactile allodynia and thermal hyperalgesia in rats following chronic compression of dorsal root of ganglion

    Institute of Scientific and Technical Information of China (English)

    Xian-jie WEN; Zhang-jun LI; Zhi-xin CHEN; Zhi-yuan FANG; Chen-xiang YANG; Heng LI; Yin-ming ZENG

    2006-01-01

    Aim: The present study aimed to elucidate the role of T-subtype calcium channels (Cav3.1, Cav3.2, and Cav3.3) in the pathogenesis of neuropathic pain at spinal level. Methods: The chronic compression of the dorsal root ganglion (CCD) rat model was adopted. The antisense oligonucleotide of Cav3.1, Cav3.2, and Cav3.3 or normal saline (NS) were intrathecally administered twice per day from the first day to the fourth day after operation. Paw mechanical withdrawal threshold and paw thermal withdrawal latency were measured to evaluate the tactile allodynia and thermal hyperalgesia, respectively. Results: CCD rats developed reliable tactile allodynia and thermal hyperalgesia after operation. Intrathecal administration of antisense oligonucleotide of Cav3.2 and Cav3.3 significantly relieved tactile allodynia and thermal hyperalgesia in CCD rats, but not Cav3.1. Conclusion: Cav2 and Cav3.3 subtype calcium channels in the spinal cord may play an important role in the pathogenesis of neuropathic pain, which may contribute to the management of the neuropathic pain.

  13. Pain Modulation by Lignans (Phyllanthin and Hypophyllanthin) and Tannin (Corilagin) Rich Extracts of Phyllanthus amarus in Carrageenan-induced Thermal and Mechanical Chronic Muscle Hyperalgesia.

    Science.gov (United States)

    Chopade, Atul R; Sayyad, F J

    2015-08-01

    The current study was aimed at evaluating the antihyperalgesic effects of lignans (phyllanthin and hypophyllanthin) and tannin (corilagin) rich three standardized extracts of Phyllanthus amarus in a model of chronic musculoskeletal inflammatory pain. Three percent carrageenan injected in the gastrocnemius muscle produced hyperalgesia to mechanical and heat stimuli ipsilaterally, which spreads to the contralateral side within 7 to 9 days. To investigate the effects on chronic thermal and mechanical hypersensitivity, three extracts of P. amarus in three doses (100, 200, and 400 mg/kg) were administered to animals intraperitoneally from 14th day to 22nd day after intramuscular injection of carrageenan. It was observed that intraperitoneal administrations of Phyllanthus extracts showed antihyperalgesic activity, as they elevated thermal and mechanical threshold, which was supported by histopathological observations along with reduction in prostaglandin E2 (PGE2) concentration. In conclusion, we strongly suggest that the observed antihyperalgesic and antiinflammatory effects of P. amarus in current pain model are mediated via spinal or supraspinal neuronal mechanisms, mainly by inhibition of PGE2. Modulation of chronic muscular inflammation may be due to presence of phytoconstituents like phyllanthin, hypophyllanthin, and corilagin, which offers a promising means for treatment of chronic muscle pain.

  14. Peripheral contributions to visceral hyperalgesia.

    Science.gov (United States)

    Gebhart, G F

    1999-03-01

    Hyperalgesia has long been recognized clinically as a consequence of tissue injury. Primary hyperalgesia (arising from the site of injury) is generally considered to be due to sensitization of sensory receptors (eg, nociceptors) and perhaps activation of so-called 'silent nociceptors' by mediators released, synthesized or attracted to the site of tissue injury. Key questions associated with understanding visceral hyperalgesia relate to whether the viscera are innervated by nociceptors (ie, sensory receptors that respond selectively to noxious intensities of stimulation), whether visceral receptors and/or afferent fibres sensitize after tissue injury and whether silent nociceptors exist in the viscera. Studies in nonhuman animals have revealed that hollow organs such as the esophagus, gall bladder, stomach, urinary bladder, colon and uterus are innervated by mechanically sensitive receptors with low or high thresholds for response. Accordingly, it appears that the viscera are innervated by nociceptors, although the issue is far from settled. One characteristic of cutaneous nociceptors is their ability to be sensitized when tissue is injured. Mechanosensitive visceral receptors also sensitize when the viscera are experimentally inflamed, but both visceral receptors with low thresholds and those with high thresholds for response are sensitized. Moreover, it is often not appreciated that visceral receptors are likely polymodal rather than unimodal - that is, mechanically sensitive visceral receptors typically are also sensitive to chemical and/or thermal stimuli. In this sense, visceral receptors may be considered evolutionarily older than more highly developed, specialized cutaneous receptors. Finally, there are mechanically insensitive receptors that innervate the viscera and, when tissue is injured, develop spontaneous activity and acquire sensitivity to mechanical stimuli. In the aggregrate, visceral receptors change their behaviour in the presence of tissue injury

  15. Blockade of peripheral P2Y1 receptors prevents the induction of thermal hyperalgesia via modulation of TRPV1 expression in carrageenan-induced inflammatory pain rats: involvement of p38 MAPK phosphorylation in DRGs.

    Science.gov (United States)

    Kwon, Soon-Gu; Roh, Dae-Hyun; Yoon, Seo-Yeon; Moon, Ji-Young; Choi, Sheu-Ran; Choi, Hoon-Seong; Kang, Suk-Yun; Han, Ho-Jae; Beitz, Alvin J; Lee, Jang-Hern

    2014-04-01

    Although previous reports have suggested that P2Y1 receptors (P2Y1Rs) are involved in cutaneous nociceptive signaling, it remains unclear how P2Y1Rs contribute to peripheral sensitization. The current study was designed to delineate the role of peripheral P2Y1Rs in pain and to investigate potential linkages to mitogen-activated protein kinase (MAPK) in DRGs and Transient Receptor Potential Vanilloid 1 (TRPV1) expression in a rodent inflammatory pain model. Following injection of 2% carrageenan into the hind paw, expressions of P2Y1 and TRPV1 and the phosphorylation rates of both p38 MAPK and ERK but not JNK were increased and peaked at day 2 post-injection. Blockade of peripheral P2Y1Rs by the P2Y1R antagonist, MRS2500 injection (i.pl, D0 to D2) significantly reduced the induction of thermal hyperalgesia, but not mechanical allodynia. Simultaneously, MRS2500 injections suppressed upregulated TRPV1 expression and DRG p38 phosphorylation, while pERK signaling was not affected. Furthermore, inhibition of p38 activation in the DRGs by SB203580 (a p38 inhibitor, i.t, D0 to D2) prevented the upregulation of TRPV1 and a single i.t injection of SB203580 reversed the established thermal hyperalgesia, but not mechanical allodynia. Lastly, to identify the mechanism of action of P2Y1Rs, we repeatedly injected the P2Y1 agonist, MRS2365 into the naïve rat's hind paw and observed a dose-dependent increase in TRPV1 expression and p38 MAPK phosphorylation. These data demonstrate a sequential role for P2Y1R, p38 MAPK and TRPV1 in inflammation-induced thermal hyperalgesia; thus, peripheral P2Y1Rs activation modulates p38 MAPK signaling and TRPV1 expression, which ultimately leads to the induction of thermal hyperalgesia.

  16. 损毁炎症大鼠下丘脑弓状核对痛觉过敏的影响%The effect of hypothalamic arcuate nucleus lesion on the hyperalgesia of inflammatory rats

    Institute of Scientific and Technical Information of China (English)

    戴友爱; 龚珊; 蒋星红

    2012-01-01

    that in the control hyperosmotic saline-treated rats. Results indicated that the CFA-produced hyperalgesia was significantly attenuated after the neuronal damage of ARC induced by MSG neonatally. (3) In CFA-induced inflammatory rats both thermal and mechanical pain thresholds were increased significantly after electrolytical lesion of ARC as compared with those in the sham lesioned rats, showing that ARC lesion could also attenuate the hyperalgesia induced by CFA. Conclusion Under the condition of peripheral inflammation, both neonatal MSG injection and electrolytical ARC lesion could attenuate the hyperalgesia. It suggests that ARC takes part and presumably mediates its descending facilitatory control on the hyperalgesia induced by peripheral tissue inflammation.

  17. Effect of transient receptor potential vanilloid 1 (TRPV1) receptor antagonist compounds SB705498, BCTC and AMG9810 in rat models of thermal hyperalgesia measured with an increasing-temperature water bath.

    Science.gov (United States)

    Tékus, Valéria; Bölcskei, Kata; Kis-Varga, Agnes; Dézsi, László; Szentirmay, Eva; Visegrády, András; Horváth, Csilla; Szolcsányi, János; Petho, Gábor

    2010-09-01

    The transient receptor potential vanilloid 1 (TRPV1) receptor is activated by noxious heat, various endogenous mediators and exogenous irritants. The aim of the present study was to compare three TRPV1 receptor antagonists (SB705498, BCTC and AMG9810) in rat models of heat hyperalgesia. The behavioural noxious heat threshold, defined as the lowest temperature evoking nocifensive reaction, was measured with an increasing-temperature water bath. The effects of TRPV1 receptor antagonists were assessed in thermal hyperalgesia induced by the TRPV1 agonist resiniferatoxin (RTX), mild heat injury (51 degrees C, 20s) or plantar incision in rats. The control heat threshold was 43.2+/-0.4 degrees C. RTX induced an 8-10 degrees C decrease in heat threshold which was dose-dependently inhibited by oral pre-treatment with any of the TRPV1 receptor antagonists with a minimum effective dose of 1mg/kg. The mild heat injury-evoked 7-8 degrees C heat threshold drop was significantly reversed by all three antagonists injected i.p. as post-treatment. The minimum effective doses were as follows: SB705498 10, BCTC 3 and AMG9810 1mg/kg. Plantar incision-induced heat threshold drop (7-8 degrees C) was dose-dependently diminished by an oral post-treatment with any of the antagonists with minimum effective doses of 10, 3 and 3mg/kg, respectively. Assessment of RTX hyperalgesia by measurement of the paw withdrawal latency with a plantar test apparatus yielded 30 mg/kg minimum effective dose for each antagonist. In conclusion, measurement of the noxious heat threshold with the increasing-temperature water bath is suitable to sensitively detect the effects of TRPV1 receptor antagonists in thermal hyperalgesia models.

  18. The C-type natriuretic peptide induces thermal hyperalgesia through a noncanonical Gβγ-dependent modulation of TRPV1 channel.

    Science.gov (United States)

    Loo, Lipin; Shepherd, Andrew J; Mickle, Aaron D; Lorca, Ramón A; Shutov, Leonid P; Usachev, Yuriy M; Mohapatra, Durga P

    2012-08-29

    Natriuretic peptides (NPs) control natriuresis and normalize changes in blood pressure. Recent studies suggest that NPs are also involved in the regulation of pain sensitivity, although the underlying mechanisms remain essentially unknown. Many biological effects of NPs are mediated by guanylate cyclase (GC)-coupled NP receptors, NPR-A and NPR-B, whereas the third NP receptor, NPR-C, lacks the GC kinase domain and acts as the NP clearance receptor. In addition, NPR-C can couple to specific Gα(i)-Gβγ-mediated intracellular signaling cascades in numerous cell types. We found that NPR-C is coexpressed in transient receptor potential vanilloid-1 (TRPV1)-expressing mouse dorsal root ganglia (DRG) neurons. NPR-C can be coimmunoprecipitated with Gα(i), and C-type natriuretic peptide (CNP) treatment induced translocation of protein kinase Cε (PKCε) to the plasma membrane of these neurons, which was inhibited by pertussis toxin pretreatment. Application of CNP potentiated capsaicin- and proton-activated TRPV1 currents in cultured mouse DRG neurons and increased their firing frequency, an effect that was absent in DRG neurons from TRPV1(-/-) mice. CNP-induced sensitization of TRPV1 activity was attenuated by pretreatment of DRG neurons with the specific inhibitors of Gβγ, phospholipase C-β (PLCβ), or PKC, but not of protein kinase A, and was abolished by mutations at two PKC phosphorylation sites in TRPV1. Furthermore, CNP injection into mouse hindpaw led to the development of thermal hyperalgesia that was attenuated by administration of specific inhibitors of Gβγ or TRPV1 and was also absent in TRPV1(-/-) mice. Thus, our work identifies the Gβγ-PLCβ-PKC-dependent potentiation of TRPV1 as a novel signaling cascade recruited by CNP in mouse DRG neurons that can lead to enhanced nociceptor excitability and thermal hypersensitivity.

  19. Secondary hyperalgesia to heat stimuli after burn injury in man

    DEFF Research Database (Denmark)

    Pedersen, J L; Kehlet, H

    1998-01-01

    area). The burns decreased pain thresholds and increased pain responses to both thermal and mechanical stimuli within the burn (P hyperalgesia (mean 89 cm2) to punctate mechanical stimuli (P ...The aim of the study was to examine the presence of hyperalgesia to heat stimuli within the zone of secondary hyperalgesia to punctate mechanical stimuli. A burn was produced on the medial part of the non-dominant crus in 15 healthy volunteers with a 50 x 25 mm thermode (47 degrees C, 7 min......), and assessments were made 70 min and 40 min before, and 0, 1, and 2 h after the burn injury. Hyperalgesia to mechanical and heat stimuli were examined by von Frey hairs and contact thermodes (3.75 and 12.5 cm2), and pain responses were rated with a visual analog scale (0-100). The area of secondary hyperalgesia...

  20. The effect of pre- versus postinjury infiltration with lidocaine on thermal and mechanical hyperalgesia after heat injury to the skin

    DEFF Research Database (Denmark)

    Dahl, J B; Brennum, J; Arendt-Nielsen, L

    1993-01-01

    The aim of the study was to evaluate the effects of pre- and postinjury infiltration with lidocaine on alterations in mechanical and thermal sensitivity after heat injury to the skin. In the first part of the study, burn injuries (15 x 25 mm rectangular thermode, 50 degrees C, 7 min) were produced...... twice in each subject on the medial side of the left and right calves at least 24 h apart in 8 healthy, unmedicated male volunteers, in order to investigate the effects of the injury on sensitivity in untreated skin. In the second part of the study, burn injuries (15 x 25 mm rectangular thermode, 50...... degrees C, 6 min) were produced twice in each subject on the medial side of the left and right calves at least 24 h apart (n = 10). This was preceded by subcutaneous (s.c.) infiltration with 5-6 ml of 1% plain lidocaine (pre-injury block) on one day, and the same block was performed 35 min after injury...

  1. IL-17 induces hyperalgesia via TNF-dependent neutrophil infiltration.

    Science.gov (United States)

    McNamee, Kay E; Alzabin, Saba; Hughes, Jane P; Anand, Praveen; Feldmann, Marc; Williams, Richard O; Inglis, Julia J

    2011-08-01

    Interleukin-17 (IL-17) and tumour necrosis factor-α (TNF) are critical in the pathogenesis of arthritis but their relationship during inflammatory pain has received limited attention. We aimed to establish whether IL-17 can induce hyperalgesia in acute conditions, and investigated the role of TNF in mediating the pain response. Hyperalgesia was elicited in C57BL/6 mice by injection of recombinant IL-17, TNF or vehicle into the plantar tissue. Elevated pain was measured by the Hargreaves test for thermal hyperalgesia and Linton incapacitance tester for weight-bearing change. Cellular infiltration during hyperalgesia was determined by histological analysis and myeloperoxidase assay. IL-17 was found to induce hyperalgesia, but this was dependent on neutrophil migration and TNF binding to TNF receptor 1 (TNFR1). Because TNF-induced hyperalgesia was also dependent on neutrophil migration, the relationship between the resident fibroblasts, the cytokines and the migrating neutrophils was further investigated. By means of an air pouch model of cell migration, it was established that IL-17-induced neutrophil infiltration was dependent of TNF/TNFR1 as this interaction was required for the induction of the chemokine keratinocyte chemoattractant. These findings suggest that IL-17 causes acute hyperalgesia indirectly by inducing TNF from resident cells. The subsequent production of keratinocyte chemoattractant then triggers neutrophil chemotaxis to the plantar tissue, releasing algesic mediators locally to sensitise the nerve.

  2. Enhancement of antinociception by coadminstration of minocycline and a non-steroidal anti-inflammatory drug indomethacin in naïve mice and murine models of LPS-induced thermal hyperalgesia and monoarthritis

    Directory of Open Access Journals (Sweden)

    Masocha Willias

    2010-12-01

    Full Text Available Abstract Background Minocycline and a non-steroidal anti-inflammatory drug (NSAID indomethacin, have anti-inflammatory activities and are both used in the management of rheumatoid arthritis. However, there are no reports on whether coadministration of these drugs could potentiate each other's activities in alleviating pain and weight bearing deficits during arthritis. Methods LPS was injected to BALB/c mice intraperitoneally (i.p. to induce thermal hyperalgesia. The hot plate test was used to study thermal nociception in naïve BALB/c and C57BL/6 mice and BALB/c mice with LPS-induced thermal hyperalgesia and to evaluate antinociceptive effects of drugs administered i.p. Monoarthritis was induced by injection of LPS intra-articularly into the right hind (RH limb ankle joint of C57BL/6 mice. Weight bearing changes and the effect of i.p. drug administration were analyzed in freely moving mice using the video-based CatWalk gait analysis system. Results In naïve mice indomethacin (5 to 50 mg/kg had no significant activity, minocycline (25 to 100 mg/kg produced hyperalgesia to thermal nociception, however, coadministration of minocycline 50 mg/kg with indomethacin 5 or 10 mg/kg produced significant antinociceptive effects in the hot plate test. A selective inhibitor of COX-1, FR122047 (10 mg/kg and a selective COX-2 inhibitor, CAY10404 (10 mg/kg had no significant antinociceptive activities to thermal nociception in naïve mice, however, coadministration of minocycline, with CAY10404 but not FR122047 produced significant antinociceptive effects. In mice with LPS-induced hyperalgesia vehicle, indomethacin (10 mg/kg or minocycline (50 mg/kg did not produce significant changes, however, coadministration of minocycline plus indomethacin resulted in antinociceptive activity. LPS-induced RH limb monoarthritis resulted in weight bearing (RH/left hind (LH limb paw pressure ratios and RH/LH print area ratios deficits. Treatment with indomethacin (1 mg/kg or

  3. The BDNF/TrkB signaling pathway is involved in heat hyperalgesia mediated by Cdk5 in rats.

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    Hong-Hai Zhang

    Full Text Available BACKGROUND: Cyclin-dependent kinase 5 (Cdk5 has been shown to play an important role in mediating inflammation-induced heat hyperalgesia. However, the underlying mechanism remains unclear. The aim of this study was to determine whether roscovitine, an inhibitor of Cdk5, could reverse the heat hyperalgesia induced by peripheral injection of complete Freund's adjuvant (CFA via the brain-derived neurotrophic factor (BDNF-tyrosine kinase B (TrkB signaling pathway in the dorsal horn of the spinal cord in rats. RESULTS: Heat hyperalgesia induced by peripheral injection of CFA was significantly reversed by roscovitine, TrkB-IgG, and the TrkB inhibitor K252a, respectively. Furthermore, BDNF was significantly increased from 0.5 h to 24 h after CFA injection in the spinal cord dorsal horn. Intrathecal adminstration of the Cdk5 inhibitor roscovitine had no obvious effects on BDNF levels. Increased TrkB protein level was significantly reversed by roscovitine between 0.5 h and 6 h after CFA injection. Cdk5 and TrkB co-immunoprecipitation results suggested Cdk5 mediates the heat hyperalgesia induced by CFA injection by binding with TrkB, and the binding between Cdk5 and TrkB was markedly blocked by intrathecal adminstration of roscovitine. CONCLUSION: Our data suggested that the BDNF-TrkB signaling pathway was involved in CFA-induced heat hyperalgesia mediated by Cdk5. Roscovitine reversed the heat hyperalgesia induced by peripheral injection of CFA by blocking BDNF/TrkB signaling pathway, suggesting that severing the close crosstalk between Cdk5 and the BDNF/TrkB signaling cascade may present a potential target for anti-inflammatory pain.

  4. Electroacupuncture Reduces Carrageenan- and CFA-Induced Inflammatory Pain Accompanied by Changing the Expression of Nav1.7 and Nav1.8, rather than Nav1.9, in Mice Dorsal Root Ganglia.

    Science.gov (United States)

    Huang, Chun-Ping; Chen, Hsiang-Ni; Su, Hong-Lin; Hsieh, Ching-Liang; Chen, Wei-Hsin; Lai, Zhen-Rung; Lin, Yi-Wen

    2013-01-01

    Several voltage-gated sodium channels (Navs) from nociceptive nerve fibers have been identified as important effectors in pain signaling. The objective of this study is to investigate the electroacupuncture (EA) analgesia mechanism by changing the expression of Navs in mice dorsal root ganglia (DRG). We injected carrageenan and complete Freund's adjuvant (CFA) into the mice plantar surface of the hind paw to induce inflammation and examined the antinociception effect of EA at the Zusanli (ST36) acupoint at 2 Hz low frequency. Mechanical hyperalgesia was evaluated by using electronic von Frey filaments, and thermal hyperalgesia was assessed using Hargreaves' test. Furthermore, we observed the expression and quality of Navs in DRG neurons. Our results showed that EA reduced mechanical and thermal pain in inflammatory animal model. The expression of Nav1.7 and Nav1.8 was increased after 4 days of carrageenan- and CFA-elicited inflammatory pain and further attenuated by 2 Hz EA stimulation. The attenuation cannot be observed in Nav1.9 sodium channels. We demonstrated that EA at Zusanli (ST36) acupoint at 2 Hz low-frequency stimulation attenuated inflammatory pain accompanied by decreasing the expression of Nav1.7 and 1.8, rather than Nav1.9, sodium channels in peripheral DRG neurons.

  5. Electroacupuncture Reduces Carrageenan- and CFA-Induced Inflammatory Pain Accompanied by Changing the Expression of Nav1.7 and Nav1.8, rather than Nav1.9, in Mice Dorsal Root Ganglia

    Directory of Open Access Journals (Sweden)

    Chun-Ping Huang

    2013-01-01

    Full Text Available Several voltage-gated sodium channels (Navs from nociceptive nerve fibers have been identified as important effectors in pain signaling. The objective of this study is to investigate the electroacupuncture (EA analgesia mechanism by changing the expression of Navs in mice dorsal root ganglia (DRG. We injected carrageenan and complete Freund's adjuvant (CFA into the mice plantar surface of the hind paw to induce inflammation and examined the antinociception effect of EA at the Zusanli (ST36 acupoint at 2 Hz low frequency. Mechanical hyperalgesia was evaluated by using electronic von Frey filaments, and thermal hyperalgesia was assessed using Hargreaves' test. Furthermore, we observed the expression and quality of Navs in DRG neurons. Our results showed that EA reduced mechanical and thermal pain in inflammatory animal model. The expression of Nav1.7 and Nav1.8 was increased after 4 days of carrageenan- and CFA-elicited inflammatory pain and further attenuated by 2 Hz EA stimulation. The attenuation cannot be observed in Nav1.9 sodium channels. We demonstrated that EA at Zusanli (ST36 acupoint at 2 Hz low-frequency stimulation attenuated inflammatory pain accompanied by decreasing the expression of Nav1.7 and 1.8, rather than Nav1.9, sodium channels in peripheral DRG neurons.

  6. Serotonergic signaling inhibits hyperalgesia induced by spinal cord damage.

    Science.gov (United States)

    Horiuchi, Hideki; Ogata, Tadanori; Morino, Tadao; Takeba, Jun; Yamamoto, Haruyasu

    2003-02-14

    Although dysesthesia is one of the most serious problems in patients with spinal cord injury, most of them being unresponsive to conventional treatments. In this study, we established a rat thoracic spinal cord mild-compression model that revealed thermal hyperalgesia in the hind limb. The thoracic spinal cord was compressed gently, using a 20 g weight for 20 min. The withdrawal latency of the thermal stimulation of the bilateral hind-limb was monitored using Hargreaves' Plantar test apparatus. In this model, thermal-hyperalgesia was observed for 1 week after the injury. The spinal cord injury-induced thermal-hyperalgesia was mimicked by the intrathecal application of metergoline, a non-selective 5-HT antagonist, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl]-piperazine hydrobromide (NAN190), a selective 5-HT1 antagonist, and 3-tropanyl-3,5-dichlorobenzoate (MDL72222), a selective 5-HT3 antagonist. Intraperitoneal application of fluvoxamine maleate, a selective serotonin reuptake inhibitor, reduced the intensity of hyperalgesia induced by spinal cord injury. The inhibitory effect of fluvoxamine maleate on thermal hyperalgesia was prevented by the application of the aforementioned nonselective or selective 5-HT receptor antagonists. Intrathecal application of fluvoxamine maleate and selective 5-HT receptor agonists, i.e., 8-hydroxy-2-(di-n-proplyamino)-tetralin hydrobromide (8-OH-DPAT: 5HT-1 selective) and 2-methyl-5-hydroxytryptamine maleate (2-m-5-HT: 5HT-3 selective), inhibited the spinal cord injury-induced hyperalgesia. These results suggest that the change in the descending serotonergic signal plays an important role in hyperalgesia after the spinal cord injury, and that the application of selective serotonin reuptake inhibitors will be one of the candidates for new therapeutic methods against post-spinal cord injury dysesthesia.

  7. 小胶质细胞在脂多糖引起的热高敏中的作用%Role of Microglia in Lipopolysaccharide-induced Thermal Hyperalgesia

    Institute of Scientific and Technical Information of China (English)

    王爱桃; 武庆平; 徐建军; 姚尚龙; 崔永武; 邱颐

    2011-01-01

    目的 探讨小胶质细胞在脂多糖引起的热高敏中的作用.方法 清洁级雄性昆明小鼠,随机分成两组,每组5只,腹腔注射LPS组和注射PBS组,在注射前及后30、60、120、240min测量小鼠足底的热痛阈;每组于注射前及后4h各处死5只取脑组织检测IL-1β、TNF-α;每组于腹腔注射 4h时处死动物,免疫荧光确定脑组织中小胶质细胞的激活情况.然后分为四组,米诺环素+PBS组,米诺环素+LPS组,PBS+PBS组,PBS+LPS组,每组5只,连续三天腹腔注射米诺环素或PBS,第三天注射LPS或PBS,在注射前及后30、60、120、240min测量小鼠足底的热痛阈;每组于注射前及后4h各处死5只取脑组织检测IL-1β、TNF-α.结果 与注射PBS相比,注射LPS导致IL-1β、TNF-α分泌增加,注射60、120、240min小鼠的热痛阈降低;与米诺环素+PBS组、米诺环素+LPS组、PBS+PBS组相比,PBS+LPS组导致 IL-1β、TNF-α分泌增加,注射60、120、240min小鼠的热痛阈降低.结论 LPS激活小胶质细胞分泌促炎细胞因子导致热高敏.%Objective To explore the role of microglia in the lipopolysaccharide (LPS)-induced thermal hyperalgesia. Methods After adult kunming mice received an intraperitoneal injection of PBS or LPS,thermal nociceptive thresholds, IL-1β and TNF-α were determined; activation of microglia in the brain was determined by immunofluorescence. Then, according to the different agents , injected mice were divided into 4 groups: minocycline + PBS, minocycline + LPS, PBS+ PBS, and PBS+ LPS. The mice received an intraperitoneal injection of PBS or minocycline (the former agent of each group) for 3 consecutive days.On the 3 day, PBS or LPS (the latter agent of each group was added). The thermal nociceptive thresholds and the expressions of brain IL-1β and TNF-α were assayed. Results LPS injection led to proinflammatory cytokine secretion and thermal hyperalgesia in kunming mice. Minocycline blocked LPS-stimulated inflammatory cytokine

  8. 乙咪酯全身及鞘内用药对蜜蜂毒诱致大鼠热和机械性痛敏的抑制作用%Effects of intravenous and/or intrathecal etomidate on thermal and mechanical hyperalgesia induced by intraplantar injection of bee venum in rats

    Institute of Scientific and Technical Information of China (English)

    孙焱芫; 熊利泽; 曾祥龙; 陈军; 李会莉

    2001-01-01

    Objective To investigate whether etomidate (E) has any suppressive effects on hyperalgesia induced by intraplantar subcutaneous injection of bee venum (BV). Methods BV was injected into the plantar surface of one hind paw to produce hyperalgesia. Pain was estimated by measuring withdrawal response latency of the hindpaw to radiant heat and withdrawal threshold to von Frey filament of different stimulation intensity (40-580mN). Both injected and contralateral hind paw were tested. 36 adult male and female SD rats weighing 180-250g were randomly divided into 6 groups of 6 rats each:group C1 :normal control; group C2: hyperalgesia induced by BV; group V: intravenous E 1.28mg/kg before BV-induced hyperalgesia; group T: intrathecal E 20μg/10μl before BV-induced hyperalgesia; group TT: intrathecal E 20μg/10μl before induced hyperalgesia + intrathecal E 20μg/10μl 4h after induced hyperalgesia; group TV: intrathecal E 20μg/10μl before induced hyperalgesia + intravenous E 1.28mg/kg 4h after induced hyperalgesia. Intrathecal E was given through an implanted spinal cannulae. Pain response was measured 2 h after BV-induced hyperalgesia in group C2, V and T and 4 h after BV-induced latency of the injected hindpaw to heat stimulation drop by 86 % and withdrawal threshold to mechanical stimulation drop by 89% but also reduced the withdrawal latency of the contralateral hindpaw to heat prolonged the withdrawal latency to heat stimulation after intraplantar BV injection. Withdrawal latency to heat stimulation was further prolonged by intravenous or intrathecal etomidate given after BV-induced hyperalgesia. Withdrawal threshold to mechanical von Frey filament stimulation was increased significantly only by intrathecal etomidate pretreatment combined with intravenous etomidate given after BV-induced hyperalgesia. Conclusions Etomidate has suppressive effects on the primary and secondary BV-induced thermal hyperalgesia in a dose accumulative manner. The mechanism of

  9. Fear of pain potentiates nocebo hyperalgesia

    Directory of Open Access Journals (Sweden)

    Aslaksen PM

    2015-10-01

    Full Text Available Per M Aslaksen,1 Peter S Lyby2 1Department of Psychology, Research Group for Cognitive Neuroscience, The Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway; 2Catosenteret Rehabilitation Center, Son, Norway Abstract: Nocebo hyperalgesia has received sparse experimental attention compared to placebo analgesia. The aim of the present study was to investigate if personality traits and fear of pain could predict experimental nocebo hyperalgesia. One hundred and eleven healthy volunteers (76 females participated in an experimental study in which personality traits and fear of pain were measured prior to induction of thermal heat pain. Personality traits were measured by the Big-Five Inventory-10. Fear of pain was measured by the Fear of Pain Questionnaire III. Heat pain was induced by a PC-controlled thermode. Pain was measured by a computerized visual analog scale. Stress levels during the experiment were measured by numerical rating scales. The participants were randomized to a Nocebo group or to a no-treatment Natural History group. The results revealed that pain and stress levels were significantly higher in the Nocebo group after nocebo treatment. Mediation analysis showed that higher levels of the Fear of Pain Questionnaire III factor "fear of medical pain" significantly increased stress levels after nocebo treatment and that higher stress levels were associated with increased nocebo hyperalgesic responses. There were no significant associations between any of the personality factors and the nocebo hyperalgesic effect. The results from the present study suggest that dispositional fear of pain might be a useful predictor for nocebo hyperalgesia and emotional states concomitant with expectations of increased pain. Furthermore, measurement of traits that are specific to pain experience is probably better suited for prediction of nocebo hyperalgesic responses compared to broad measures of personality

  10. Effects of target-controlled infusion of high-dose naloxone on pain and hyperalgesia in a human thermal injury model: a study protocol: A randomized, double-blind, placebo-controlled, crossover trial with an enriched design.

    Science.gov (United States)

    Springborg, Anders D; Jensen, Elisabeth K; Taylor, Bradley K; Werner, Mads U

    2016-11-01

    Mu-opioid-receptor antagonists have been extensively studied in experimental research as pharmacological tools uncovering mechanisms of pain modulation by the endogenous opioid system. In rodents, administration of high doses of mu-opioid-receptor antagonists after the resolution of an inflammatory injury has demonstrated reinstatement of nociceptive hypersensitivity indicating unmasking of latent sensitization. In a recent human study, pain hypersensitivity assessed as secondary hyperalgesia area (SHA), was reinstated 7 days after a mild thermal injury, in 4 out of 12 subjects after a naloxone infusion.The aims of the present study are first, to replicate our previous findings in a larger-sized study; second, to examine if high sensitizers (subjects presenting with large SHA after a thermal injury) develop a higher degree of hypersensitivity after naloxone challenge than low sensitizers (subjects presenting with restricted SHA after a thermal injury); and third to examine a dose-response relationship between 3 stable naloxone concentrations controlled by target-controlled infusion, and the unmasking of latent sensitization.Healthy participants (n = 80) underwent a screening day (day 0) with induction of a thermal skin injury (47°C, 420 seconds, 12.5 cm). Assessment of SHA was performed 1 and 2 hours after the injury. Using an enriched design, only participants belonging to the upper quartile of SHA (Q4, high sensitizers; n = 20) and the lower quartile of SHA (Q1, low sensitizers; n = 20) continued the study, comprising 4 consecutive days-days 1 to 4. Thermal skin injuries were repeated on day 1 and day 3, whereas day 2 and day 4 (7 days after day 1 and day 3, respectively) were target-controlled infusion days in which the subjects were randomly allocated to receive either naloxone (3.25 mg/kg, 4 mg/mL) or placebo (normal saline) intravenous. The primary outcome was SHA assessed by weighted-pin instrument (128 mN) 0, 1, 2, and 165 to 169

  11. Demarcation of secondary hyperalgesia zones

    DEFF Research Database (Denmark)

    Ringsted, Thomas K; Enghuus, Casper; Petersen, Morten A;

    2015-01-01

    of analgesic drug effects in humans. However, since the methods applied in demarcating the secondary hyperalgesia zone seem inconsistent across studies, we examined the effect of a standardized approach upon the measurement of SHA following a first degree burn injury (BI). NEW METHOD: The study was a two...... presented. CONCLUSIONS: This is the first study to demonstrate that demarcation of secondary hyperalgesia zones depends on the developed pressure of the punctate stimulator used....

  12. The Area of Secondary Hyperalgesia following Heat Stimulation in Healthy Male Volunteers

    DEFF Research Database (Denmark)

    Hansen, Morten Sejer; Wetterslev, Jørn; Pipper, Christian Bressen;

    2016-01-01

    -individual variation in secondary hyperalgesia elicited by brief thermal sensitization (45°C for 3 min) in healthy volunteers. MATERIAL AND METHODS: Fifty healthy volunteers were included. Areas of secondary hyperalgesia following brief thermal sensitization were investigated by 2 observers on 4 experimental days......, with a minimum interval of 7 days. Additionally, heat pain detection threshold and pain during thermal stimulation (45°C for 1 min.), and the psychological tests Pain Catastrophizing Scale and Hospital Anxiety and Depression Score were applied. RESULTS: For areas of secondary hyperalgesia, an intra...... and above the 3rd quartile considering all included participants. Heat pain detection threshold predicted area of secondary hyperalgesia with an adjusted R2 of 0.20 (P = 0.0006). CONCLUSIONS: We have demonstrated a low intra-individual, and a high inter-individual variation in thermally induced secondary...

  13. Spinal mechanism of baicalin on oxaliplatin induced thermal hyperalgesia%黄芩苷减轻奥沙利铂导致热痛觉过敏的脊髓机制

    Institute of Scientific and Technical Information of China (English)

    宋超; 赵静; 嵇绍干

    2014-01-01

    目的:研究黄芩苷对奥沙利铂导致热痛觉过敏的脊髓机制。方法建立奥沙利铂导致疼痛的大鼠动物模型,将大鼠随机分为模型对照组,黄芩苷治疗组, nNOS抑制剂(7-NI)对照组和空白对照组。比较各组大鼠在接受奥沙利铂冲击和/或黄芩苷治疗之后热刺激缩足阈值的大小。结果奥沙利铂可以导致大鼠热学反射缩足阈值显著缩短,而黄芩苷治疗组可模拟7-NI的作用,显著提高热刺激缩足阈值(P<0.05或P<0.01)。结论黄芩苷对于奥沙利铂导致的热痛觉过敏具有显著的抑制作用,其作用机制可能与抑制脊髓部位的nNOS合成有关。%Objective To investigate the spinal mechanism of baicalin on oxaliplatin induced thermal hyperalgesia. Methods Oxaliplatin induced neuropathic pain was established in rats, and the rats were randomly divided into model group, baicalin group, 7-NI group and naive group. The behavioral test of thermal hyperalgesia was used to confirm the role of baicalin and 7-NI. Results Compared with model group, baicalin treatment could mimic the role of 7-NI and significantly increase thermal paw withdrawal latency induced by oxaliplatin. Conclusion Baicalin reduces oxaliplatin induced neuropathic pain and the mechanism may be related to inhibition of nNOS expression in spinal cord.

  14. Electroacupuncture Reduces Hyperalgesia after Injections of Acidic Saline in Rats

    Directory of Open Access Journals (Sweden)

    Leonardo Yung dos Santos Maciel

    2014-01-01

    Full Text Available Background. Injections of acidic saline into the gastrocnemius muscle in rats produce a bilateral long-lasting hyperalgesia similar to fibromyalgia in humans. No previous study investigated the effect of electroacupuncture (EA on this acidic saline model. This study aimed to identify the effects of EA in the hyperalgesia produced by repeated intramuscular injections of acidic saline. Methods. Rats were divided into four groups (n=6, each group: control, acupuncture, EA 15 Hz, and 100 Hz. Left gastrocnemius muscle was injected with 100 μL of pH 4.0 sterile saline twice five days apart. EA, acupuncture, or control therapy was daily administered (20 min for 5 consecutive days under anesthesia. Needles were placed in the St36 and Sp6 acupoints. The assessment of secondary mechanical hyperalgesia, thermal hyperalgesia, and motor performance was performed before injections and before and after the treatment performed on each day. The paw withdrawal threshold was tested using the nonparametric Kruskal-Wallis test and differences within the group Wilcoxon Matched Pairs. The latency and motor performance were tested for ANOVA parametric test for independent measures, and for differences in the group, we used t-test for paired samples. Post hoc Tukey test was used for multiple corrections. P values ​​less than 0.05 were considered statistically significant. Results. Indicate that there was a significant reduction of mechanical withdrawal threshold and paw withdrawal latency 24 hours following the second injection. Moreover, mechanical and thermal hyperalgesia were significantly reversed by EA 15, 100 Hz, and acupuncture. Conclusions. The results suggest that EA high and low frequency as well as acupuncture are effective in reducing hyperalgesia in chronic muscle pain model.

  15. Fear of pain potentiates nocebo hyperalgesia.

    Science.gov (United States)

    Aslaksen, Per M; Lyby, Peter S

    2015-01-01

    Nocebo hyperalgesia has received sparse experimental attention compared to placebo analgesia. The aim of the present study was to investigate if personality traits and fear of pain could predict experimental nocebo hyperalgesia. One hundred and eleven healthy volunteers (76 females) participated in an experimental study in which personality traits and fear of pain were measured prior to induction of thermal heat pain. Personality traits were measured by the Big-Five Inventory-10. Fear of pain was measured by the Fear of Pain Questionnaire III. Heat pain was induced by a PC-controlled thermode. Pain was measured by a computerized visual analog scale. Stress levels during the experiment were measured by numerical rating scales. The participants were randomized to a Nocebo group or to a no-treatment Natural History group. The results revealed that pain and stress levels were significantly higher in the Nocebo group after nocebo treatment. Mediation analysis showed that higher levels of the Fear of Pain Questionnaire III factor "fear of medical pain" significantly increased stress levels after nocebo treatment and that higher stress levels were associated with increased nocebo hyperalgesic responses. There were no significant associations between any of the personality factors and the nocebo hyperalgesic effect. The results from the present study suggest that dispositional fear of pain might be a useful predictor for nocebo hyperalgesia and emotional states concomitant with expectations of increased pain. Furthermore, measurement of traits that are specific to pain experience is probably better suited for prediction of nocebo hyperalgesic responses compared to broad measures of personality.

  16. Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-α and IL-1β is mediated by glial cells.

    Science.gov (United States)

    Gruber-Schoffnegger, Doris; Drdla-Schutting, Ruth; Hönigsperger, Christoph; Wunderbaldinger, Gabriele; Gassner, Matthias; Sandkühler, Jürgen

    2013-04-10

    Long-term potentiation (LTP) of synaptic strength in nociceptive pathways is a cellular model of hyperalgesia. The emerging literature suggests a role for cytokines released by spinal glial cells for both LTP and hyperalgesia. However, the underlying mechanisms are still not fully understood. In rat lumbar spinal cord slices, we now demonstrate that conditioning high-frequency stimulation of primary afferents activated spinal microglia within hyperalgesia induced by spinal application of either IL-1β or TNF-α in naive animals also required activation of spinal glial cells. These results reveal a novel, decisive role of spinal glial cells for the synaptic effects of IL-1β and TNF-α and for some forms of hyperalgesia.

  17. Colocalization of aromatase in spinal cord astrocytes: differences in expression and relationship to mechanical and thermal hyperalgesia in murine models of a painful and a non-painful bone tumor.

    Science.gov (United States)

    O'Brien, E E; Smeester, B A; Michlitsch, K S; Lee, J-H; Beitz, A J

    2015-08-20

    While spinal cord astrocytes play a key role in the generation of cancer pain, there have been no studies that have examined the relationship of tumor-induced astrocyte activation and aromatase expression during the development of cancer pain. Here, we examined tumor-induced mechanical hyperalgesia and cold allodynia, and changes in Glial fibrillary acid protein (GFAP) and aromatase expression in murine models of painful and non-painful bone cancer. We demonstrate that implantation of fibrosarcoma cells, but not melanoma cells, produces robust mechanical hyperalgesia and cold allodynia in tumor-bearing mice compared to saline-injected controls. Secondly, this increase in mechanical hyperalgesia and cold allodynia is mirrored by significant increases in both spinal astrocyte activity and aromatase expression in the dorsal horn of fibrosarcoma-bearing mice. Importantly, we show that aromatase is only found within a subset of astrocytes and not in neurons in the lumbar spinal cord. Finally, administration of an aromatase inhibitor reduced tumor-induced hyperalgesia in fibrosarcoma-bearing animals. We conclude that a painful fibrosarcoma tumor induces a significant increase in spinal astrocyte activation and aromatase expression and that the up-regulation of aromatase plays a role in the development of bone tumor-induced hyperalgesia. Since spinal aromatase is also upregulated, but to a lesser extent, in non-painful melanoma bone tumors, it may also be neuroprotective and responsive to the changing tumor environment.

  18. Chronic at-level thermal hyperalgesia following rat cervical contusion spinal cord injury is accompanied by neuronal and astrocyte activation and loss of the astrocyte glutamate transporter, GLT1, in superficial dorsal horn.

    Science.gov (United States)

    Putatunda, Rajarshi; Hala, Tamara J; Chin, Jeannie; Lepore, Angelo C

    2014-09-18

    Neuropathic pain is a form of pathological nociception that occurs in a significant portion of traumatic spinal cord injury (SCI) patients, resulting in debilitating and often long-term physical and psychological burdens. While many peripheral and central mechanisms have been implicated in neuropathic pain, central sensitization of dorsal horn spinothalamic tract (STT) neurons is a major underlying substrate. Furthermore, dysregulation of extracellular glutamate homeostasis and chronic astrocyte activation play important underlying roles in persistent hyperexcitability of these superficial dorsal horn neurons. To date, central sensitization and astrocyte changes have not been characterized in cervical SCI-induced neuropathic pain models, despite the fact that a major portion of SCI patients suffer contusion trauma to cervical spinal cord. In this study, we have characterized 2 rat models of unilateral cervical contusion SCI that behaviorally result in chronic persistence of thermal hyperalgesia in the ipsilateral forepaw. In addition, we find that STT neurons are chronically activated in both models when compared to laminectomy-only uninjured rats. Finally, persistent astrocyte activation and significantly reduced expression of the major CNS glutamate transporter, GLT1, in superficial dorsal horn astrocytes are associated with both excitability changes in STT neurons and the neuropathic pain behavioral phenotype. In conclusion, we have characterized clinically-relevant rodent models of cervical contusion-induced neuropathic pain that result in chronic activation of both STT neurons and astrocytes, as well as compromise in astrocyte glutamate transporter expression. These models can be used as important tools to further study mechanisms underlying neuropathic pain post-SCI and to test potential therapeutic interventions.

  19. Effects of target-controlled infusion of high-dose naloxone on pain and hyperalgesia in a human thermal injury model

    DEFF Research Database (Denmark)

    Springborg, Anders D; Jensen, Elisabeth K; Taylor, Bradley K

    2016-01-01

    ) with induction of a thermal skin injury (47°C, 420 seconds, 12.5 cm). Assessment of SHA was performed 1 and 2 hours after the injury. Using an enriched design, only participants belonging to the upper quartile of SHA (Q4, high sensitizers; n = 20) and the lower quartile of SHA (Q1, low sensitizers; n = 20...

  20. Is the Volume of the Caudate Nuclei Associated With Area of Secondary Hyperalgesia?

    DEFF Research Database (Denmark)

    Hansen, Morten Sejer; Asghar, Mohammad Sohail; Wetterslev, Jørn

    2016-01-01

    volunteers with differences in size of the area of secondary hyperalgesia following a standardized burn injury. OBJECTIVE: We aim to investigate the degree of association between the volume of pain-relevant structures in the brain and the size of the area of secondary hyperalgesia following brief thermal...... participants will undergo experimental pain testing in a parallel study (Clinicaltrials.gov Identifier: NCT02527395). Results from this experimental pain testing, as well as the size of the area of secondary hyperalgesia from the included participants, will be extracted from this parallel study. RESULTS......: The association between the volume of pain-relevant structures in the brain and the area of secondary hyperalgesia will be investigated by linear regression of the estimated best linear unbiased predictors on the individual volumes of the pain relevant brain structures. CONCLUSIONS: We plan to investigate...

  1. Central activation of TRPV1 and TRPA1 by novel endogenous agonists contributes to mechanical allodynia and thermal hyperalgesia after burn injury.

    Science.gov (United States)

    Green, Dustin; Ruparel, Shivani; Gao, Xiaoli; Ruparel, Nikita; Patil, Mayur; Akopian, Armen; Hargreaves, Kenneth

    2016-01-01

    The primary complaint of burn victims is an intense, often devastating spontaneous pain, with persistence of mechanical and thermal allodynia. The transient receptor potential channels, TRPV1 and TRPA1, are expressed by a subset of nociceptive sensory neurons and contribute to inflammatory hypersensitivity. Although their function in the periphery is well known, a role for these TRP channels in central pain mechanisms is less well defined. Lipid agonists of TRPV1 are released from peripheral tissues via enzymatic oxidation after burn injury; however, it is not known if burn injury triggers the release of oxidized lipids in the spinal cord. Accordingly, we evaluated whether burn injury evoked the central release of oxidized lipids . Analysis of lipid extracts of spinal cord tissue with HPLC-MS revealed a significant increase in levels of the epoxide and diol metabolites of linoleic acid: 9,10-DiHOME, 12,13-DiHOME, 9(10)-EpOME, and 12(13)-EpOME, that was reduced after intrathecal (i.t.) injection of the oxidative enzyme inhibitor ketoconazole. Moreover, we found that these four lipid metabolites were capable of specifically activating both TRPV1 and TRPA1. Intrathecal injection of specific antagonists to TRPV1 (AMG-517) or TRPA1 (HC-030031) significantly reduced post-burn mechanical and thermal allodynia. Finally, i.t. injection of ketoconazole significantly reversed post-burn mechanical and thermal allodynia. Our data indicate that spinal cord TRPV1 and TRPA1 contributes to pain after burn and identifies a novel class of oxidized lipids elevated in the spinal cord after burn injury. Since the management of burn pain is problematic, these findings point to a novel approach for treating post-burn pain.

  2. Intrathecal AAV serotype 9-mediated delivery of shRNA against TRPV1 attenuates thermal hyperalgesia in a mouse model of peripheral nerve injury.

    Science.gov (United States)

    Hirai, Takashi; Enomoto, Mitsuhiro; Kaburagi, Hidetoshi; Sotome, Shinichi; Yoshida-Tanaka, Kie; Ukegawa, Madoka; Kuwahara, Hiroya; Yamamoto, Mariko; Tajiri, Mio; Miyata, Haruka; Hirai, Yukihiko; Tominaga, Makoto; Shinomiya, Kenichi; Mizusawa, Hidehiro; Okawa, Atsushi; Yokota, Takanori

    2014-02-01

    Gene therapy for neuropathic pain requires efficient gene delivery to both central and peripheral nervous systems. We previously showed that an adenoassociated virus serotype 9 (AAV9) vector expressing short-hairpin RNA (shRNA) could suppress target molecule expression in the dorsal root ganglia (DRG) and spinal cord upon intrathecal injection. To evaluate the therapeutic potential of this approach, we constructed an AAV9 vector encoding shRNA against vanilloid receptor 1 (TRPV1), which is an important target gene for acute pain, but its role in chronic neuropathic pain remains unclear. We intrathecally injected it into the subarachnoid space at the upper lumbar spine of mice 3 weeks after spared nerve injury (SNI). Delivered shTRPV1 effectively suppressed mRNA and protein expression of TRPV1 in the DRG and spinal cord, and it attenuated nerve injury-induced thermal allodynia 10-28 days after treatment. Our study provides important evidence for the contribution of TRPV1 to thermal hypersensitivity in neuropathic pain and thus establishes intrathecal AAV9-mediated gene delivery as an investigative and potentially therapeutic platform for the nervous system.

  3. Traumatic Stress Promotes Hyperalgesia via Corticotropin-Releasing Factor-1 Receptor (CRFR1) Signaling in Central Amygdala.

    Science.gov (United States)

    Itoga, Christy A; Roltsch Hellard, Emily A; Whitaker, Annie M; Lu, Yi-Ling; Schreiber, Allyson L; Baynes, Brittni B; Baiamonte, Brandon A; Richardson, Heather N; Gilpin, Nicholas W

    2016-09-01

    Hyperalgesia is an exaggerated response to noxious stimuli produced by peripheral or central plasticity. Stress modifies nociception, and humans with post-traumatic stress disorder (PTSD) exhibit co-morbid chronic pain and amygdala dysregulation. Predator odor stress produces hyperalgesia in rodents. Systemic blockade of corticotropin-releasing factor (CRF) type 1 receptors (CRFR1s) reduces stress-induced thermal hyperalgesia. We hypothesized that CRF-CRFR1 signaling in central amygdala (CeA) mediates stress-induced hyperalgesia in rats with high stress reactivity. Adult male Wistar rats were exposed to predator odor stress in a conditioned place avoidance paradigm and indexed for high (Avoiders) and low (Non-Avoiders) avoidance of predator odor-paired context, or were unstressed Controls. Rats were tested for the latency to withdraw hindpaws from thermal stimuli (Hargreaves test). We used pharmacological, molecular, and immunohistochemical techniques to assess the role of CRF-CRFR1 signaling in CeA in stress-induced hyperalgesia. Avoiders exhibited higher CRF peptide levels in CeA that did not appear to be locally synthesized. Intra-CeA CRF infusion mimicked stress-induced hyperalgesia. Avoiders exhibited thermal hyperalgesia that was reversed by systemic or intra-CeA injection of a CRFR1 antagonist. Finally, intra-CeA infusion of tetrodotoxin produced thermal hyperalgesia in unstressed rats and blocked the anti-hyperalgesic effect of systemic CRFR1 antagonist in stressed rats. These data suggest that rats with high stress reactivity exhibit hyperalgesia that is mediated by CRF-CRFR1 signaling in CeA.

  4. Effect of riluzole on acute pain and hyperalgesia in humans

    DEFF Research Database (Denmark)

    Hammer, N A; Lillesø, J; Pedersen, J L;

    1999-01-01

    Riluzole modulates several transmitter systems which may be involved in nociception. Antinociceptive effects have been shown in animal studies, but there are no human data. Therefore, we have examined the acute analgesic effect of riluzole in a human model of inflammatory pain induced by a thermal...... injury on the distal leg (47 degrees C, 7 min, 12.5 cm2) in 20 healthy volunteers. Hyperalgesia to mechanical and heat stimuli were examined by von Frey hairs and thermodes. We used a randomized, double-blind, placebo-controlled design, and subjects received riluzole 100 mg or placebo for 2 days...... with a 14-day interval. The burns produced significant hyperalgesia, but riluzole had no acute analgesic effects in normal or hyperalgesic skin....

  5. Contributions of spinal D-amino acid oxidase to chronic morphine-induced hyperalgesia.

    Science.gov (United States)

    Ma, Shuai; Li, Xin-Yan; Gong, Nian; Wang, Yong-Xiang

    2015-12-10

    Spinal D-amino acid oxidase (DAAO) is an FAD-dependent peroxisomal flavoenzyme which mediates the conversion of neutral and polar D-amino acids (including D-serine) to the corresponding α-keto acids, and simultaneously produces hydrogen peroxide and ammonia. This study has aimed to explore the potential contributions of spinal DAAO and its mediated hydrogen peroxide/D-serine metabolism to the development of morphine-induced hyperalgesia. Bi-daily subcutaneous injections of morphine to mice over 7 days induced thermal hyperalgesia as measured by both the hot-plate and tail-immersion tests, and spinal astroglial activation with increased spinal gene expression of DAAO, glial fibrillary acidic protein (GFAP) and pro-inflammatory cytokines (interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)). Subcutaneous injections of the potent DAAO inhibitor CBIO (5-chloro-benzo[D]isoxazol-3-ol) prevented and reversed the chronic morphine-induced hyperalgesia. CBIO also inhibited both astrocyte activation and the expression of pro-inflammatory cytokines. Intrathecal injection of the hydrogen peroxide scavenger PBN (phenyl-N-tert-butylnitrone) and of catalase completely reversed established morphine hyperalgesia, whereas subcutaneous injections of exogenous D-serine failed to alter chronic morphine-induced hyperalgesia. These results provided evidence that spinal DAAO and its subsequent production of hydrogen peroxide rather than the D-serine metabolism contributed to the development of morphine-induced hyperalgesia.

  6. Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia.

    Directory of Open Access Journals (Sweden)

    Folabomi A Oladosu

    Full Text Available A subset of the population receiving opioids for the treatment of acute and chronic clinical pain develops a paradoxical increase in pain sensitivity known as opioid-induced hyperalgesia. Given that opioid analgesics are one of few treatments available against clinical pain, it is critical to determine the key molecular mechanisms that drive opioid-induced hyperalgesia in order to reduce its prevalence. Recent evidence implicates a splice variant of the mu opioid receptor known as MOR-1K in the emergence of opioid-induced hyperalgesia. Results from human genetic association and cell signaling studies demonstrate that MOR-1K contributes to decreased opioid analgesic responses and produces increased cellular activity via Gs signaling. Here, we conducted the first study to directly test the role of MOR-1K in opioid-induced hyperalgesia.In order to examine the role of MOR-1K in opioid-induced hyperalgesia, we first assessed pain responses to mechanical and thermal stimuli prior to, during, and following chronic morphine administration. Results show that genetically diverse mouse strains (C57BL/6J, 129S6, and CXB7/ByJ exhibited different morphine response profiles with corresponding changes in MOR-1K gene expression patterns. The 129S6 mice exhibited an analgesic response correlating to a measured decrease in MOR-1K gene expression levels, while CXB7/ByJ mice exhibited a hyperalgesic response correlating to a measured increase in MOR-1K gene expression levels. Furthermore, knockdown of MOR-1K in CXB7/ByJ mice via chronic intrathecal siRNA administration not only prevented the development of opioid-induced hyperalgesia, but also unmasked morphine analgesia.These findings suggest that MOR-1K is likely a necessary contributor to the development of opioid-induced hyperalgesia. With further research, MOR-1K could be exploited as a target for antagonists that reduce or prevent opioid-induced hyperalgesia.

  7. The Area of Secondary Hyperalgesia following Heat Stimulation in Healthy Male Volunteers: Inter- and Intra-Individual Variance and Reproducibility.

    Directory of Open Access Journals (Sweden)

    Morten Sejer Hansen

    Full Text Available Clinical pain models can be applied when investigating basic physiologic pain responses in healthy volunteers. Several pain models exist; however, only few have been adequately validated. Our primary aim with this prospective study was to investigate the intra- and inter-individual variation in secondary hyperalgesia elicited by brief thermal sensitization (45°C for 3 min in healthy volunteers.Fifty healthy volunteers were included. Areas of secondary hyperalgesia following brief thermal sensitization were investigated by 2 observers on 4 experimental days, with a minimum interval of 7 days. Additionally, heat pain detection threshold and pain during thermal stimulation (45°C for 1 min., and the psychological tests Pain Catastrophizing Scale and Hospital Anxiety and Depression Score were applied.For areas of secondary hyperalgesia, an intra-observer intra-person correlation of 0.85, 95% CI [0.78, 0.90], an intra-observer inter-person correlation of 0.03, 95% CI [0.00, 0.16], and a coefficient of variation of 0.17, 95% CI [0.14, 0.21] was demonstrated. Four percent of the study population had areas of secondary hyperalgesia both below the 1st and above the 3rd quartile considering all included participants. Heat pain detection threshold predicted area of secondary hyperalgesia with an adjusted R2 of 0.20 (P = 0.0006.We have demonstrated a low intra-individual, and a high inter-individual variation in thermally induced secondary hyperalgesia. We conclude that brief thermal sensitization produce secondary hyperalgesia with a high level of reproducibility, which can be applied to investigate different phenotypes related to secondary hyperalgesia in healthy volunteers.clinicaltrials.gov NCT02166164.

  8. Pathogenesis of spinally mediated hyperalgesia in diabetes.

    Science.gov (United States)

    Ramos, Khara M; Jiang, Yun; Svensson, Camilla I; Calcutt, Nigel A

    2007-06-01

    Hyperalgesia to noxious stimuli is accompanied by increased spinal cyclooxygenase (COX)-2 protein in diabetic rats. The present studies were initiated to establish causality between increased spinal COX-2 activity and hyperalgesia during diabetes and to assess the potential involvement of polyol pathway activity in the pathogenesis of spinally mediated hyperalgesia. Rats with 1, 2, or 4 weeks of streptozotocin-induced diabetes exhibited significantly increased levels of spinal COX-2 protein and activity, along with exaggerated paw flinching in response to 0.5% paw formalin injection. Increased flinching of diabetic rats was attenuated by intrathecal pretreatment with a selective COX-2 inhibitor immediately before formalin injection, confirming the involvement of COX-2 activity in diabetic hyperalgesia. Chronic treatment with insulin or ICI222155, an aldose reductase inhibitor (ARI) previously shown to prevent spinal polyol accumulation and formalin-evoked hyperalgesia in diabetic rats, prevented elevated spinal COX-2 protein and activity in diabetic rats. In contrast, the ARI IDD676 had no effect on spinal polyol accumulation, elevated spinal COX-2, or hyperalgesia to paw formalin injection. In the spinal cord, aldose reductase immunoreactivity was present solely in oligodendrocytes, which also contained COX-2 immunoreactivity. Polyol pathway flux in spinal oligodendrocytes provides a pathogenic mechanism linking hyperglycemia to hyperalgesia in diabetic rats.

  9. Motor cortex stimulation reduces hyperalgesia in an animal model of central pain.

    Science.gov (United States)

    Lucas, Jessica M; Ji, Yadong; Masri, Radi

    2011-06-01

    Electrical stimulation of the primary motor cortex has been used since 1991 to treat chronic neuropathic pain. Since its inception, motor cortex stimulation (MCS) treatment has had varied clinical outcomes. Until this point, there has not been a systematic study of the stimulation parameters that most effectively treat chronic pain, or of the mechanisms by which MCS relieves pain. Here, using a rodent model of central pain, we perform a systematic study of stimulation parameters used for MCS and investigate the mechanisms by which MCS reduces hyperalgesia. Specifically, we study the role of the inhibitory nucleus zona incerta (ZI) in mediating the analgesic effects of MCS. In animals with mechanical and thermal hyperalgesia, we find that stimulation at 50 μA, 50 Hz, and 300 μs square pulses for 30 minutes is sufficient to reverse mechanical and thermal hyperalgesia. We also find that stimulation of the ZI mimics the effects of MCS and that reversible inactivation of ZI blocks the effects of MCS. These findings suggest that the reduction of hyperalgesia may be due to MCS effects on ZI. In an animal model of central pain syndrome, motor cortex stimulation reduces hyperalgesia by activating zona incerta and therefore restoring inhibition in the thalamus.

  10. SPINAL CORD MECHANISMS MEDIATING BEHAVIORAL HYPERALGESIA INDUCED BY NEUROKININ-1 TACHYKININ RECEPTOR ACTIVATION IN THE ROSTRAL VENTROMEDIAL MEDULLA

    OpenAIRE

    Lagraize, S. C.; Guo, W; Yang, K.; Wei, F.; Ren, K; Dubner, R.

    2010-01-01

    Hyperalgesia in animal injury models is linked to activation of descending raphespinal modulatory circuits originating in the rostral ventromedial medulla (RVM). A neurokinin-1 (NK-1) receptor antagonist microinjected into the RVM before or after inflammation produced by complete Freund’s adjuvant (CFA) resulted in an attenuation of thermal hyperalgesia. A transient (acute) or a continuous infusion of Substance P (SP) microinjected into the RVM of non-inflamed animals led to similar pain hype...

  11. Sphingosine 1-phosphate mediates hyperalgesia via a neutrophil-dependent mechanism.

    Directory of Open Access Journals (Sweden)

    Amanda Finley

    Full Text Available Novel classes of pain-relieving molecules are needed to fill the void between non-steroidal anti-inflammatory agents and narcotics. We have recently shown that intraplantar administration of sphingosine 1-phosphate (S1P in rats causes peripheral sensitization and hyperalgesia through the S1P(1 receptor subtype (S1PR(1: the mechanism(s involved are largely unknown and were thus explored in the present study. Intraplantar injection of carrageenan in rats led to a time-dependent development of thermal hyperalgesia that was associated with pronounced edema and infiltration of neutrophils in paw tissues. Inhibition of 1 S1P formation with SK-I, a sphingosine kinase inhibitor, 2 S1P bioavailability with the S1P blocking antibody Sphingomab, LT1002 (but not its negative control, LT1017 or 3 S1P actions through S1PR(1 with the selective S1PR(1 antagonist, W146 (but not its inactive enantiomer, W140 blocked thermal hyperalgesia and infiltration of neutrophils. Taken together, these findings identify S1P as an important contributor to inflammatory pain acting through S1PR(1 to elicit hyperalgesia in a neutrophil-dependant manner. In addition and in further support, we demonstrate that the development of thermal hyperalgesia following intraplantar injection of S1P or SEW2871 (an S1PR(1 agonist was also associated with neutrophilic infiltration in paw tissues as these events were attenuated by fucoidan, an inhibitor of neutrophilic infiltration. Importantly, FTY720, an FDA-approved S1P receptor modulator known to block S1P-S1PR(1 signaling, attenuated carrageenan-induced thermal hyperalgesia and associated neutrophil infiltration. Targeting the S1P/S1PR(1 axis opens a therapeutic strategy for the development of novel non-narcotic anti-hyperalgesic agents.

  12. Effect of selective inhibition of cyclooxygenase-2 on lipopolysaccharide-induced hyperalgesia.

    Science.gov (United States)

    Satyanarayana, Padi S V; Jain, Naveen K; Singh, Sukhjeet; Kulkarni, Shrinivas K

    2004-01-01

    Lipopolysaccharide (LPS) is known to increase the expression and release of various pro-inflammatory mediators, including cyclooxygenase-2 (COX-2) and produce hyperalgesia. It is also well known that prostaglandins (PGs), synthesised both in the periphery and centrally by COX isoforms, play a key role in sensitisation of nociceptors and nociceptive processing. To investigate the role of COX-2 in LPS-induced hyperalgesia, parecoxib, a selective COX-2-inhibiting pro-drug, was injected intravenously 30 min before assessing hyperalgesia induced by intraperitoneal or subcutaneous administration of LPS (50 microg/mouse or 25 microg/paw of rat, respectively). Acetic acid-induced writhing and tail immersion assay in mice and paw withdrawal response to thermal and mechanical stimuli in rats were used to assess the effect of inhibition of COX-2 on LPSinduced hyperalgesia. Animals showed significant hyperalgesic behavior 8 h after LPS injection. Parecoxib (up to 20 mg/kg, i.v.) had no effect in the two acute nociceptive assays but showed marked antinociceptive activity in writhing and tail immersion assay in LPS-pretreated mice. Similarly, parecoxib reversed the hyperalgesia in the LPS-injected paw but not in the contralateral paw of rats. Pre-treatment with dexamethasone, an inhibitor of COX-2 expression before LPS injection significantly affected the development of hyperalgesia in both mice and rats. These findings suggest that inducible COX-2 derived PGs are involved in central nociceptive processing, which resulted in hyperalgesic behavior following LPS administration and inhibition of COX-2 or its expression attenuated LPS-induced hyperalgesia.

  13. Secondary hyperalgesia to heat stimuli after burn injury in man

    DEFF Research Database (Denmark)

    Pedersen, J L; Kehlet, H

    1998-01-01

    was not significantly different between the two zones of hyperalgesia. In conclusion, secondary hyperalgesia in man is not restricted to mechanical stimuli, as significant hyperalgesia to heat developed within the zone of secondary hyperalgesia to punctate mechanical stimuli. The data, combined with other evidence......The aim of the study was to examine the presence of hyperalgesia to heat stimuli within the zone of secondary hyperalgesia to punctate mechanical stimuli. A burn was produced on the medial part of the non-dominant crus in 15 healthy volunteers with a 50 x 25 mm thermode (47 degrees C, 7 min......), and assessments were made 70 min and 40 min before, and 0, 1, and 2 h after the burn injury. Hyperalgesia to mechanical and heat stimuli were examined by von Frey hairs and contact thermodes (3.75 and 12.5 cm2), and pain responses were rated with a visual analog scale (0-100). The area of secondary hyperalgesia...

  14. Central immune overactivation in the presence of reduced plasma corticosterone contributes to swim stress-induced hyperalgesia.

    Science.gov (United States)

    Suarez-Roca, H; Quintero, L; Avila, R; Medina, S; De Freitas, M; Cárdenas, R

    2014-01-01

    Although it is widely known that immunological, hormonal and nociceptive mechanisms are altered by exposure to repeated stress, the interplaying roles of each function in the development of post-stress hyperalgesia are not completely clear. Thus, we wanted to establish how interleukin 1-beta (IL-1β), corticosterone and microglia interact to contribute in the development of hyperalgesia following repeated forced swim. Rats were subjected to either forced swim, sham swim or non-conditioned. Each group was then treated with minocycline, ketoconazole, or saline. Thermal nociception was measured via the hot plate test, before and after the behavioral conditioning, whereas blood and lumbar spinal cord tissue samples were obtained at the end of the protocol. Serum levels of corticosterone, spinal tissue concentration of IL-1β and spinal OX-42 labeling (microglial marker) were determined. Rats exposed to forced swim stress developed thermal hyperalgesia along with elevated spinal tissue IL-1β, increased OX-42 labeling and relatively diminished serum corticosterone. Pre-treatment with minocycline and ketoconazole prevented the development of thermal hyperalgesia and the increase in IL-1β, without significantly modifying serum corticosterone. These results suggest that the development of forced swim-induced thermal hyperalgesia requires the simultaneous presence of increased spinal IL-1β, microglial activation, and relatively decreased serum corticosterone.

  15. Nerve growth factor induced hyperalgesia in the rat hind paw is dependent on circulating neutrophils.

    Science.gov (United States)

    Bennett, G; al-Rashed, S; Hoult, J R; Brain, S D

    1998-09-01

    The mechanisms by which nerve growth factor (NGF) induces thermal hyperalgesia and neutrophil accumulation have been investigated in the rat. Thermal nociceptive thresholds in rat hind paw were measured as the time taken for paw withdrawal from a heat source and neutrophil accumulation was measured in hind paw and dorsal skin samples using a myeloperoxidase assay. NGF (23-80 pmol intraplantar (i.pl.) injection) induced a significant (P NGF (40 pmol). In dorsal skin, where multiple samples can be assessed, intradermal (i.d.) NGF was 10-30 times less potent than interleukin-1beta in inducing neutrophil accumulation. The 5-lipoxygenase inhibitor ZM230487 (10 nmol co-injected with NGF) significantly attenuated neutrophil accumulation and hyperalgesia induced by NGF; unlike the histamine and 5-hydroxytryptamine antagonists (mepyramine and methysergide) which were without effect at the times measured. Furthermore, depletion of circulating neutrophils (using a rabbit anti-rat neutrophil antibody) abolished NGF induced hyperalgesia. These results indicate that neutrophils, which accumulate in response to a 5-lipoxygenase product, play a crucial role in NGF-induced hyperalgesia.

  16. Hyperalgesia and Contributing Factors%痛觉过敏与其发生机制的相关因子

    Institute of Scientific and Technical Information of China (English)

    吕兴业

    2011-01-01

    Injuries can induce pain hypersensitivity and hyperalgesia in the injured tissue, adjacent tissue, or remote area.Hyperalgesia consists of thermal hyperalgesia and mechanical hyperalgesia.Activated N-Methyl-D-aspartate receptor leads to thermal hyperalgesia and is caused by calcium influx.It further activates protein kinase C and nitric oxide synthase,and enhances the production of nitric oxide.Mechanical hyperalgesia is mainly induced by activated a-amino-3-hydroxy-5-methyl-4-isoxa-zolep-propionate and metabtropic receptors.The interaction among excitatory amino acids and its receptors, protein kinase C and nitric oxide plays an important role in the development and progression of hyperalgesia.%外周组织损伤后,在受损部位及周围组织或远处可产生各种敏感性增强的疼痛和痛觉过敏.痛觉过敏分为热痛觉过敏和机械性痛觉过敏.热痛觉过敏主要是兴奋了N-甲基-D-天冬氨酸受体后引起钙离子向细胞内流,激活蛋白激酶C(PKC)的同时又激活了一氧化氮合酶,促进了一氧化氮的生成.机械性痛觉过敏主要是激活了α氨基羟甲基异唑丙酸受体和代谢型受体.兴奋性氮基酸及其受体、PKC及一氧化氮之间的相互影响在痛觉过敏的发生、发展过程中起着重要作用.

  17. Aberrant TRPV1 Expression in Heat Hyperalgesia Associated with Trigeminal Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Hiroko Urano, Toshiaki Ara, Yoshiaki Fujinami, B. Yukihiro Hiraoka

    2012-01-01

    Full Text Available Trigeminal neuropathic pain is a facial pain syndrome associated with trigeminal nerve injury. However, the mechanism of trigeminal neuropathic pain is poorly understood. This study aimed to determine the role of transient receptor potential vanilloid 1 (TRPV1 in heat hyperalgesia in a trigeminal neuropathic pain model. We evaluated nociceptive responses to mechanical and heat stimuli using a partial infraorbital nerve ligation (pIONL model. Withdrawal responses to mechanical and heat stimuli to vibrissal pads (VP were assessed using von Frey filaments and a thermal stimulator equipped with a heat probe, respectively. Changes in withdrawal responses were measured after subcutaneous injection of the TRP channel antagonist capsazepine. In addition, the expression of TRPV1 in the trigeminal ganglia was examined. Mechanical allodynia and heat hyperalgesia were observed in VP by pIONL. Capsazepine suppressed heat hyperalgesia but not mechanical allodynia. The number of TRPV1-positive neurons in the trigeminal ganglia was significantly increased in the large-diameter-cell group. These results suggest that TRPV1 plays an important role in the heat hyperalgesia observed in the pIONL model.

  18. The chemokine CCL5 induces CCR1-mediated hyperalgesia in mice inoculated with NCTC 2472 tumoral cells.

    Science.gov (United States)

    Pevida, M; Lastra, A; Meana, Á; Hidalgo, A; Baamonde, A; Menéndez, Luis

    2014-02-14

    Although the expression of the chemokine receptor CCR1 has been demonstrated in several structures related to nociception, supporting the nociceptive role of chemokines able to activate it, the involvement of CCR1 in neoplastic pain has not been previously assessed. We have assayed the effects of a CCR1 antagonist, J113863, in two murine models of neoplastic hyperalgesia based on the intratibial injection of either NCTC 2472 fibrosarcoma cells, able to induce osteolytic bone injury, or B16-F10 melanoma cells, associated to mixed osteolytic/osteoblastic bone pathological features. The systemic administration of J113863 inhibited thermal and mechanical hyperalgesia but not mechanical allodynia in mice inoculated with NCTC 2472 cells. Moreover, in these mice, thermal hyperalgesia was counteracted following the peritumoral (10-30μg) but not spinal (3-5μg) administration of J113863. In contrast, hyperalgesia and allodynia measured in mice inoculated with B16-F10 cells remained unaffected after the administration of J113863. The inoculation of tumoral cells did not modify the levels of CCL3 at tumor or spinal cord. In contrast, although the concentration of CCL5 remained unmodified in mice inoculated with B16-F10 cells, increased levels of this chemokine were measured in tumor-bearing limbs, but not the spinal cord, of mice inoculated with NCTC 2472 cells. Increased levels of CCL5 were also found following the incubation of NCTC 2472, but not B16-F10, cells in the corresponding culture medium. The intraplantar injection of CCL5 (0.5ng) to naïve mice evoked thermal hyperalgesia prevented by the coadministration of J113863 or the CCR5 antagonist, d-Ala-peptide T-amide (DAPTA), demonstrating that CCL5 can induce thermal hyperalgesia in mice through the activation of CCR1 or CCR5. However, contrasting with the inhibitory effect evoked by J113863, the systemic administration of DAPTA did not prevent tumoral hyperalgesia. Finally, the peritumoral administration of an anti

  19. Bilateral mechanical and thermal hyperalgesia and tactile allodynia after chronic compression of dorsal root ganglion in mice%小鼠背根节慢性压迫诱致的双侧机械性痛敏和热痛敏行为

    Institute of Scientific and Technical Information of China (English)

    陈荣贵; 孔微微; 葛大龙; 罗层; 胡三觉

    2011-01-01

    Objective Low back pain is one of the most inextricable problems encountered in clinics.Animal models that imitate symptoms in humans are valuable tools for investigating low back pain mechanisms and the possible therapeutic applications.With the development of genetic technology in pain field,the possibility of mutating specific genes in mice has provided a potent tool for investigating the specific mechanisms of pain.The aim of the present study was to develop a mouse model of chronic compression of dorsal root ganglion (CCD),in which gene mutation can be applied to facilitate the studies of chronic pain.Methods Chronic compression of L4 and L5 dorsal root ganglia was conducted in mice by inserting fine stainless steel rods into the intervertebral foramina,one at L4 and the other at L5.Mechanical allodynia and thermal hyperalgesia were examined with von Frey filaments and radiating heat stimulator,respectively.Results The CCD mice displayed dramatic mechanical and thermal hyperalgesia as well as tactile allodynia in the hindpaw ipsilateral to CCD.In addition,this mechanical and thermal hyperaigesia as well as tactile allodynia was also found to spread to the contralateral hindpaw.Conclusion This model,combined with the possible genetic modification,will strengthen our knowledge of the underlying mechanisms of low back pain.It also favors the development of new treatment strategies for pain and hyperalgesia after spinal injury and other disorders which affect the dorsal root ganglion in humans.%目的 腰背痛是一个临床常见的棘手问题.动物模型可以很好地模拟人类的临床症状,并为研究腰背痛的机制及其药物治疗带来希望.随着转基因技术的发展,特定的转基因小鼠模型为研究疼痛机制提供了一个强有力的工具.本研究旨在建立慢性背根节压迫小鼠模型,为应用转基因动物深入研究慢性痛的发生机制提供重要工具.方法 向小鼠腰4和腰5椎间

  20. 鞘内注射γ-氨基丁酸转运体抑制剂NO-711抑制坐骨神经慢性挤压伤大鼠神经病理性痛觉过敏%Inhibition of thermal hyperalgesia and tactile allodynia by intrathecal administration ofγ-aminobutyric acid transporter-1 inhibitor NO-711 in rats with chronic constriction injury

    Institute of Scientific and Technical Information of China (English)

    朱珊珊; 曾因明; 王俊科; 严蓉; 聂鑫; 曹君利

    2005-01-01

    The present study was undertaken to explore the role of γ-aminobutyric acid transporters in the neuropathic pain. On the chronic constriction injury (CCI) rats 4 doses (5, 10, 20, 40 μg in group N5, N10, N20, N40, respectively) of specific γ-aminobutyric acid transporter-1 inhibitor NO-711 or normal saline (in group NS) were intrathecally administered before sciatic nerve ligation (pretreatment) or at the third day after ligation (post-treatment). The paw withdrawl latency (PWL) from a noxious thermal stimulus and paw withdrawl mechanical threshold (PWMT) of von Frey filament was used as measure of thermal hyperalgesia and tactile allodynia respectively. The results demonstrated that post-treatment of NO-711 significantly suppressed thermal hyperalgesia and allodynia in CCI rats (P<0.05, P<0.01), the inhibitory effect lasted for 2 h (N40 group) and 4 h (N20 group) respectively. NO-711 inhibited thermal hyperalgesia induced by CCI in a dose-dependent manner. Intrathecal pretreatment with different doses of NO-711 delayed the occurrence of thermal hyperalgesia, but could not delay the emergence of allodynia induced by CCI. This study indicates that γaminobutyric acid transporter inhibiwr has anti-thermal hyperalgesia and anti-tactile allodynia effects in neuropathic rats.%为研究γ-氨基丁酸转运体在神经病理性痛中的作用,实验用坐骨神经慢性挤压伤致神经病理性痛模型大鼠,以清醒大鼠分别对辐射热刺激和机械性触觉刺激的缩腿潜伏期和机械阈值为指标,分为NS组、N5组、N10组、N20组、N40组5组,分别在坐骨神经结扎前和结扎后第三天鞘内给予生理盐水或不同剂量的γ-氨基丁酸转运体特异性抑制剂NO-711(5、10、20、40μg),观察鞘内注射NO-711对大鼠热痛敏和触诱发痛的影响.结果表明,NO-711可显著抑制神经病理性痛大鼠的热痛觉过敏和触诱发痛(P<0.05,P<0.01),其抑制作用持续时间最长分别可达2 h(N40组)和4 h

  1. 美普他酚及其同分异构体对角叉菜胶引起的炎症大鼠具有抗热痛敏作用%Antinociceptive effects of meptazinol and its isomers on carrageenan-induced thermal hyperalgesia in rats

    Institute of Scientific and Technical Information of China (English)

    王佩芬; 张玉秋; 仇缀百; 赵志奇

    2004-01-01

    实验以清醒大鼠的缩腿潜伏期为指标,观察了腹腔注射美普他酚及其同分异构体112824和112825对角叉菜胶引起的热痛敏的影响.外周炎症由单侧足底注射角叉菜胶(2 mg/100 μl)引起.注射角叉菜胶3 h后,注射侧后肢局部红肿及热痛过敏反应达到高峰,持续数小时.腹腔注射0.1 mg/kg美普他酚对炎症和非炎症侧后肢的缩腿潜伏期无明显影响(P>0.05,n=8).腹腔注射1mg/kg和10 mg/kg美普他酚对炎症和非炎症侧后肢产生明显的抗痛敏和抗伤害效应,且对炎症侧缩腿反应的抑制(抗痛敏)作用明显强于非炎症侧(抗伤害)(P<0.05,n=8~11).预先腹腔注射1.5 mg/kg纳洛酮明显阻断美普他酚引起的抗伤害和抗痛敏效应.腹腔注射美普他酚的同分异构体112824(1 mg/kg)和112825(1.5 ms/kg)可产生与美普他酚类似的抗痛敏作用,该效应可被预先腹腔注射1.5 mg/kg纳洛酮完全阻断.提示美普他酚及其同分异构体具有明显抗伤害和抗痛敏作用,且以后者为强.该作用主要通过mu阿片受体介导.本研究为扩展美普他酚及其同分异构体在临床上的应用提供了依据.%Using the latency of paw withdrawal (PWL) from a noxious thermal stimulus as a measure of hyperalgesia, the effects of i.p.injection of meptazinol and its isomers, 112824 and 112825, on carrageenan-induced thermal hyperalgesia were studied in awaked carrageenan-inflamed rats. Peripheral inflammation was induced by intraplantar (i.pl.) injection of carrageenan (2 mg/100 μl) into one hindpaw in rats. Carrageenan produced marked inflammation (edema and erythema) and thermal hyperalgesia in the injected paws, which peaked at 3 h after injection and showed little change in magnitude for another 3 h. Injection of 0.1 mg/kg meptazinol (i.p.) at 3 h after carrageenan had no effect on the PWLs of either inflamed or non-inflamed hindpaw during the next 100 ain (P>0.05, n=8). At the dosage of 1 and 10 mg

  2. Fear of pain potentiates nocebo hyperalgesia

    OpenAIRE

    Aslaksen PM; Lyby PS

    2015-01-01

    Per M Aslaksen,1 Peter S Lyby2 1Department of Psychology, Research Group for Cognitive Neuroscience, The Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway; 2Catosenteret Rehabilitation Center, Son, Norway Abstract: Nocebo hyperalgesia has received sparse experimental attention compared to placebo analgesia. The aim of the present study was to investigate if personality traits and fear of pain could predict experimental noc...

  3. Placebo manipulations reduce hyperalgesia in neuropathic pain.

    Science.gov (United States)

    Petersen, Gitte Laue; Finnerup, Nanna Brix; Nørskov, Kathrine Næsted; Grosen, Kasper; Pilegaard, Hans K; Benedetti, Fabrizio; Price, Donald D; Jensen, Troels Staehelin; Vase, Lene

    2012-06-01

    Several studies have shown that placebo analgesia effects can be obtained in healthy volunteers, as well as patients suffering from acute postoperative pain and chronic pain conditions such as irritable bowel syndrome. However, it is unknown whether placebo analgesia effects can be elicited in chronic pain conditions with a known pathophysiology such as a nerve injury. Nineteen patients who had developed neuropathic pain after thoracotomy were exposed to a placebo manipulation in which they received either open or hidden administrations of lidocaine. Before the treatment, the patients rated their levels of spontaneous pain and expected pain and completed a questionnaire on their emotional feelings (Positive Affect Negative Affect Schedule) and went through quantitative sensory testing of evoked pain (brush and cold allodynia, heat pain tolerance, area of pinprick hyperalgesia, wind-up-like pain after pinprick stimulation). The placebo manipulation significantly reduced the area of pinprick hyperalgesia (P=.027), and this placebo effect was significantly related to low levels of negative affect (P=.008; R(2)=0.362) but not to positive affect or expected pain levels. No placebo effect was observed in relation to spontaneous pain or evoked pain, which is most likely due to low pain levels resulting in floor effects. This is the first study to demonstrate a placebo effect in neuropathic pain. The possible mechanisms underlying the placebo effects in hyperalgesia are discussed, and implications for treatment are outlined.

  4. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy.

    Science.gov (United States)

    Bierhaus, Angelika; Fleming, Thomas; Stoyanov, Stoyan; Leffler, Andreas; Babes, Alexandru; Neacsu, Cristian; Sauer, Susanne K; Eberhardt, Mirjam; Schnölzer, Martina; Lasitschka, Felix; Lasischka, Felix; Neuhuber, Winfried L; Kichko, Tatjana I; Konrade, Ilze; Elvert, Ralf; Mier, Walter; Pirags, Valdis; Lukic, Ivan K; Morcos, Michael; Dehmer, Thomas; Rabbani, Naila; Thornalley, Paul J; Edelstein, Diane; Nau, Carla; Forbes, Josephine; Humpert, Per M; Schwaninger, Markus; Ziegler, Dan; Stern, David M; Cooper, Mark E; Haberkorn, Uwe; Brownlee, Michael; Reeh, Peter W; Nawroth, Peter P

    2012-06-01

    This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Na(v)1.8 knockout (Scn10(-/-)) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal- and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy.

  5. The degree of acute descending control of spinal nociception in an area of primary hyperalgesia is dependent on the peripheral domain of afferent input.

    Science.gov (United States)

    Drake, Robert A R; Hulse, Richard P; Lumb, Bridget M; Donaldson, Lucy F

    2014-08-15

    Descending controls of spinal nociceptive processing play a critical role in the development of inflammatory hyperalgesia. Acute peripheral nociceptor sensitization drives spinal sensitization and activates spino-supraspinal-spinal loops leading to descending inhibitory and facilitatory controls of spinal neuronal activity that further modify the extent and degree of the pain state. The afferent inputs from hairy and glabrous skin are distinct with respect to both the profile of primary afferent classes and the degree of their peripheral sensitization. It is not known whether these differences in afferent input differentially engage descending control systems to different extents or in different ways. Injection of complete Freund's adjuvant resulted in inflammation and swelling of hairy hind foot skin in rats, a transient thermal hyperalgesia lasting hyperalgesia (≥7 days). Much longer lasting thermal hyperalgesia was apparent in glabrous skin (1 h to >72 h). In hairy skin, transient hyperalgesia was associated with sensitization of withdrawal reflexes to thermal activation of either A- or C-nociceptors. The transience of the hyperalgesia was attributable to a rapidly engaged descending inhibitory noradrenergic mechanism, which affected withdrawal responses to both A- and C-nociceptor activation and this could be reversed by intrathecal administration of yohimbine (α-2-adrenoceptor antagonist). In glabrous skin, yohimbine had no effect on an equivalent thermal inflammatory hyperalgesia. We conclude that acute inflammation and peripheral nociceptor sensitization in hind foot hairy skin, but not glabrous skin, rapidly activates a descending inhibitory noradrenergic system. This may result from differences in the engagement of descending control systems following sensitization of different primary afferent classes that innervate glabrous and hairy skin.

  6. Subjects with Knee Osteoarthritis Exhibit Widespread Hyperalgesia to Pressure and Cold.

    Directory of Open Access Journals (Sweden)

    Penny Moss

    Full Text Available Hyperalgesia to mechanical and thermal stimuli are characteristics of a range of disorders such as tennis elbow, whiplash and fibromyalgia. This study evaluated the presence of local and widespread mechanical and thermal hyperalgesia in individuals with knee osteoarthritis, compared to healthy control subjects. Twenty-three subjects with knee osteoarthritis and 23 healthy controls, matched for age, gender and body mass index, were recruited for the study. Volunteers with any additional chronic pain conditions were excluded. Pain thresholds to pressure, cold and heat were tested at the knee, ipsilateral heel and ipsilateral elbow, in randomized order, using standardised methodology. Significant between-groups differences for pressure pain and cold pain thresholds were found with osteoarthritic subjects demonstrating significantly increased sensitivity to both pressure (p = .018 and cold (p = .003 stimuli, compared with controls. A similar pattern of results extended to the pain-free ipsilateral ankle and elbow indicating widespread pressure and cold hyperalgesia. No significant differences were found between groups for heat pain threshold, although correlations showed that subjects with greater sensitivity to pressure pain were also likely to be more sensitive to both cold pain and heat pain. This study found widespread elevated pain thresholds in subjects with painful knee osteoarthritis, suggesting that altered nociceptive system processing may play a role in ongoing arthritic pain for some patients.

  7. The beta-lactam antibiotic, ceftriaxone, inhibits the development of opioid-induced hyperalgesia in mice.

    Science.gov (United States)

    Chen, Zhijun; He, Ying; Wang, Zaijie Jim

    2012-02-16

    The glutamate transporter GLT-1 is primarily responsible for glutamate clearance in the spinal cord. beta-Lactam antibiotics have been shown to attenuate neuropathic pain behaviors by promoting GLT-1 expression and function in the CNS. The present study tested the hypothesis that ceftriaxone, a prototype beta-lactam antibiotic, can prevent the development of opioid-induced hyperalgesia (OIH) in mice. Repeated morphine administration produced mechanical allodynia and thermal hyperalgesia, signs of OIH, and reduced spinal GLT-1 expression in mice. Ceftriaxone (200mg/kg/d, i.p., for 7 d) inhibited OIH. Correlating with the behavioral effects, ceftriaxone reversed downregulation of GLT-1 expression that was induced by OIH. These results suggest that ceftriaxone inhibited the development of OIH by up-regulating spinal GLT-1 expression.

  8. Tyrosine phosphorylation of the N-Methyl-D-Aspartate receptor 2B subunit in spinal cord contributes to remifentanil-induced postoperative hyperalgesia: the preventive effect of ketamine

    Directory of Open Access Journals (Sweden)

    Cui Songqin

    2009-12-01

    Full Text Available Abstract Background Experimental and clinical studies showed that intraoperative infusionof remifentanil has been associated with postoperative hyperalgesia. Previous reports suggested that spinal N-methyl-D-aspartate (NMDA receptors may contribute to the development and maintenance of opioid-induced hyperalgesia. In the present study, we used a rat model of postoperative pain to investigate the role of tyrosine phosphorylation of NMDA receptor 2B (NR2B subunit in spinal cord in the postoperative hyperalgesia induced by remifentanil and the intervention of pretreatment with ketamine. Results Intraoperative infusion of remifentanil (0.04 mg/kg, subcutaneous significantly enhanced mechanical allodynia and thermal hyperalgesia induced by the plantar incision during the postoperative period (each lasting between 2 h and 48 h, which was attenuated by pretreatment with ketamine (10 mg/kg, subcutaneous. Correlated with the pain behavior changes, immunocytochemical and western blotting experiments in our study revealed that there was a marked increase in NR2B phosphorylation at Tyr1472 in the superficial dorsal horn after intraoperative infusion of remifentanil, which was attenuated by pretreatment with ketamine. Conclusions This study provides direct evidence that tyrosine phosphorylation of the NR2B at Tyr1472 in spinal dosal horn contributes to postoperative hyperalgesia induced by remifentanil and supports the potential therapeutic value of ketamine for improving postoperative hyperalgesia induced by remifentanil.

  9. 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.

  10. Opioid-induced hyperalgesia and burn pain.

    Science.gov (United States)

    Holtman, Joseph R; Jellish, W Scott

    2012-01-01

    The treatment of pain produced during the management of burn injury has been an ongoing problem for physicians caring for these patients. The main therapeutic option for analgesia has been the repeated and prolonged use of opioids. The adverse effects of opioids are well known but the long term use of opioids which produces tolerance with accompanying dose escalation and dependence is most problematic. Another potentially important consequence of opioid exposure that sometimes masks as tolerance is that of opioid induced hyperalgesia. This syndrome is manifest as enhanced pain, sensitivity and loss of analgesic efficacy in patients treated with opioids who actually become sensitized to painful stimuli. This article focuses on the treatment of burn pain and how current analgesic therapies with opioids may cause hyperalgesia and affect the adequacy of treatment for burn pain. This article also provides possible modalities to help therapeutically manage these patients and considers future analgesic strategies which may help to improve pain management in this complicated patient population.

  11. The major brain endocannabinoid 2-AG controls neuropathic pain and mechanical hyperalgesia in patients with neuromyelitis optica.

    Directory of Open Access Journals (Sweden)

    Hannah L Pellkofer

    Full Text Available Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO. While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST following the protocol of the German Research Network on Neuropathic Pain (DFNS. Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11 suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG. These data emphasize the high prevalence of neuropathic pain and hyperalgesia

  12. Effects of ginsenosides on opioid-induced hyperalgesia in mice.

    Science.gov (United States)

    Li, Peng; Tang, Minke; Li, Hui; Huang, Xinjie; Chen, Lei; Zhai, Haifeng

    2014-07-01

    Opioid-induced hyperalgesia (OIH) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. OIH can limit the clinical use of opioid analgesics and complicate withdrawal from opioid addiction. In this study, we investigated the effects of Re, Rg1, and Rb1 ginsenosides, the bioactive components of ginseng, on OIH. OIH was achieved in mice after subcutaneous administration of morphine for 7 consecutive days three times per day. During withdrawal (days 8 and 9), these mice were administered Re, Rg1, or Rb1 intragastrically two times per day. On the test day (day 10), mice were subjected to the thermal sensitivity test and the acetic acid-induced writhing test. Re (300 mg/kg) inhibited OIH in both the thermal sensitivity test and the acetic acid-induced writhing test. However, the Rg1 and Rb1 ginsenosides failed to prevent OIH in either test. Furthermore, Rg1 showed a tendency to aggravate OIH in the acetic acid-induced writhing test. Our data suggested that the ginsenoside Re, but not Rg1 or Rb1, may contribute toward reversal of OIH.

  13. THE ROLES OF GLIAL AND PROINFLAMMATORY CYTOKINES IN TACTILE ALLODYNIA AND THERMAL HYPERALGESIA INDUCED BY INTRATHECAL ADMINISTRATION OF PLATELETACTIVATING FACTOR%胶质细胞和促炎性细胞因子参与鞘内注射血小板活化因子诱发的触诱发痛和热痛敏

    Institute of Scientific and Technical Information of China (English)

    杨京利; 马国平; 秦成名; 刘菊英; 王贤裕

    2012-01-01

    Objective: To investigate the roles of glial, proinflammatory cytokines and NF-kB pathway in development of tactile allodynia and thermal hyperalgesia induced by platelet-activating factor (PAF) administered intrathecally. Methods: 64 Sprague-Dawley rats with intrathecal PE-10 catheters were randomly divided into 6 groups: ACSF group (artificial cerebral spinal fluid, 10 ul), PAF group (10 ug, dissolved in 10 ul ACSF) group, DMSO group, SC-514 (10 mg/kg) group I , SC-514 (50 mg/kg) group II and SC-514 (100 mg/kg) group HI . SC-514 were injected intraperitoneally 2 hours before intrathecal injection with PAF. Paw withdrawal mechanical threshold and thermal latency were measured after PAF administered intrathecally. The activation of astrocyte and microglia in lumbar spinal cord were assessed with immunohistochemical staining of glial fibrillary acid protein (GFAP) and OX-42 respectively. Proinflammatory cytokines TNF-a and IL-ip in lumbar spinal cord were analyzed with ELISA. Results: Intrathecally administered PAF induced tactile allodynia and thermal hyperalgesia rapidly, activated astrocyte and microglia, and increased the expressions of TNF-a and IL-ip in lumbar spinal cord. Pretreatment with SC-514 dose-dependently attenuated pain induced by PAF and inhibited the increasing of TNF-a and IL-ip expression in spinal cord. Conclusion: Intrathecally administered PAF may inducedevelopment of tactile allodynia and thermal hyperalgesia in rats. Activation of glia and NF-kB pathwayand increased expression of TNF-a and IL-ip in spinal cord may be involved in its mechanism.%目的:探讨脊髓胶质细胞、促炎性细胞因子TNF-α和IL-1β以及NF-κ B通路在鞘内注射血小板活化因子(PAF)诱发大鼠痛敏中的作用.方法:鞘内置管成功的雄性Sprague-Dawley大鼠64只随机分为6组:人工脑脊液(artificial cerebral spinal fluid,ACSF),对照组(n=16),鞘内注射ACSF 10μl;PAF组(n=16),鞘内注射PAF 10 μg,溶解于10μl人工脑脊液;

  14. Fentanyl-induced hyperalgesia in acute pain management.

    Science.gov (United States)

    Lyons, Pamela J; Rivosecchi, Ryan M; Nery, Jose P; Kane-Gill, Sandra L

    2015-06-01

    There are safety concerns with the use of fentanyl, including respiratory depression, nausea, constipation, and possibly opioid-induced hyperalgesia (OIH). The purpose of this review is to evaluate the occurrence and significance of opioid-induced hyperalgesia (OIH) after acute fentanyl exposure. A literature search was conducted from October 1995 through January 2015 using MEDLINE, Embase, and Scopus with the terms hyperalgesia, fentanyl, pronociceptive, acute tolerance, and acute. Published articles evaluating the adverse effects of fentanyl during acute pain management (≤96 hours) in humans were included. Opioid-induced hyperalgesia is a phenomenon defined by increasing pain after opioid exposure with the worsening of pain occurring when opioid doses are increased. Hyperalgesia has been described following remifentanil and morphine use, but the question remains about the associated risk with acute fentanyl exposure. Six randomized, controlled trials evaluating the effect of fentanyl on pain in the acute setting have been conducted. Two trials oppose whereas four trials support the occurrence of fentanyl-induced hyperalgesia. The data on OIH after acute fentanyl exposure are limited and conflicting. Hyperalgesia should be considered in patients with uncontrolled pain despite escalating fentanyl doses, since the possibility of fentanyl-induced OIH exists in the acute setting. Well-designed trials are needed to determine the clinical significance of this phenomenon.

  15. Failure of intrathecal ketorolac to reduce remifentanil-induced postinfusion hyperalgesia in humans.

    Science.gov (United States)

    Eisenach, James C; Tong, Chuanyao; Curry, Regina S

    2015-01-01

    In rodents, acute exposure to opioids results in transient antinociception followed by longer lasting hypersensitivity to tactile or thermal stimuli, a phenomenon termed opioid-induced hyperalgesia. This hypersensitivity can be blocked or reversed by intrathecally administered cyclooxygenase inhibitors, including ketorolac, suggesting a role for spinal prostaglandins. In surgical patients, the dose of intraoperative opioid, particularly the short-acting drug, remifentanil, is directly related to increased pain and opioid requirements for many hours postoperatively. In addition, experimentally induced tactile hypersensitivity in humans is exaggerated after cessation of remifentanil infusions. The degree of this experimental opioid-induced hyperalgesia is reduced by systemic treatment with cyclooxygenase inhibitors, and investigators have speculated that this reduction reflects the actions in the central nervous system, most likely in the spinal cord. To test this hypothesis, we measured cerebrospinal fluid prostaglandin E2 concentrations during and after remifentanil infusion in 30 volunteers. These volunteers received intrathecal ketorolac or saline in a random, blinded manner during intravenous remifentanil infusion after generation of hypersensitivity by topical capsaicin. Remifentanil reduced pain to noxious heat stimuli and reduced areas of capsaicin-induced hypersensitivity similarly in those receiving intrathecal ketorolac or saline. The primary outcome measure, area of capsaicin-induced hypersensitivity after stopping remifentanil, showed a similar increase in those receiving ketorolac as in those receiving saline. Cerebrospinal fluid prostaglandin E2 concentrations did not increase during postinfusion hyperalgesia compared with those during infusion, and they were not increased during infusion compared with those in historical controls. These data fail to support the hypothesis that acute opioid-induced hyperalgesia reflects spinal cyclooxygenase activation

  16. Opioid induced hyperalgesia in anesthetic settings.

    Science.gov (United States)

    Lee, Hyeon Jeong; Yeomans, David C

    2014-11-01

    Pain is difficult to investigate and difficult to treat, in part, because of problems in quantification and assessment. The use of opioids, combined with classic anesthetics to maintain hemodynamic stability by controlling responses to intraoperative painful events has gained significant popularity in the anesthetic field. However, several side effects profiles concerning perioperative use of opioid have been published. Over the past two decades, many concerns have arisen with respect to opioid-induced hyperalgesia (OIH), which is the paradoxical effect wherein opioid usage may decrease pain thresholds and increase atypical pain unrelated to the original, preexisting pain. This brief review focuses on the evidence, mechanisms, and modulatory and pharmacologic management of OIH in order to elaborate on the clinical implication of OIH.

  17. PHARMACOLOGIC TREATMENT OF HYPERALGESIA EXPERIMENTALLY INDUCED BY NUCLEUS PULPOSUS

    OpenAIRE

    de Souza Grava, André Luiz; Ferrari,Luiz Fernando; Parada, Carlos Amílcar; Defino, Helton Luiz Aparecido

    2015-01-01

    Objective: To evaluate the effect of anti-inflammatory drugs (dexamethasone, indomethacin, atenolol and indomethacin plus atenolol) and analgesic drugs (morphine) on hyperalgesia experimentally induced by the nucleus pulposus (NP) in contact with the L5 dorsal root ganglion (DRG). Methods: Thirty male Wistar rats of weights ranging from 220 to 250 g were used in the study. Hyperalgesia was induced by means of a fragment of NP removed from the sacrococcygeal region that was placed in contact w...

  18. Time course of primary and secondary hyperalgesia after heat injury to the skin

    DEFF Research Database (Denmark)

    Møiniche, S; Dahl, J B; Kehlet, H

    1993-01-01

    We have examined the time course of, and relationship between, primary and secondary hyperalgesia after thermal injury to the skin in humans. Burn injuries (15 x 25 mm rectangular thermode, 49 degrees C, 5 min) were produced in eight healthy, unmedicated male volunteers, on the medial side...... of the right calf, on two occasions at least 8 days apart. Heat pain detection thresholds (HPDT), heat pain tolerance (HPT), mechanical pain detection threshold (MPDT) and the intensity of burn-injury induced erythema (skin erythema index, SEI) were assessed inside the burn injury. HPT was assessed only in one...

  19. Ursolic acid prevents augmented peripheral inflammation and inflammatory hyperalgesia in high-fat diet-induced obese rats by restoring downregulated spinal PPARα.

    Science.gov (United States)

    Zhang, Yanan; Song, Chengwei; Li, Haiou; Hou, Jingdong; Li, Dongliang

    2016-06-01

    Obesity is a risk factor for several pain syndromes and is associated with increased pain sensitivity. Evidence suggests that obesity causes the downregulation of peroxisome proliferator‑activated receptor (PPAR)α in the spinal cord, contributing to augmented peripheral edema and inflammatory hyperalgesia. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, has been shown to upregulate PPARα in the peripheral tissues of obese animals. The present study hypothesized that UA prevents augmented peripheral inflammation and inflammatory hyperalgesia in obesity by restoring downregulated spinal PPARα. The present study demonstrated that Sprague‑Dawley rats fed a high‑fat diet (HFD) for 12 weeks developed obesity and metabolic disorder. Following carrageenan injection, the HFD rats exhibited increased thermal hyperalgesia and paw edema, compared with the rats fed a low‑fat diet. Molecular investigations revealed that the HFD rats exhibited decreased PPARα activity, and exaggerated expression of inflammatory mediators and nuclear factor‑kB activity in the spinal cord in response to carrageenan. Oral administration of UA ameliorated obesity and metabolic disorder, and prevented increased thermal hyperalgesia and paw edema in the HFD rats. Additionally, UA normalized PPARα activity and inhibited the exaggerated spinal cord inflammatory response to carrageenan. Although the knockdown of spinal PPARα with small interfering RNA following the administration of UA did not alter obesity or metabolic parameters, it eradicated the beneficial effects of UA on thermal hyperalgesia and paw edema, and reversed the spinal cord inflammatory response. These results suggested that the systemic administration of UA inhibited the exaggerated spinal cord inflammatory response to peripheral inflammatory stimulation in HFD‑induced obesity by restoring downregulated spinal PPARα, preventing peripheral inflammation and inflammatory hyperalgesia. UA may be a

  20. Bilateral hand/wrist heat and cold hyperalgesia, but not hypoesthesia, in unilateral carpal tunnel syndrome.

    Science.gov (United States)

    de la Llave-Rincón, Ana Isabel; Fernández-de-las-Peñas, César; Fernández-Carnero, Josué; Padua, Luca; Arendt-Nielsen, Lars; Pareja, Juan A

    2009-10-01

    The aim of the current study was to evaluate bilaterally warm/cold detection and heat/cold pain thresholds over the hand/wrist in patients with carpal tunnel syndrome (CTS). A total of 25 women with strictly unilateral CTS (mean 42 +/- 10 years), and 20 healthy matched women (mean 41 +/- 8 years) were recruited. Warm/cold detection and heat/cold pain thresholds were assessed bilaterally over the carpal tunnel and the thenar eminence in a blinded design. Self-reported measures included both clinical pain history (intensity, location and area) and Boston Carpal Tunnel Questionnaire. No significant differences between groups for both warm and cold detection thresholds in either carpal tunnel or thenar eminence (P > 0.5) were found. Further, significant differences between groups, but not between sides, for both heat and cold pain thresholds in both the carpal tunnel and thenar eminence were found (all P < 0.001). Heat pain thresholds (P < 0.01) were negatively correlated, whereas cold pain thresholds (P < 0.001) were positively correlated with hand pain intensity and duration of symptoms. Our findings revealed bilateral thermal hyperalgesia (lower heat pain and reduced cold pain thresholds) but not hypoesthesia (normal warm/cold detection thresholds) in patients with strictly unilateral CTS when compared to controls. We suggest that bilateral heat and cold hyperalgesia may reflect impairments in central nociceptive processing in patients with unilateral CTS. The bilateral thermal hyperalgesia associated with pain intensity and duration of pain history supports a role of generalized sensitization mechanisms in the initiation, maintenance and spread of pain in CTS.

  1. Opioid-Induced Hyperalgesia: A Diagnostic Dilemma.

    Science.gov (United States)

    Carullo, Veronica; Fitz-James, Ingrid; Delphin, Ellise

    2015-01-01

    Opioids are utilized frequently for the treatment of moderate to severe acute pain in the perioperative setting, as well as in the treatment of cancer-related pain. When prescribing chronic opioid therapy to patients with chronic pain, it is crucial for the practitioner to be aware not only of the issues of tolerance and withdrawal, but also to have knowledge of the possibility for opioid-induced hyperalgesia (OIH). An understanding of the differences between tolerance and OIH when escalating opioid therapy allows the titration of opioid as well as nonopioid analgesics in order to obtain maximum control of both chronic and acute pain. A case study is described to highlight the importance of judicious utilization of opioids in the treatment of cancer-related pain. In this case, high-dose opioid therapy did not improve chronic pain and contributed to a hyperalgesic state in which a young man experienced severe intractable pain postoperatively after two routine thoracotomies, despite aggressive pharmacologic measures to manage his perioperative pain. Furthermore, it illustrates the potential advantages of opioid rotation to methadone when OIH is suspected.

  2. Visceral hyperalgesia caused by peptide YY deletion and Y2 receptor antagonism

    Science.gov (United States)

    Hassan, Ahmed M.; Jain, Piyush; Mayerhofer, Raphaela; Fröhlich, Esther E.; Farzi, Aitak; Reichmann, Florian; Herzog, Herbert; Holzer, Peter

    2017-01-01

    Altered levels of colonic peptide YY (PYY) have been reported in patients suffering from functional and inflammatory bowel disorders. While the involvement of neuropeptide Y (NPY) and Y receptors in the regulation of nociception is well established, the physiological role of PYY in somatic and visceral pain is poorly understood. In this work, the role of PYY in pain sensitivity was evaluated using PYY knockout (PYY(−/−)) mice and Y2 receptor ligands. PYY(−/−) mice were more sensitive to somatic thermal pain compared to wild type (WT) mice. Visceral pain was assessed by evaluating pain-related behaviors, mouse grimace scale (MGS) and referred hyperalgesia after intrarectal administration of allyl isothiocyanate (AITC, 1 or 2%) or its vehicle, peanut oil. The pain-related behaviors induced by AITC were significantly exaggerated by PYY deletion, whereas the MGS readout and the referred hyperalgesia were not significantly affected. The Y2 receptor antagonist, BII0246, increased pain-related behaviors in response to intrarectal AITC compared to vehicle treatment while the Y2 receptor agonist, PYY(3–36), did not have a significant effect. These results indicate that endogenous PYY has a hypoalgesic effect on somatic thermal and visceral chemical pain. The effect on visceral pain seems to be mediated by peripheral Y2 receptors. PMID:28106168

  3. Interactions of estradiol and NSAIDS on carrageenan-induced hyperalgesia.

    Science.gov (United States)

    Hunter, Deirtra A; Barr, Gordon A; Shivers, Kai-Yvonne; Amador, Nicole; Jenab, Shirzad; Inturrisi, Charles; Quinones-Jenab, Vanya

    2011-03-25

    How exogenous estrogen affects inflammatory responses is poorly understood despite the large numbers of women receiving estrogen-alone hormone therapy. The aim of this study was to determine if estradiol alters injury- or inflammation-induced nociceptive responses after carrageenan administration in females and whether its effects are mediated through cyclo-oxygenase (COX) and prostaglandins (PG). To this end, paw withdrawal latencies and serum levels of PGE2 and PGD2 were measured in rats treated with estradiol (0, 10, 20, and 30%) and/or SC560 (COX-1 inhibitor) or NS398 (COX-2 inhibitor) after intraplantar carrageenan administration. Estradiol significantly increased withdrawal latencies before (baseline condition) and after carrageenan administration to one hindpaw. NS398 was anti-nociceptive only in carrageenan treated animals. SC560 increased withdrawal latencies in both paws at 1 and 5hours after carrageenan administration. Co-administration of estradiol and NS398, but not SC560, was additive except for a prolonged anti-nociceptive effects of estradiol combined with NS398. The anti-nociceptive effect extended beyond that observed with either drug or estradiol alone at the 5-hour time point. Estradiol had no significant effect on PGE2 serum levels, but both COX antagonists decreased them. Although neither estradiol nor the COX inhibitors alone had an effect on PGD2 serum levels, co-administration of NS398 and estradiol significantly elevated PGD2 levels. Taken together, our results suggest that estradiol is anti-nociceptive in the thermal test and reduces carrageenan-induced hyperalgesia. These effects are minimally altered through PG-mediated mechanisms.

  4. Spinal processing of bee venom-induced pain and hyperalgesia

    Institute of Scientific and Technical Information of China (English)

    Jun CHEN

    2008-01-01

    Subcutaneous injection of bee venom causes long-term neural activation and hypersensitization in the dorsal horn of the spinal cord, which contributes to the development and maintenance of various pain-related behaviors. The unique behavioral 'pheno-types' of nociception and hypersensitivity identified in the rodent bee venom test are believed to reflect a complex pathological state of inflammatory pain and might be appropriate to the study of phenotype-based mechanisms of pain and hyperalgesia. In this review, the spinal processing of the bee venom-induced different 'phenotypes' of pain and hyperalgesia will be described. The accumulative electrophysiological, pharmacological, and behavioral data strongly suggest that different 'phenotypes' of pain and hyperalgesia are mediated by different spinal signaling pathways. Unraveling the phenotype-based mechanisms of pain might be useful in development of novel therapeutic drugs against complex clinic pathological pain.

  5. Leishmania (L). amazonensis induces hyperalgesia in balb/c mice: Contribution of endogenous spinal cord TNFα and NFκB activation.

    Science.gov (United States)

    Borghi, Sergio M; Fattori, Victor; Ruiz-Miyazawa, Kenji W; Miranda-Sapla, Milena M; Casagrande, Rúbia; Pinge-Filho, Phileno; Pavanelli, Wander R; Verri, Waldiceu A

    2017-02-17

    Cutaneous leishmaniasis (CL) is the most common form of the leishmaniasis in humans. Ulcerative painless skin lesions are predominant clinical features of CL. Wider data indicate pain accompanies human leishmaniasis, out with areas of painless ulcerative lesions per se. In rodents, Leishmania (L.) major infection induces nociceptive behaviors that correlate with peripheral cytokine levels. However, the role of the spinal cord in pain processing after Leishmania infection has not been investigated. Balb/c mice received intraplantar (i.pl.) injection of Leishmania (L). amazonensis and hyperalgesia, edema, parasitism, and spinal cord TNFα, TNFR1 and TNFR2 mRNA expression, and NFκB activation were evaluated. The effects of intrathecal (i.t.) injection of morphine, TNFα, TNFα inhibitors (etanercept and adalimumab) and NFκB inhibitor (PDTC) were investigated. The present study demonstrates that Leishmania (L.) amazonensis infection in balb/c mice induces chronic mechanical and thermal hyperalgesia in an opioid-sensitive manner. Spinal cord TNFα mRNA expression increased in a time-dependent manner, peaking between 30 and 40 days after infection. At the peak of TNFα mRNA expression (day 30), there was a concomitant increase in TNFR1 and TNFR2 mRNA expression. TNFα i.t. injection enhanced L. (L.) amazonensis-induced hyperalgesia. Corroborating a role for TNFα in L. (L.) amazonensis-induced hyperalgesia, i.t. treatment with the TNFα inhibitors, etanercept and adalimumab inhibited the hyperalgesia. L. (L.) amazonensis also induced spinal cord activation of NFκB, and PDTC (given i.t.), also inhibited L. (L.) amazonensis-induced hyperalgesia, and spinal cord TNFα, TNFR1 and TNFR2 mRNA expression. Moreover, L. (L.) amazonensis-induced spinal cord activation of NFκB was also inhibited by etanercept and adalimumab as well as PDTC i.t.

  6. Pain referral and regional deep tissue hyperalgesia in experimental human hip pain models.

    Science.gov (United States)

    Izumi, Masashi; Petersen, Kristian Kjær; Arendt-Nielsen, Lars; Graven-Nielsen, Thomas

    2014-04-01

    Hip disorder patients typically present with extensive pain referral and hyperalgesia. To better understand underlying mechanisms, an experimental hip pain model was established in which pain referrals and hyperalgesia could be studied under standardized conditions. In 16 healthy subjects, pain was induced by hypertonic saline injection into the gluteus medius tendon (GMT), adductor longus tendon (ALT), or gluteus medius muscle (GMM). Isotonic saline was injected contralaterally as control. Pain intensity was assessed on a visual analogue scale (VAS), and subjects mapped the pain distribution. Before, during, and after injections, passive hip joint pain provocation tests were completed, together with quantitative sensory testing as follows: pressure pain thresholds (PPTs), cuff algometry pain thresholds (cuff PPTs), cutaneous pin-prick sensitivity, and thermal pain thresholds. Hypertonic saline injected into the GMT resulted in higher VAS scores than hypertonic injections into the ALT and GMM (Ppain areas spread to larger parts of the leg after GMT and GMM injections compared with more regionalized pain pattern after ALT injections (Ppain provocation tests after hypertonic compared with isotonic saline injections (Ppain mechanisms associated with painful hip disorders.

  7. Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain.

    Science.gov (United States)

    Matsuo, Hideaki; Uchida, Kenzo; Nakajima, Hideaki; Guerrero, Alexander Rodriguez; Watanabe, Shuji; Takeura, Naoto; Sugita, Daisuke; Shimada, Seiichiro; Nakatsuka, Terumasa; Baba, Hisatoshi

    2014-09-01

    Although transcutaneous electrical nerve stimulation (TENS) is widely used for the treatment of neuropathic pain, its effectiveness and mechanism of action in reducing neuropathic pain remain uncertain. We investigated the effects of early TENS (starting from the day after surgery) in mice with neuropathic pain, on hyperalgesia, glial cell activation, pain transmission neuron sensitization, expression of proinflammatory cytokines, and opioid receptors in the spinal dorsal horn. Following nerve injury, TENS and behavioral tests were performed every day. Immunohistochemical, immunoblot, and flow cytometric analysis of the lumbar spinal cord were performed after 8 days. Early TENS reduced mechanical and thermal hyperalgesia and decreased the activation of microglia and astrocytes (PEarly TENS decreased p-p38 within microglia (Pearly TENS relieved hyperalgesia in our mouse model of neuropathic pain by inhibiting glial activation, MAP kinase activation, PKC-γ, and p-CREB expression, and proinflammatory cytokines expression, as well as maintenance of spinal opioid receptors. The findings indicate that TENS treatment is more effective when applied as early after nerve injury as possible.

  8. Peripheral Receptor Mechanisms Underlying Orofacial Muscle Pain and Hyperalgesia

    Science.gov (United States)

    Saloman, Jami L.

    Musculoskeletal pain conditions, particularly those associated with temporomandibular joint and muscle disorders (TMD) are severely debilitating and affect approximately 12% of the population. Identifying peripheral nociceptive mechanisms underlying mechanical hyperalgesia, a prominent feature of persistent muscle pain, could contribute to the development of new treatment strategies for the management of TMD and other muscle pain conditions. This study provides evidence of functional interactions between ligand-gated channels, P2X3 and TRPV1/TRPA1, in trigeminal sensory neurons, and proposes that these interactions underlie the development of mechanical hyperalgesia. In the masseter muscle, direct P2X3 activation, via the selective agonist αβmeATP, induced a dose- and time-dependent hyperalgesia. Importantly, the αβmeATP-induced hyperalgesia was prevented by pretreatment of the muscle with a TRPV1 antagonist, AMG9810, or the TRPA1 antagonist, AP18. P2X3 was co-expressed with both TRPV1 and TRPA1 in masseter muscle afferents confirming the possibility for intracellular interactions. Moreover, in a subpopulation of P2X3 /TRPV1 positive neurons, capsaicin-induced Ca2+ transients were significantly potentiated following P2X3 activation. Inhibition of Ca2+-dependent kinases, PKC and CaMKII, prevented P2X3-mechanical hyperalgesia whereas blockade of Ca2+-independent PKA did not. Finally, activation of P2X3 induced phosphorylation of serine, but not threonine, residues in TRPV1 in trigeminal sensory neurons. Significant phosphorylation was observed at 15 minutes, the time point at which behavioral hyperalgesia was prominent. Similar data were obtained regarding another nonselective cation channel, the NMDA receptor (NMDAR). Our data propose P2X3 and NMDARs interact with TRPV1 in a facilitatory manner, which could contribute to the peripheral sensitization underlying masseter hyperalgesia. This study offers novel mechanisms by which individual pro-nociceptive ligand

  9. Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia.

    Science.gov (United States)

    Chen, Yan; Yang, Cheng; Wang, Zaijie Jim

    2010-01-01

    Repeated administration of opioids not only leads to tolerance and dependence, but also results in nociceptive enhancement called opioid-induced hyperalgesia (OIH). Nociceptive mediators involved in OIH generation remain poorly understood. In the present study, we tested the hypothesis that Ca(2+)/calmodulin-depent protein kinase II (CaMKIIalpha) is critical for OIH. Opioid-induced hyperalgesia was produced by repeated morphine administration or pellet implantation in mice. Correlating with the development of tactile allodynia and thermal hyperalgesia, spinal CaMKIIalpha activity was significantly increased in OIH. KN93, a CaMKII inhibitor, dose- and time-dependently reversed OIH and CaMKII activation without impairing locomotor coordination. To elucidate the specific CaMKII isoform involved, we targeted CaMKIIalpha by using small interfering RNA and demonstrated that knockdown of spinal CaMKIIalpha attenuated OIH. Furthermore, morphine failed to induce OIH in CaMKIIalpha(T286A) point mutant mice, although wild-type littermate mice developed robust OIH after repeated treatments with morphine. These data implicate, for the first time, an essential role of CaMKIIalpha as a cellular mechanism leading to and maintaining opioid-induced hyperalgesia.

  10. 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.

  11. Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion.

    Science.gov (United States)

    Mitchell, Kendall; Lebovitz, Evan E; Keller, Jason M; Mannes, Andrew J; Nemenov, Michael I; Iadarola, Michael J

    2014-04-01

    TRPV1 is expressed in a subpopulation of myelinated Aδ and unmyelinated C-fibers. TRPV1+ fibers are essential for the transmission of nociceptive thermal stimuli and for the establishment and maintenance of inflammatory hyperalgesia. We have previously shown that high-power, short-duration pulses from an infrared diode laser are capable of predominantly activating cutaneous TRPV1+ Aδ-fibers. Here we show that stimulating either subtype of TRPV1+ fiber in the paw during carrageenan-induced inflammation or following hind-paw incision elicits pronounced hyperalgesic responses, including prolonged paw guarding. The ultrapotent TRPV1 agonist resiniferatoxin (RTX) dose-dependently deactivates TRPV1+ fibers and blocks thermal nociceptive responses in baseline or inflamed conditions. Injecting sufficient doses of RTX peripherally renders animals unresponsive to laser stimulation even at the point of acute thermal skin damage. In contrast, Trpv1-/- mice, which are generally unresponsive to noxious thermal stimuli at lower power settings, exhibit withdrawal responses and inflammation-induced sensitization using high-power, short duration Aδ stimuli. In rats, systemic morphine suppresses paw withdrawal, inflammatory guarding, and hyperalgesia in a dose-dependent fashion using the same Aδ stimuli. The qualitative intensity of Aδ responses, the leftward shift of the stimulus-response curve, the increased guarding behaviors during carrageenan inflammation or after incision, and the reduction of Aδ responses with morphine suggest multiple roles for TRPV1+ Aδ fibers in nociceptive processes and their modulation of pathological pain conditions.

  12. Lateral Hypothalamic Stimulation Reduces Hyperalgesia Through Spinally Descending Orexin-A Neurons in Neuropathic Pain.

    Science.gov (United States)

    Wardach, Jacob; Wagner, Monica; Jeong, Younhee; Holden, Janean E

    2016-03-01

    No evidence to date shows that lateral hypothalamic (LH) stimulation produces orexin-A-mediated antinociception in the spinal cord dorsal horn (SCDH) in a model of neuropathic pain. We conducted experiments to examine the effect of orexin-A-mediated LH stimulation in female rats with chronic constriction injury (CCI) on thermal hyperalgesia. Rats receiving carbachol into the LH demonstrated antinociception on both the left CCI and right nonligated paws (p orexin-1 (OX1) receptor antagonist SB-334867, which blocked LH-induced antinociception compared with control groups (p orexin-A connection between the LH and the SCDH. Identification of this pathway may lead to studies using orexins to manage clinical pain.

  13. Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice

    Directory of Open Access Journals (Sweden)

    Carlton Susan M

    2010-03-01

    Full Text Available Abstract Background Cisplatin is primarily used for treatment of ovarian and testicular cancer. Oxaliplatin is the only effective treatment for metastatic colorectal cancer. Both are known to cause dose related, cumulative toxic effects on the peripheral nervous system and thirty to forty percent of cancer patients receiving these agents experience painful peripheral neuropathy. The mechanisms underlying painful platinum-induced neuropathy remain poorly understood. Previous studies have demonstrated important roles for TRPV1, TRPM8, and TRPA1 in inflammation and nerve injury induced pain. Results In this study, using real-time, reverse transcriptase, polymerase chain reaction (RT-PCR, we analyzed the expression of TRPV1, TRPM8, and TRPA1 induced by cisplatin or oxaliplatin in vitro and in vivo. For in vitro studies, cultured E15 rat dorsal root ganglion (DRG neurons were treated for up to 48 hours with cisplatin or oxaliplatin. For in vivo studies, trigeminal ganglia (TG were isolated from mice treated with platinum drugs for three weeks. We show that cisplatin and oxaliplatin-treated DRG neurons had significantly increased in TRPV1, TRPA1, and TRPM8 mRNA expression. TG neurons from cisplatin treated mice had significant increases in TRPV1 and TRPA1 mRNA expression while oxaliplatin strongly induced only TRPA1. Furthermore, compared to the cisplatin-treated wild-type mice, cisplatin-treated TRPV1-null mice developed mechanical allodynia but did not exhibit enhancement of noxious heat- evoked pain responses. Immunohistochemistry studies showed that cisplatin-treated mice had no change in the proportion of the TRPV1 immunopositive TG neurons. Conclusion These results indicate that TRPV1 and TRPA1 could contribute to the development of thermal hyperalgesia and mechanical allodynia following cisplatin-induced painful neuropathy but that TRPV1 has a crucial role in cisplatin-induced thermal hyperalgesia in vivo.

  14. Suspected opioid-induced hyperalgesia in an infant.

    Science.gov (United States)

    Hallett, B R; Chalkiadis, G A

    2012-01-01

    One explanation for diminished opioid analgesic efficacy is opioid-induced hyperalgesia (OIH). We report a case of OIH in an infant with gastroschisis, requiring multiple surgical interventions and prolonged sedation for ventilation. This is the first report of OIH in an infant. On day 41 of life after nine separate surgical interventions, the patient's pain scores increased and remained elevated, despite increasing opioid administration. The patient also developed hyperalgesia, allodynia, and photophobia and became extremely irritable upon handling. Other possible causes were excluded, including interruption to opioid delivery, sepsis, acid-base and electrolyte disturbance, and ongoing surgical pathology. An opioid rotation to hydromorphone was initiated and ketamine was commenced. Sedation for ventilation was achieved with dexmedetomidine and midazolam infusions. Over a period of 24 h after opioid de-escalation, pain scores reduced rapidly and the patient became significantly less irritable with handling. All infusions were gradually weaned and eventually ceased.

  15. When medications make pain worse: opioid-induced hyperalgesia.

    Science.gov (United States)

    Martin, Caren McHenry

    2011-08-01

    Opioid medications are commonly used to treat moderate-to-severe pain. While these medications are generally an effective means of pain control, they can, in rare cases, actually exacerbate the pain. This paradoxical reaction is called opioid-induced hyperalgesia (OIH). Patients experiencing OIH may benefit from decreasing or discontinuing the opioid, switching to an alternative opioid, and/or using a nonopioid medication for pain.

  16. [Opioid-induced hyperalgesia. Pathophysiology and clinical relevance].

    Science.gov (United States)

    Koppert, W

    2004-05-01

    Opioids are the drugs of choice for the treatment of moderate to severe acute and chronic pain. However, clinical evidence suggests that opioids can elicit increased sensitivity to noxious stimuli suggesting that administration of opioids can activate both pain inhibitory and pain facilitatory systems. Acute receptor desensitization via uncoupling of the receptor from G-proteins, up-regulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA) receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports exist demonstrating that opioid-induced hyperalgesia is observed both in animal and human experimental models. Brief exposures to micro-receptor agonists induce long-lasting hyperalgesic effects for days, which might by reflected by clinical observations that large doses of intraoperative micro-receptor agonists increased postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients often requires increasing doses and may be accompanied by the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, alpha(2)-agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor selectivity.

  17. Carbamazepine Withdrawal-induced Hyperalgesia in Chronic Neuropathic Pain.

    Science.gov (United States)

    Ren, Zhenyu; Yang, Bing; Yang, Bin; Shi, Le; Sun, Qing-Li; Sun, A-Ping; Lu, Lin; Liu, Xiaoguang; Zhao, Rongsheng; Zhai, Suodi

    2015-11-01

    Combined pharmacological treatments are the most used approach for neuropathic pain. Carbamazepine, an antiepileptic agent, is generally used as a third-line treatment for neuropathic pain and can be considered an option only when patients have not responded to the first- and second-line medications. In the case presented herein, a patient with neuropathic pain was treated using a combined pharmacological regimen. The patient's pain deteriorated, despite increasing the doses of opioids, when carbamazepine was discontinued, potentially because carbamazepine withdrawal disrupted the balance that was achieved by the multifaceted pharmacological regimen, thus inducing hyperalgesia. Interestingly, when carbamazepine was prescribed again, the patient's pain was successfully managed. Animal research has reported that carbamazepine can potentiate the analgesic effectiveness of morphine in rodent models of neuropathic pain and postoperative pain. This clinical case demonstrates that carbamazepine may have a synergistic effect on the analgesic effectiveness of morphine and may inhibit or postpone opioid-induced hyperalgesia. We postulate that a probable mechanism of action of carbamazepine may involve -aminobutyric acid-ergic potentiation and the interruption of glutamatergic function via N-methyl-D-aspartate receptors. Further research is warranted to clarify the analgesic action of carbamazepine and its potential use for the prevention of opioid-induced hyperalgesia in chronic neuropathic pain patients.

  18. The impact of opioid-induced hyperalgesia for postoperative pain.

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    Koppert, Wolfgang; Schmelz, Martin

    2007-03-01

    Clinical evidence suggests that--besides their well known analgesic activity - opioids can increase rather than decrease sensitivity to noxious stimuli. Based on the observation that opioids can activate pain inhibitory and pain facilitatory systems, this pain hypersensitivity has been attributed to a relative predominance of pronociceptive mechanisms. Acute receptor desensitization via uncoupling of the receptor from G-proteins, upregulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA)-receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports exist demonstrating that opioid-induced hyperalgesia is observed both in animal and human experimental models. Brief exposures to micro-receptor agonists induce long-lasting hyperalgesic effects for days in rodents, and also in humans large-doses of intraoperative micro-receptor agonists were found to increase postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients is often associated with a requirement for increasing doses and the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, alpha2-agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor/selectivity.

  19. Opioid-induced hyperalgesia and rapid opioid detoxification after tacrolimus administration.

    Science.gov (United States)

    Siniscalchi, Antonio; Piraccini, Emanuele; Miklosova, Zuzana; Taddei, Stefania; Faenza, Stefano; Martinelli, Gerardo

    2008-02-01

    Opioids can induce central sensitization and hyperalgesia, referred to as "opioid-induced hyperalgesia." Our report describes a patient who underwent intestinal transplant followed by immunosuppressant-related neuropathic pain. Her pain was treated with limited success over the course of 3 yr with different therapies, including i.v. morphine. She developed opioid-induced hyperalgesia, which was successfully treated with rapid detoxification under general anesthesia. Detoxification improved her quality of life, including the ability to resume physiotherapy. Six months after treatment, she remained opioid free. Our experience suggests that rapid detoxification under general anesthesia may be an effective treatment for opioid-induced hyperalgesia and merits comparison to traditional detoxification methods.

  20. Comparison of pain models to detect opioid-induced hyperalgesia

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    Krishnan S

    2012-04-01

    Full Text Available Sumithra Krishnan1, Amy Salter2, Thomas Sullivan2, Melanie Gentgall3, Jason White4, Paul Rolan11Discipline of Pharmacology, School of Medical Sciences, The University of Adelaide, 2Discipline of Public Health, The University of Adelaide, 3Pain and Anesthesia Research Clinic, Royal Adelaide Hospital, 4Pharmacy School, University of South Australia, Adelaide, South Australia, AustraliaObjective: Chronic opioid therapy may be associated with hyperalgesia. Our objective was to determine if opioid-induced hyperalgesia detection sensitivity is dependent on the stimulus used to detect it.Methods: This open design study compared the detection of hyperalgesia in opioid-dependent subjects (n = 16 and healthy control subjects (n = 16 using the following pain stimuli: cold pain, electrical stimulation, mechanical pressure, and ischemic pain. The opioid-dependent subjects were maintained on either methadone (n = 8 or buprenorphine (n = 8 for at least 3 months. None of the controls was dependent on opioids or other drugs of abuse.Results: The opioid-dependent subjects were markedly more sensitive than controls to the cold pain test. Compared with the control group, the hazard ratio for ceasing the test due to intolerable pain was 7.7 (95% confidence interval [CI] 2.6–23.3 in the buprenorphine group and 4.5 (95% CI 1.7–15.6 in the methadone group, with similar data for the cold pain threshold. Of the remaining tests, there were differences only for the electrical pain threshold between treatment groups, with the geometric mean threshold in the buprenorphine group being 1.5 (95% CI 1.1–1.9-fold higher (ie, less sensitive than that of the controls; the geometric mean for the methadone group was 1.3 (95% CI 1.04–1.7-fold higher than that of the controls. There were no significant differences between buprenorphine and methadone patients in test responses. Women were more sensitive to the cold pain (hazard ratio for tolerance, 3.1 [95% CI 1.4–7.3] and

  1. Inhibition of glycogen synthase kinase-3β prevents remifentanil-induced hyperalgesia via regulating the expression and function of spinal N-methyl-D-aspartate receptors in vivo and vitro.

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    Yize Li

    Full Text Available A large number of experimental and clinical studies have confirmed that brief remifentanil exposure can enhance pain sensitivity presenting as opioid-induced hyperalgesia (OIH. N-methyl-D-aspartate (NMDA receptor antagonists have been reported to inhibit morphine analgesic tolerance in many studies. Recently, we found that glycogen synthase kinase-3β (GSK-3β modulated NMDA receptor trafficking in a rat model of remifentanil-induced postoperative hyperalgesia. In the current study, it was demonstrated that GSK-3β inhibition prevented remifentanil-induced hyperalgesia via regulating the expression and function of spinal NMDA receptors in vivo and in vitro. We firstly investigated the effects of TDZD-8, a selective GSK-3β inhibitor, on thermal and mechanical hyperalgesia using a rat model of remifentanil-induced hyperalgesia. GSK-3β activity as well as NMDA receptor subunits (NR1, NR2A and NR2B expression and trafficking in spinal cord L4-L5 segments were measured by Western blot analysis. Furthermore, the effects of GSK-3β inhibition on NMDA-induced current amplitude and frequency were studied in spinal cord slices by whole-cell patch-clamp recording. We found that remifentanil infusion at 1 μg·kg(-1·min(-1 and 2 μg·kg(-1·min(-1 caused mechanical and thermal hyperalgesia, up-regulated NMDA receptor subunits NR1 and NR2B expression in both membrane fraction and total lysate of the spinal cord dorsal horn and increased GSK-3β activity in spinal cord dorsal horn. GSK-3β inhibitor TDZD-8 significantly attenuated remifentanil-induced mechanical and thermal hyperalgesia from 2 h to 48 h after infusion, and this was associated with reversal of up-regulated NR1 and NR2B subunits in both membrane fraction and total lysate. Furthermore, remifentanil incubation increased amplitude and frequency of NMDA receptor-induced current in dorsal horn neurons, which was prevented with the application of TDZD-8. These results suggest that inhibition of

  2. Effects of symptomatic treatments on cutaneous hyperalgesia and laser evoked potentials during migraine attack.

    Science.gov (United States)

    de Tommaso, M; Losito, L; Libro, G; Guido, M; Di Fruscolo, O; Sardaro, M; Sciruicchio, V; Lamberti, P; Livrea, P

    2005-05-01

    Previously an amplitude enhancement of laser evoked potentials (LEPs) was detected during migraine attack: we further examined pain threshold to CO2 laser stimuli and LEPs during attacks, evaluating the effect of almotriptan, lysine-acetylsalicylate and placebo treatment on cutaneous hyperalgesia to thermal stimuli delivered by CO2 laser and on LEP components. Eighteen patients suffering from migraine without aura were analysed. They were divided into three groups of six patients each, randomly assigned to lysine acetyl-salicylate, almotriptan or placebo treatments. The supraorbital zones and the dorsum of the hand were stimulated on both the symptomatic and not symptomatic side in all patients. The LEPs were recorded by 25 scalp electrodes. During attacks, the P2 wave was significantly enhanced; the amplitude of the P2 component obtained by the stimulation of the supraorbital zone during the attack on the side of the headache was significantly correlated with the intensity of pain and the frequency of headache. Both almotriptan and lysine acetyl-salicylate significantly reduced the P2 amplitude but they showed no effects on hyperalgesia to laser stimulation; headache relief following therapy was correlated with the reduction of the P2 amplitude. The cortical elaboration of laser-induced experimental pain seemed increased during migraine attack, and the severity of headache was mainly related to the increase of the later LEPs components expressing the attentive and emotive compounds of suffering. Reversion of this process appeared to be primarily responsible for the efficacy of drugs in treating migraine, though both almotriptan and lysine-acetil salicilate seemed to have no effect in reducing sensitization at second and third order nociceptive neurons.

  3. GABAergic transmission in rat pontine reticular formation regulates the induction phase of anesthesia and modulates hyperalgesia caused by sleep deprivation.

    Science.gov (United States)

    Vanini, Giancarlo; Nemanis, Kriste; Baghdoyan, Helen A; Lydic, Ralph

    2014-07-01

    The oral part of the pontine reticular formation (PnO) contributes to the regulation of sleep, anesthesia and pain. The role of PnO γ-aminobutyric acid (GABA) in modulating these states remains incompletely understood. The present study used time to loss and time to resumption of righting response (LoRR and RoRR) as surrogate measures of loss and resumption of consciousness. This study tested three hypotheses: (i) pharmacologically manipulating GABA levels in rat PnO alters LoRR, RoRR and nociception; (ii) propofol decreases GABA levels in the PnO; and (iii) inhibiting GABA synthesis in the PnO blocks hyperalgesia caused by sleep deprivation. Administering a GABA synthesis inhibitor [3-mercaptopropionic acid (3-MPA)] or a GABA uptake inhibitor [nipecotic acid (NPA)] into rat PnO significantly altered LoRR caused by propofol. 3-MPA significantly decreased LoRR for propofol (-18%). NPA significantly increased LoRR during administration of propofol (36%). Neither 3-MPA nor NPA altered RoRR following cessation of propofol or isoflurane delivery. The finding that LoRR was decreased by 3-MPA and increased by NPA is consistent with measures showing that extracellular GABA levels in the PnO were decreased (41%) by propofol. Thermal nociception was significantly decreased by 3-MPA and increased by NPA, and 3-MPA blocked the hyperalgesia caused by sleep deprivation. The results demonstrate that GABA levels in the PnO regulate the time for loss of consciousness caused by propofol, extend the concept that anesthetic induction and emergence are not inverse processes, and suggest that GABAergic transmission in the PnO mediates hyperalgesia caused by sleep loss.

  4. Influence of clonidine and ketamine on m-RNA expression in a model of opioid-induced hyperalgesia in mice.

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    Henning Ohnesorge

    Full Text Available BACKGROUND: We investigated the influence of morphine and ketamine or clonidine in mice on the expression of genes that may mediate pronociceptive opioid effects. MATERIAL AND METHODS: C57BL/6 mice received morphine injections thrice daily using increasing doses (5-20 mg∙kg(-1 for 3 days (sub-acute, n=6 or 14 days (chronic, n=6 and additionally either s-ketamine (5 mg∙kg(-1, n=6 or clonidine (0.1 mg∙kg(-1, n=6. Tail flick test and the assessment of the mechanical withdrawal threshold of the hindpaw was performed during and 4 days after cessation of opioid treatment. Upon completion of the behavioural testing the mRNA-concentration of the NMDA receptor (NMDAR1 and β-arrestin 2 (Arrb2 were measured by PCR. RESULTS: Chronic opioid treatment resulted in a delay of the tail flick latency with a rapid on- and offset. Simultaneously the mice developed a static mechanical hyperalgesia with a delayed onset that that outlasted the morphine treatment. Sub-acute morphine administration resulted in a decrease of NMDAR1 and Arrb2 whereas during longer opioid treatment the expression NMDAR1 and Arrb2 mRNA increased again to baseline values. Coadministration of s-ketamine or clonidine resulted in a reversal of the mechanical hyperalgesia and inhibited the normalization of NMDAR1 mRNA expression but had no effect on the expression of Arrb2 mRNA. CONCLUSION: In the model of chronic morphine therapy the antinociceptive effects of morphine are represented by the thermal analgesia while the proniceptive effects are represented by the mechanical hyperalgesia. The results indicate that the regulation of the expression of NMDAR1 and Arrb2 may be associated to the development of OIH in mice. PERSPECTIVE: The results indicate that co-administration of clonidine or ketamine may influence the underlying mechanisms of OIH.

  5. Visceral hyperalgesia induced by forebrain-specific suppression of native Kv7/KCNQ/M-current in mice

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    Bian Xiling

    2011-10-01

    Full Text Available Abstract Background Dysfunction of brain-gut interaction is thought to underlie visceral hypersensitivity which causes unexplained abdominal pain syndromes. However, the mechanism by which alteration of brain function in the brain-gut axis influences the perception of visceral pain remains largely elusive. In this study we investigated whether altered brain activity can generate visceral hyperalgesia. Results Using a forebrain specific αCaMKII promoter, we established a line of transgenic (Tg mice expressing a dominant-negative pore mutant of the Kv7.2/KCNQ2 channel which suppresses native KCNQ/M-current and enhances forebrain neuronal excitability. Brain slice recording of hippocampal pyramidal neurons from these Tg mice confirmed the presence of hyperexcitable properties with increased firing. Behavioral evaluation of Tg mice exhibited increased sensitivity to visceral pain induced by intraperitoneal (i.p. injection of either acetic acid or magnesium sulfate, and intracolon capsaicin stimulation, but not cutaneous sensation for thermal or inflammatory pain. Immunohistological staining showed increased c-Fos expression in the somatosensory SII cortex and insular cortex of Tg mice that were injected intraperitoneally with acetic acid. To mimic the effect of cortical hyperexcitability on visceral hyperalgesia, we injected KCNQ/M channel blocker XE991 into the lateral ventricle of wild type (WT mice. Intracerebroventricular injection of XE991 resulted in increased writhes of WT mice induced by acetic acid, and this effect was reversed by co-injection of the channel opener retigabine. Conclusions Our findings provide evidence that forebrain hyperexcitability confers visceral hyperalgesia, and suppression of central hyperexcitability by activation of KCNQ/M-channel function may provide a therapeutic potential for treatment of abdominal pain syndromes.

  6. [The clinical relevance of opioid-induced hyperalgesia remains unresolved].

    Science.gov (United States)

    Sørensen, Jakob; Sjøgren, Per

    2011-03-28

    Opioids are widely used as analgesics in chronic pain of malignant as well as non-malignant origin. During opioid treatment, pain is occasionally worsened. This could be due to progression of the disease or tolerance or opioid-induced hyperalgesia (OIH). The present article summarizes the preclinical and clinical data in support of the existence of OIH. Further, possible mechanisms and potential treatments are outlined. We conclude that only a few clinical studies on OIH are available. However, a growing body of experimental data supports the presence of OIH in clinical settings. Diagnostic tools for assessment of OIH have yet to be developed.

  7. Does naloxone reinstate secondary hyperalgesia in humans after resolution of a burn injury?

    DEFF Research Database (Denmark)

    Pereira, Manuel P; Werner, Mads U; Ringsted, Thomas K;

    2013-01-01

    Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain, h......, have demonstrated reinstatement of tactile hypersensitivity following administration of μ-opioid-receptor-antagonists. In the present study in humans, we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury.......Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain...

  8. Opioid-induced hyperalgesia: is it clinically relevant for the treatment of pain patients?

    Science.gov (United States)

    Raffa, Robert B; Pergolizzi, Joseph V

    2013-09-01

    There is a curious and paradoxic phenomenon, reliably demonstrated in animal models, that consists of an increased sensitivity to pain that is apparently induced by the very opioid drugs used to ameliorate the pain. This phenomenon is termed "opioid-induced hyperalgesia." Whether opioid-induced hyperalgesia occurs in humans, and, if so, to what extent and consequence, is far less established. This is a critical question for attempting to treat pain. If opioid-induced hyperalgesia develops in a patient, it would masquerade as tolerance (because the clinical effectiveness of the opioid would be diminished), yet the appropriate clinical adjustment would be precisely the opposite to that of tolerance. It would be to decrease, rather than increase, the dose of opioid. We review the evidence, particularly the clinical evidence, about opioid-induced hyperalgesia and the postulated mechanisms. We conclude that given the clinical ramifications, opioid-induced hyperalgesia is one of the most understudied important aspects of opioid research.

  9. Fucoidan attenuates the existing allodynia and hyperalgesia in a rat model of neuropathic pain.

    Science.gov (United States)

    Hu, Chuanyin; Zhang, Guoping; Zhao, Yun-Tao

    2014-06-13

    Fucoidan is an active constituent found in brown seaweeds, which have potential neuroprotection. The current study aimed to investigate the effects of fucoidan on the maintenance of neuropathic pain induced by L5 spinal nerve ligation (SNL) and the underlying mechanism related to the spinal neuroimmune responses. Animals were randomized into 5 groups: sham-operation with vehicle and SNL with vehicle or fucoidan (15, 50, and 100mg/kg). Different doses of fucoidan or vehicle were administered intrathecally once daily from postoperative day (POD) 11-20. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) was measured on 1 day before operation and days 10, 20, 22, 24, 26, 28, 30 after operation. Glial activation markers such as glial fibrillary acidic protein (GFAP) and macrophage antigen complex-1 (mac-1), inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 activation, and extracellular signalregulated protein kinase (ERK) activation in the lumbar spinal cord were determined on day 30 after operation. The results showed that fucoidan caused dose-dependently attenuation of mechanical allodynia and thermal hyperalgesia. Furthermore, fucoidan could markedly inhibit neuroimmune activation characterized by glial activation, production of cytokines as well as ERK activation. The analgesic effect of intrathecal fucoidan in rats receiving SNL might partly attribute to the inhibition of neuroimmune activation associated with the maintenance of neuropathic pain.

  10. Effects of COX inhibition on experimental pain and hyperalgesia during and after remifentanil infusion in humans.

    Science.gov (United States)

    Lenz, Harald; Raeder, Johan; Draegni, Tomas; Heyerdahl, Fridtjof; Schmelz, Martin; Stubhaug, Audun

    2011-06-01

    Opioids may enhance pain sensitivity resulting in opioid-induced hyperalgesia (OIH). Activation of spinal cyclooxygenase may play a role in the development of OIH. The aim of this study was to demonstrate remifentanil-induced postinfusion hyperalgesia in an electrical pain and a cold pain model, and to investigate whether COX-2 (parecoxib) or COX-1 (ketorolac) inhibition could prevent hyperalgesia after remifentanil infusion. Sixteen healthy males were enrolled in this randomized, double-blind, placebo-controlled crossover study. Each subject went through 4 sessions: control, remifentanil, parecoxib+remifentanil, and ketorolac+remifentanil. Transcutaneous electrical stimulation induced acute pain and areas of pinprick hyperalgesia. The areas of pinprick hyperalgesia were assessed before, during, and after a 30-minute infusion of either remifentanil or saline. The cold-pressor test (CPT) was performed before, at the end of, and 1 hour after the infusions. The subjects received a bolus of either saline, 40 mg parecoxib, or 30 mg ketorolac intravenously after the first CPT. The areas of pinprick hyperalgesia and CPT pain after the end of remifentanil infusion increased significantly compared to control (P pain and cold-pressor pain. Both parecoxib and ketorolac prevented hyperalgesia in the electrical model, parecoxib to a larger extent.

  11. TDAG8 involved in initiating inflammatory hyperalgesia and establishing hyperalgesic priming in mice

    Science.gov (United States)

    Dai, Shih-Ping; Huang, Ya-Han; Chang, Chung-Jen; Huang, Yu-Fen; Hsieh, Wei-Shan; Tabata, Yasuhiko; Ishii, Satoshii; Sun, Wei-Hsin

    2017-01-01

    Chronic pain, resulting from injury, arthritis, and cancer, is often accompanied by inflammation. High concentrations of protons found in inflamed tissues results in tissue acidosis, a major cause of pain and hyperalgesia. Acidosis signals may mediate a transition from acute to chronic hyperalgesia (hyperalgesic priming) via proton-sensing G-protein-coupled receptors (GPCRs). The expression of T-cell death-associated gene 8 (TDAG8), a proton-sensing GPCR, is increased during inflammatory hyperalgesia. Attenuating TDAG8 expression in the spinal cord inhibits bone cancer pain, but whether TDAG8 is involved in inflammatory hyperalgesia or hyperalgesic priming remains unclear. In this study, we used TDAG8-knockout or -knockdown to explore the role of TDAG8 in pain. Suppressed TDAG8 expression delayed the onset of inflammatory hyperalgesia and shortened hyperalgesic time in mice. In a dual acid-injection model (acid [pH 5.0] injected twice, 5 days apart), shRNA inhibition of TDAG8 shortened the duration of the second hyperalgesia. Similar results were found in TDAG8-deficient mice. The dual administration of TDAG8 agonist also confirmed that TDAG8 is involved in hyperalgsic priming. Accordingly, TDAG8 may mediate acidosis signals to initiate inflammatory hyperalgesia and establish hyperalgesic priming. PMID:28145512

  12. Role of acid-sensing ion channel 3 in sub-acute-phase inflammation

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    Chen Chien-Ju

    2009-01-01

    Full Text Available Abstract Background Inflammation-mediated hyperalgesia involves tissue acidosis and sensitization of nociceptors. Many studies have reported increased expression of acid-sensing ion channel 3 (ASIC3 in inflammation and enhanced ASIC3 channel activity with pro-inflammatory mediators. However, the role of ASIC3 in inflammation remains inconclusive because of conflicting results generated from studies of ASIC3 knockout (ASIC3-/- or dominant-negative mutant mice, which have shown normal, decreased or increased hyperalgesia during inflammation. Results Here, we tested whether ASIC3 plays an important role in inflammation of subcutaneous tissue of paw and muscle in ASIC3-/- mice induced by complete Freund's adjuvant (CFA or carrageenan by investigating behavioral and pathological responses, as well as the expression profile of ion channels. Compared with the ASIC3+/+ controls, ASIC3-/- mice showed normal thermal and mechanical hyperalgesia with acute (4-h intraplantar CFA- or carrageenan-induced inflammation, but the hyperalgesic effects in the sub-acute phase (1–2 days were milder in all paradigms except for thermal hyperalgesia with CFA-induced inflammation. Interestingly, carrageenan-induced primary hyperalgesia was accompanied by an ASIC3-dependent Nav1.9 up-regulation and increase of tetrodotoxin (TTX-resistant sodium currents. CFA-inflamed muscle did not evoke hyperalgesia in ASIC3-/- or ASIC3+/+ mice, whereas carrageenan-induced inflammation in muscle abolished mechanical hyperalgesia in ASIC3-/- mice, as previously described. However, ASIC3-/- mice showed attenuated pathological features such as less CFA-induced granulomas and milder carrageenan-evoked vasculitis as compared with ASIC3+/+ mice. Conclusion We provide a novel finding that ASIC3 participates in the maintenance of sub-acute-phase primary hyperalgesia in subcutaneous inflammation and mediates the process of granuloma formation and vasculitis in intramuscular inflammation.

  13. Hyperalgesia and temporal summation of pain after heat injury in man

    DEFF Research Database (Denmark)

    Pedersen, J L; Andersen, O K; Arendt-Nielsen, L

    1998-01-01

    , in three areas: primary and secondary mechanical hyperalgesia induced by the heat injury, and in a mirror image of the injury on the opposite leg. Temporal summation of pain was induced by repeated electrical stimuli (five stimuli at 2 Hz) and assessed by visual analog scale (VAS). Primary hyperalgesia...... and pain intensity during the induction of heat injury. We conclude that the development of primary and secondary mechanical hyperalgesia after heat injury in man was not associated with changes in temporal summation of painful electrical stimuli....

  14. Opioid-induced hyperalgesia: when pain killers make pain worse.

    Science.gov (United States)

    Kaneria, Anshuni

    2014-06-04

    A 44-year-old woman had a temporal glioma and was admitted to the hospice with pain that was not controlled despite escalating opioids. Her pain levels rose after every dose increase resulting now in continuous pain, making her very low in mood. Her short-term memory had also declined in a stepwise fashion with each increase in opioids. Additionally, her poor health had had a detrimental effect on family life. Physical examination was difficult due to allodynia but no major abnormality was found. The team suspected opioid-induced hyperalgesia and decided to cut the patient's opioids by one-third initially. This immediately improved the overall pain. The opioids continued to be decreased incrementally every 1-2 days until the pain had disappeared completely. She was stabilised on a dose almost one-seventh of her original regime. Mood and memory also improved as opioids decreased and she was discharged home after 8 days.

  15. Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon?

    Science.gov (United States)

    Tompkins, D Andrew; Campbell, Claudia M

    2011-04-01

    Opioids have become the unequivocal therapy of choice in treating many varieties of chronic pain. With the increased prescription of opioids, some unintended consequences have occurred. After prolonged opioid exposure, opioid-induced hyperalgesia (OIH), the paradoxical effect that opioid therapy may in fact enhance or aggravate preexisting pain, may occur. Over the past several decades, an increasing number of laboratory and clinical reports have suggested lowered pain thresholds and heightened atypical pain unrelated to the original perceived pain sensations as hallmarks of OIH. However, not all evidence supports the clinical importance of OIH, and some question whether the phenomenon exists at all. Here, we present a nonexhaustive, brief review of the recent literature. OIH will be reviewed in terms of preclinical and clinical evidence for and against its existence; recommendations for clinical evaluation and intervention also will be discussed.

  16. Classical conditioning and pain: conditioned analgesia and hyperalgesia.

    Science.gov (United States)

    Miguez, Gonzalo; Laborda, Mario A; Miller, Ralph R

    2014-01-01

    This article reviews situations in which stimuli produce an increase or a decrease in nociceptive responses through basic associative processes and provides an associative account of such changes. Specifically, the literature suggests that cues associated with stress can produce conditioned analgesia or conditioned hyperalgesia, depending on the properties of the conditioned stimulus (e.g., contextual cues and audiovisual cues vs. gustatory and olfactory cues, respectively) and the proprieties of the unconditioned stimulus (e.g., appetitive, aversive, or analgesic, respectively). When such cues are associated with reducers of exogenous pain (e.g., opiates), they typically increase sensitivity to pain. Overall, the evidence concerning conditioned stress-induced analgesia, conditioned hyperalagesia, conditioned tolerance to morphine, and conditioned reduction of morphine analgesia suggests that selective associations between stimuli underlie changes in pain sensitivity.

  17. Tratamento farmacológico da hiperalgesia experimentalmente induzida pelo núcleo pulposo Pharmacologic treatment of hyperalgesia experimentally induced by nucleus pulposus

    Directory of Open Access Journals (Sweden)

    André Luiz de Souza Grava

    2010-01-01

    contact of a fragment of NP removed from the sacrococcygeal region and placed on the dorsal root ganglion of L5. The 30 animals were divided into experimental groups according to the drug administered. The drugs were administered during the two weeks after the surgical procedure to induce hyperalgesia. Mechanical and thermal hyperalgesia was evaluated by the paw pressure test, von Frey electronic test, and the Hargraves test, for a period of seven weeks. RESULTS: The greatest reduction of hyperalgesia was observed in animals treated by morphine and dexamethasone, followed by dexamethasone, indomethacin, and atenolol. The reduction of hyperalgesia was observed after drug administration ceased, except for animals treated with morphine, in which there was an increased hyperalgesia after cessation of treatment. CONCLUSION: Hyperalgesia induced by NP contact with L5-DRG can be reduced by administration of antiinflammatory and analgesic drugs, but there was a greater reduction observed with the administration of dexamethasone and indometacin

  18. Role of kinin B2 receptors in opioid-induced hyperalgesia in inflammatory pain in mice.

    Science.gov (United States)

    Grastilleur, Sébastien; Mouledous, Lionel; Bedel, Jerome; Etcheverry, Jonathan; Bader, Michael; Girolami, Jean-Pierre; Fourcade, Olivier; Frances, Bernard; Minville, Vincent

    2013-03-01

    Postoperative pain management is a clinical challenge that can be complicated by opioid-induced hyperalgesia (OIH). Kinin receptors could mediate both the acute and chronic phases of inflammation and pain. A few recent studies suggest that dynorphin A could maintain neuropathic pain by activating the bradykinin (BK) receptor. Thus, the effect of a single administration of sufentanil (a μ-opioid receptor agonist) was investigated in a model of carrageenan-induced inflammatory pain using three strains of mice, i.e., knockout mice for one kinin receptor, B1R or B2R (B1KO, B2KO), and wild-type C57/BL6J mice (WT) treated with either a B1R (R954) or a B2R antagonist (HOE140) or a KKS inhibitor (aprotinin). Pain was assessed and compared between the different groups using two behavioral tests exploring mechanical (von Frey filaments) and thermal (Hargreaves test) sensitivity. Pretreatment with sufentanil induced a sustained increase in pain sensitivity with a delayed return to baseline values characterizing an OIH in carrageenan-injected mice only. Sufentanil-induced OIH was not observed in B2KO but persisted in B1KO and was blunted by aprotinin and the B2R antagonist only. Collectively, our data indicate that the B2R receptor and BK synthesis or availability are essential peripheral steps in the mechanism leading to OIH in a pain context.

  19. Spatial and temporal aspects of muscle hyperalgesia induced by nerve growth factor in humans

    DEFF Research Database (Denmark)

    Andersen, H.; Arendt-Nielsen, L.; Svensson, P.

    2008-01-01

    scale were used to assess soreness during muscle function. An area of hyperalgesia was observed locally at the injected site 3 h after injection of NGF, which expanded both proximally and distally on day 1; this effect subsided on day 4. Decreased PPT was also found between 1st and 2nd metatarsal on day...... 1. Hypertonic saline evoked more pain in men when injected in the NGF treated TA compared to the control leg. Injection of NGF increased muscle soreness during muscle activity for 7 days. In this material there was no gender effect of NGF-induced muscle hyperalgesia. The expansion of muscle...... distribution of muscle hyperalgesia over time (immediately after, 3 h, 1, 4, 7 and 21 days) after injecting NGF (5 mu g) into the tibialis anterior (TA) muscle, to explore possibly involved central pain mechanisms and to investigate the effect of gender on development of hyperalgesia. Totally 20 healthy...

  20. Gender differences in pain and secondary hyperalgesia after heat/capsaicin sensitization in healthy volunteers

    DEFF Research Database (Denmark)

    Jensen, Magnus Thorsten; Petersen, Karin Lottrup

    2006-01-01

    In most published studies women are more sensitive to experimental pain than men. Enhanced central pain processing in women has been suggested, but psychosocial factors might also have affected the findings. Data from five completed healthy volunteer studies were analyzed to investigate gender...... differences in development of secondary hyperalgesia. Cutaneous hyperalgesia was induced with the heat/capsaicin sensitization model. Outcome measures were areas of secondary hyperalgesia to brush and von Frey hair stimulation after heat and capsaicin sensitization, rating of pain during heat....../capsaicin sensitization, and heat pain detection thresholds. There was a trend toward smaller areas of secondary hyperalgesia in women. After adjusting for estimated gender differences in forearm surface area, areas to brush but not von Frey hair stimulation after capsaicin sensitization were larger in women. Peak pain...

  1. Lipopolysaccharide-induced hyperalgesia of intracranial capsaicin sensitive afferents in conscious rats

    NARCIS (Netherlands)

    Kemper, RHA; Spoelstra, MB; Meijler, WJ; Ter Horst, GJ

    1998-01-01

    Migraineous and non-migraineous headache is reported to be at highest intensity after an infection. This study investigated whether activation of the immune system can induce hyperalgesia in intracranial capsaicin sensitive afferents. The effects of intraperitoneal injected lipopolysaccharides (LPS)

  2. Cyclosporin inhibits hyperalgesia and edema in arthritic rats: role of the central nervous system

    Directory of Open Access Journals (Sweden)

    J.N. Francischi

    1997-01-01

    Full Text Available Since arthritis induced by Mycobacterium products (adjuvant in rats is considered to be immunologically driven, the objective of the present study was to determine if the immunosuppressor drug cyclosporin could affect hindpaw edema and joint hyperalgesia simultaneously. Female Holtzman rats (140-170 g presented hyperalgesia and edema on the 8th and 12th day following adjuvant injection. Daily systemic (oral or intramuscular administration of cyclosporin (0.5-5.0 mg kg-1 day-1 or dexamethasone (0.01-0.1 mg kg-1 day-1 for 15 days starting on day zero dose-dependently inhibited the hindpaw edema and hyperalgesia in arthritic rats. However, hyperalgesia but not edema could be detected two days after cyclosporin withdrawal. We concluded that a the continuous presence of cyclosporin is essential to reduce the development of joint hyperalgesia and that b different mechanisms underlie the appearance of hyperalgesia and edema in this model. The intracerebroventricular (icv administration of 5-50-fold smaller doses of cyclosporin (1.5-150 µg/day or dexamethasone (15 µg/day also reduced the arthritic hindpaw edema and hyperalgesia. Peripheral blood from animals injected with effective systemic cyclosporin doses showed detectable levels of the drug, whereas peripheral blood from those injected with icv cyclosporin did not, as measured by specific RIA. Our results indicate that cyclosporin administered by the central route is as effective as by the systemic route to reduce joint hyperalgesia and hindpaw edema in arthritic rats. The antiarthritic effect induced by low doses of cyclosporin in the central nervous system (CNS could be explored to avoid its often associated systemic side effects during chronic therapy. However, the mechanism(s involved in the antiarthritic response to cyclosporin in the CNS remain to be elucidated

  3. Attenuation of reperfusion hyperalgesia in the rat by systemic administration of benzodiazepines.

    OpenAIRE

    1993-01-01

    1. An investigation into whether reperfusion hyperalgesia is modulated by prior systemic administration of two benzodiazepine agonists (diazepam and chlordiazepoxide), and an antagonist (flumazenil) was conducted. 2. Transient ischaemia was induced in conscious rats by applying an inflatable tourniquet to the base of the tail; when the rats exhibited a co-ordinated escape response, the tourniquet was deflated and reperfusion of the tail was allowed. Reperfusion hyperalgesia manifested as a de...

  4. The nitroxyl donor, Angeli’s salt, inhibits inflammatory hyperalgesia in rats

    OpenAIRE

    2013-01-01

    Nitric oxide modulates pain development. However, there is no evidence on the effect of nitroxyl (HNO/NO−) in nociception. Therefore, we addressed whether nitroxyl inhibits inflammatory hyperalgesia and its mechanism using the nitroxyl donor Angeli’s salt (AS; Na2N2O3). Mechanical hyperalgesia was evaluated using a modified Randall and Selitto method in rats, cytokine production by ELISA and nitroxyl was determined by confocal microscopy in DAF (a cell permeable reagent that is converted into...

  5. Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat.

    Science.gov (United States)

    Ferrari, L F; Levine, J D; Green, P G

    2016-03-11

    Nitroglycerin (glycerol trinitrate, GTN) induces headache in migraineurs, an effect that has been used both diagnostically and in the study of the pathophysiology of this neurovascular pain syndrome. An important feature of this headache is a delay from the administration of GTN to headache onset that, because of GTN's very rapid metabolism, cannot be due to its pharmacokinetic profile. It has recently been suggested that activation of perivascular mast cells, which has been implicated in the pathophysiology of migraine, may contribute to this delay. We reported that hyperalgesia induced by intradermal GTN has a delay to onset of ∼ 30 min in male and ∼ 45 min in female rats. This hyperalgesia was greater in females, was prevented by pretreatment with the anti-migraine drug, sumatriptan, as well as by chronic pretreatment with the mast cell degranulator, compound 48/80. The acute administration of GTN and compound 48/80 both induced hyperalgesia that was prevented by pretreatment with octoxynol-9, which attenuates endothelial function, suggesting that GTN and mast cell-mediated hyperalgesia are endothelial cell-dependent. Furthermore, A-317491, a P2X3 antagonist, which inhibits endothelial cell-dependent hyperalgesia, also prevents GTN and mast cell-mediated hyperalgesia. We conclude that delayed-onset mechanical hyperalgesia induced by GTN is mediated by activation of mast cells, which in turn release mediators that stimulate endothelial cells to release ATP, to act on P2X3, a ligand-gated ion channel, in perivascular nociceptors. A role of the mast and endothelial cell in GTN-induced hyperalgesia suggests potential novel risk factors and targets for the treatment of migraine.

  6. Endometriosis-induced vaginal hyperalgesia in the rat: role of the ectopic growths and their innervation.

    Science.gov (United States)

    McAllister, Stacy L; McGinty, Kristina A; Resuehr, David; Berkley, Karen J

    2009-12-15

    Endometriosis is a painful disorder defined by extrauteral endometrial growths whose contribution to pain symptoms is poorly understood. Endometriosis is created in rats by autotransplanting on abdominal arteries pieces of either uterus (ENDO), which form cysts, or fat (shamENDO), which do not form cysts. ENDO, but not shamENDO induces vaginal hyperalgesia. We tested the hypothesis that the cysts are necessary to maintain vaginal hyperalgesia by assessing the effect of surgically removing them. Complete-cyst-removal eliminated ENDO-induced vaginal hyperalgesia up to 4 months post-operatively. Sham-cyst-removal in ENDO rats, in which cysts were not removed, or partial cyst-removal increased the ENDO-induced hyperalgesia. The decreases and increases both took 3-6 weeks to develop. Changes in ENDO-induced hyperalgesia did not occur in a control group of ENDO rats who had no surgery after ENDO. In a double-surgery control group, neither shamENDO surgery nor a subsequent sham surgery that mimicked "removal" of non-existent cysts influenced vaginal nociception. In a no-surgery control group, vaginal nociception remained stable for >6 months. The increases in ENDO-induced hyperalgesia produced by the sham-cyst-removal surgery were smaller in proestrus than in other estrous stages. During the other stages (but not during proestrus), sympathetic innervation of the cysts increased. These results suggest that maintenance of ENDO-induced vaginal hyperalgesia requires continued presence of at least some ectopic endometrial tissue, and that surgical treatment that fails to remove ectopic endometrial tissue can exacerbate the hyperalgesia, possibly due in part to an increase in the cysts' sympathetic innervation.

  7. Endometriosis-Induced Vaginal Hyperalgesia in the Rat: Role of the Ectopic Growths and their Innervation

    OpenAIRE

    McAllister, Stacy L.; McGinty, Kristina A.; Resuehr, David; Berkley, Karen J

    2009-01-01

    Endometriosis is a painful disorder defined by extrauteral endometrial growths whose contribution to pain symptoms is poorly understood. Endometriosis is created in rats by autotransplanting on abdominal arteries pieces of either uterus (ENDO), which form cysts, or fat (shamENDO), which do not form cysts. ENDO, but not shamENDO induces vaginal hyperalgesia. We tested the hypothesis that the cysts are necessary to maintain vaginal hyperalgesia by assessing the effect of surgically removing the...

  8. Acute phenobarbital administration induces hyperalgesia: pharmacological evidence for the involvement of supraspinal GABA-A receptors

    Directory of Open Access Journals (Sweden)

    C.M. Yokoro

    2001-03-01

    Full Text Available The aim of the present study was to determine if phenobarbital affects the nociception threshold. Systemic (1-20 mg/kg phenobarbital administration dose dependently induced hyperalgesia in the tail-flick, hot-plate and formalin tests in rats and in the abdominal constriction test in mice. Formalin and abdominal constriction tests were the most sensitive procedures for the detection of hyperalgesia in response to phenobarbital compared with the tail-flick and hot-plate tests. The hyperalgesia induced by systemic phenobarbital was blocked by previous administration of 1 mg/kg ip picrotoxin or either 1-2 mg/kg sc or 10 ng icv bicuculline. Intracerebroventricular phenobarbital administration (5 µg induced hyperalgesia in the tail-flick test. In contrast, intrathecal phenobarbital administration (5 µg induced antinociception and blocked systemic-induced hyperalgesia in this test. We suggest that phenobarbital may mediate hyperalgesia through GABA-A receptors at supraspinal levels and antinociception through the same kind of receptors at spinal levels.

  9. Exercise training attenuates acute hyperalgesia in streptozotocin-induced diabetic female rats

    Directory of Open Access Journals (Sweden)

    Denise M Rossi

    2011-01-01

    Full Text Available OBJECTIVES: We investigated the effects of chronic (eight weeks low-to moderate-intensity swimming training on thermal pain sensitivity in streptozotocin-induced diabetic female rats. METHODS: Female Wistar rats (n = 51 were divided into the following groups: trained streptozotocin-induced diabetic rats [hyperglycemic trained (HT], sedentary streptozotocin-induced diabetic rats [hyperglycemic sedentary (HS], normoglycemic trained rats (NT and normoglycemic sedentary rats (NS. Diabetes was induced by a single injection of streptozotocin (50 mg/kg, i.p.. One day after the last exercise protocol (60 min/day, five days/week for eight weeks in the trained groups or after water stress exposure (ten min/twice a week in the sedentary groups, the rats were subjected to a hot plate test. RESULTS: After eight weeks of swimming training, streptozotocin-induced diabetic rats presented a significantly lower body mass (trained: 219.5±29 g, sedentary: 217.8±23 g compared with the normoglycemic groups (trained: 271±24 g, sedentary: 275.7±32 g. Interestingly, we did not find differences in blood glucose levels (mg/dl between the trained and sedentary groups of the hyperglycemic or normoglycemic rats (HT: 360.2±6.6, HS: 391.7±6.7, NT: 83.8±14.0, NS: 77.5±10.1. In the hot plate test, the rats from the HT group presented a significantly lower latency than the other rats (HT: 11.7±7.38 s, HS: 7.02±7.38 s, NT: 21.21±7.64 s, NS: 22.82±7.82 s. CONCLUSION: Low-to-moderate swimming training for a long duration reduces thermal hyperalgesia during a hot plate test in streptozotocin-induced diabetic female rats.

  10. Vinpocetine reduces carrageenan-induced inflammatory hyperalgesia in mice by inhibiting oxidative stress, cytokine production and NF-κB activation in the paw and spinal cord.

    Directory of Open Access Journals (Sweden)

    Kenji W Ruiz-Miyazawa

    Full Text Available Vinpocetine is a safe nootropic agent used for neurological and cerebrovascular diseases. The anti-inflammatory activity of vinpocetine has been shown in cell based assays and animal models, leading to suggestions as to its utility in analgesia. However, the mechanisms regarding its efficacy in inflammatory pain treatment are still not completely understood. Herein, the analgesic effect of vinpocetine and its anti-inflammatory and antioxidant mechanisms were addressed in murine inflammatory pain models. Firstly, we investigated the protective effects of vinpocetine in overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone (PBQ and formalin. The intraplantar injection of carrageenan was then used to induce inflammatory hyperalgesia. Mechanical and thermal hyperalgesia were evaluated using the electronic von Frey and the hot plate tests, respectively, with neutrophil recruitment to the paw assessed by a myeloperoxidase activity assay. A number of factors were assessed, both peripherally and in the spinal cord, including: antioxidant capacity, reduced glutathione (GSH levels, superoxide anion, tumor necrosis factor alpha (TNF-α and interleukin 1 beta (IL-1β levels, as well as nuclear factor kappa B (NF-κB activation. Vinpocetine inhibited the overt pain-like behavior induced by acetic acid, PBQ and formalin (at both phases, as well as the carrageenan-induced mechanical and thermal hyperalgesia and associated neutrophil recruitment. Both peripherally and in the spinal cord, vinpocetine also inhibited: antioxidant capacity and GSH depletion; increased superoxide anion; IL-1β and TNF-α levels; and NF-κB activation. As such, vinpocetine significantly reduces inflammatory pain by targeting oxidative stress, cytokine production and NF-κB activation at both peripheral and spinal cord levels.

  11. Intradermal glutamate and capsaicin injections: intra- and interindividual variability of provoked hyperalgesia and allodynia.

    Science.gov (United States)

    Nilsson, Matias; Lassen, Dorte; Andresen, Trine; Nielsen, Anders K; Arendt-Nielsen, Lars; Drewes, Asbjørn M

    2014-06-01

    Intradermal injections of glutamate and capsaicin are attractive to use in human experimental pain models because hyperalgesia and allodynia mimic isolated aspects of clinical pain disorders. The aim of the present study was to investigate the reproducibility of these models. Twenty healthy male volunteers (mean age 24 years; range 18-38 years) received intradermal injections of glutamate and capsaicin in the volar forearm. Magnitudes of secondary pinprick hyperalgesia and brush-evoked allodynia were investigated using von Frey filaments (gauges 10, 15, 60 and 100 g) and brush strokes. Areas of secondary hyperalgesia and allodynia were quantified immediately after injection and after 15, 30 and 60 min. Two identical experiments separated by at least 7 days were performed. Reproducibility across and within volunteers (inter- and intra-individual variation, respectively) was assessed using intraclass correlation coefficient (ICC) and coefficient of variation (CV). Secondary pinprick hyperalgesia was observed as a marked increase in the visual analogue scale (VAS) response to von Frey gauges 60 and 100 g (P capsaicin, secondary pinprick hyperalgesia was detected with all von Frey gauges (P  0.60) and brush strokes (ICC > 0.83). Capsaicin injection was reproducible for secondary hyperalgesia (ICC > 0.70) and allodynia (ICC > 0.71). Intra-individual variability was generally lower for the VAS response to von Frey and brush compared with areas of secondary hyperalgesia and allodynia. In conclusion, glutamate and capsaicin yield reproducible hyperalgesic and allodynic responses, and the present model is well suited for basic research, as well as for assessing the modulation of central phenomena.

  12. Chronic psychosocial stress induces visceral hyperalgesia in mice.

    Science.gov (United States)

    Tramullas, Mónica; Dinan, Timothy G; Cryan, John F

    2012-05-01

    Experimental and clinical evidence has shown that chronic stress plays an important role in the onset and/or exacerbation of symptoms of functional gastrointestinal disorders. Here, we aimed to investigate whether exposure to a chronic and temporally unpredictable psychosocial stressor alters visceral and somatic nociception as well as anxiety-related behaviour. In male C57BL/6J mice, chronic stress was induced by repeated exposure to social defeat (SD, 2 h) and overcrowding (OC, 24 h) during 19 consecutive days. Visceral and somatic nociception was evaluated by colorectal distension and a hot plate, respectively. The social interaction test was used to assess social anxiety. Mice exposed to psychosocial stress developed visceral hyperalgesia and somatic hypoalgesia 24 h following the last stress session. SD/OC mice also exhibited social anxiety-like behaviour. All these changes were also associated with physiological alterations, measured as a decreased faecal pellet output and hypothalamic-pituitary-adrenal (HPA) axis disruption. Taken together, these data confirm that this mouse model of chronic psychosocial stress may be useful for studies on the pathophysiological mechanisms underlying such stress-associated disorders and to further test potential therapies.

  13. Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia.

    Science.gov (United States)

    Chen, Lucy; Sein, Michael; Vo, Trang; Amhmed, Shihab; Zhang, Yi; Hilaire, Kristin St; Houghton, Mary; Mao, Jianren

    2014-01-01

    Opioid analgesics are commonly used to manage moderate to severe pain. However, the long-term use of opioids could lead to opioid tolerance (OT) and opioid-induced hyperalgesia (OIH). Distinguishing OIH from OT would impact the practice of opioid therapy because opioid dose adjustment may differentially influence OT and OIH. Currently, there are no standard criteria of OT versus OIH causing considerable ambiguity in clinical interpretation and management of these conditions. The authors designed a practitioner-based survey consisting of 20 targeted questions. Answering these questions would require responders' actual clinical experiences with opioid therapy. The survey was conducted between 2011 and 2012 through direct mails or e-mails to 1,408 physicians who are currently practicing in the United States. The authors find that certain clinical characteristics (eg, increased pain despite opioid dose escalation) are often used by practitioners to make differential diagnosis of OT and OIH despite some overlap in their clinical presentation. A key difference in clinical outcome is that OT and OIH could be improved and exacerbated by opioid dose escalation, respectively. Our survey results revealed a significant knowledge gap in some responders regarding differential diagnosis and management of OT and OIH. The results also identified several issues, such as opioid dose adjustment and clinical comorbidities related to OT and OIH, which require future patient-based studies.

  14. Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations.

    Science.gov (United States)

    Arout, Caroline A; Edens, Ellen; Petrakis, Ismene L; Sofuoglu, Mehmet

    2015-06-01

    Opioid analgesics have become a cornerstone in the treatment of moderate to severe pain, resulting in a steady rise of opioid prescriptions. Subsequently, there has been a striking increase in the number of opioid-dependent individuals, opioid-related overdoses, and fatalities. Clinical use of opioids is further complicated by an increasingly deleterious profile of side effects beyond addiction, including tolerance and opioid-induced hyperalgesia (OIH), where OIH is defined as an increased sensitivity to already painful stimuli. This paradoxical state of increased nociception results from acute and long-term exposure to opioids, and appears to develop in a substantial subset of patients using opioids. Recently, there has been considerable interest in developing an efficacious treatment regimen for acute and chronic pain. However, there are currently no well-established treatments for OIH. Several substrates have emerged as potential modulators of OIH, including the N-methyl-D-aspartate and γ-aminobutyric acid receptors, and most notably, the innate neuroimmune system. This review summarizes the neurobiology of OIH in the context of clinical treatment; specifically, we review evidence for several pathways that show promise for the treatment of pain going forward, as prospective adjuvants to opioid analgesics. Overall, we suggest that this paradoxical state be considered an additional target of clinical treatment for chronic pain.

  15. Synthesis of lipid mediators during UVB-induced inflammatory hyperalgesia in rats and mice.

    Directory of Open Access Journals (Sweden)

    Marco Sisignano

    Full Text Available Peripheral sensitization during inflammatory pain is mediated by a variety of endogenous proalgesic mediators including a number of oxidized lipids, some of which serve endogenous modulators of sensory TRP-channels. These lipids are eicosanoids of the arachidonic acid and linoleic acid pathway, as well as lysophophatidic acids (LPAs. However, their regulation pattern during inflammatory pain and their contribution to peripheral sensitization is still unclear. Here, we used the UVB-model for inflammatory pain to investigate alterations of lipid concentrations at the site of inflammation, the dorsal root ganglia (DRGs as well as the spinal dorsal horn and quantified 21 lipid species from five different lipid families at the peak of inflammation 48 hours post irradiation. We found that known proinflammatory lipids as well as lipids with unknown roles in inflammatory pain to be strongly increased in the skin, whereas surprisingly little changes of lipid levels were seen in DRGs or the dorsal horn. Importantly, although there are profound differences between the number of cytochrome (CYP genes between mice and rats, CYP-derived lipids were regulated similarly in both species. Since TRPV1 agonists such as LPA 18∶1, 9- and 13-HODE, 5- and 12-HETE were elevated in the skin, they may contribute to thermal hyperalgesia and mechanical allodynia during UVB-induced inflammatory pain. These results may explain why some studies show relatively weak analgesic effects of cyclooxygenase inhibitors in UVB-induced skin inflammation, as they do not inhibit synthesis of other proalgesic lipids such as LPA 18∶1, 9-and 13-HODE and HETEs.

  16. Acidosis Mediates the Switching of Gs-PKA and Gi-PKCε Dependence in Prolonged Hyperalgesia Induced by Inflammation.

    Science.gov (United States)

    Huang, Wei-Yu; Dai, Shih-Ping; Chang, Yan-Ching; Sun, Wei-Hsin

    2015-01-01

    Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Previous studies suggested that in male Sprague Dawley rats, prostaglandin E2 (PGE2)-induced short-term hyperalgesia depends on protein kinase A (PKA) activity, whereas long-lasting hyperalgesia induced by PGE2 with carrageenan pre-injection, requires protein kinase Cε (PKCε). However, the mechanism underlying the kinase switch with short- to long-term hyperalgesia remains unclear. In this study, we used the inflammatory agents carrageenan or complete Freund's adjuvant (CFA) to induce long-term hyperalgesia, and examined PKA and PKCε dependence and switching time. Hyperalgesia induced by both agents depended on PKA/PKCε and Gs/Gi-proteins, and the switching time from PKA to PKCε and from Gs to Gi was about 3 to 4 h after inflammation induction. Among the single inflammatory mediators tested, PGE2 and 5-HT induced transient hyperalgesia, which depended on PKA and PKCε, respectively. Only acidic solution-induced hyperalgesia required Gs-PKA and Gi-PKCε, and the switch time for kinase dependency matched inflammatory hyperalgesia, in approximately 2 to 4 h. Thus, acidosis in inflamed tissues may be a decisive factor to regulate switching of PKA and PKCε dependence via proton-sensing G-protein-coupled receptors.

  17. Acidosis Mediates the Switching of Gs-PKA and Gi-PKCε Dependence in Prolonged Hyperalgesia Induced by Inflammation.

    Directory of Open Access Journals (Sweden)

    Wei-Yu Huang

    Full Text Available Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Previous studies suggested that in male Sprague Dawley rats, prostaglandin E2 (PGE2-induced short-term hyperalgesia depends on protein kinase A (PKA activity, whereas long-lasting hyperalgesia induced by PGE2 with carrageenan pre-injection, requires protein kinase Cε (PKCε. However, the mechanism underlying the kinase switch with short- to long-term hyperalgesia remains unclear. In this study, we used the inflammatory agents carrageenan or complete Freund's adjuvant (CFA to induce long-term hyperalgesia, and examined PKA and PKCε dependence and switching time. Hyperalgesia induced by both agents depended on PKA/PKCε and Gs/Gi-proteins, and the switching time from PKA to PKCε and from Gs to Gi was about 3 to 4 h after inflammation induction. Among the single inflammatory mediators tested, PGE2 and 5-HT induced transient hyperalgesia, which depended on PKA and PKCε, respectively. Only acidic solution-induced hyperalgesia required Gs-PKA and Gi-PKCε, and the switch time for kinase dependency matched inflammatory hyperalgesia, in approximately 2 to 4 h. Thus, acidosis in inflamed tissues may be a decisive factor to regulate switching of PKA and PKCε dependence via proton-sensing G-protein-coupled receptors.

  18. EP2 receptor antagonism reduces peripheral and central hyperalgesia in a preclinical mouse model of endometriosis

    Science.gov (United States)

    Greaves, Erin; Horne, Andrew W.; Jerina, Helen; Mikolajczak, Marta; Hilferty, Lisa; Mitchell, Rory; Fleetwood-Walker, Sue M.; Saunders, Philippa T. K.

    2017-01-01

    Endometriosis is an incurable gynecological disorder characterized by debilitating pain and the establishment of innervated endometriosis lesions outside the uterus. In a preclinical mouse model of endometriosis we demonstrated overexpression of the PGE2-signaling pathway (including COX-2, EP2, EP4) in endometriosis lesions, dorsal root ganglia (DRG), spinal cord, thalamus and forebrain. TRPV1, a PGE2-regulated channel in nociceptive neurons was also increased in the DRG. These findings support the concept that an amplification process occurs along the pain neuroaxis in endometriosis. We then tested TRPV1, EP2, and EP4 receptor antagonists: The EP2 antagonist was the most efficient analgesic, reducing primary hyperalgesia by 80% and secondary hyperalgesia by 40%. In this study we demonstrate reversible peripheral and central hyperalgesia in mice with induced endometriosis. PMID:28281561

  19. Secondary hyperalgesia phenotypes exhibit differences in brain activation during noxious stimulation

    DEFF Research Database (Denmark)

    Asghar, Mohammad Sohail; Pereira, Manuel Pedro; Werner, Mads Utke;

    2015-01-01

    . To study differences in the propensity to develop central sensitization we examined differences in brain activity and anatomy according to individual phenotypical expression of secondary hyperalgesia by magnetic resonance imaging. Forty healthy volunteers received a first-degree burn-injury (47 °C, 7 min...... hyperalgesia areas after burn-injury. In addition, T1-weighted images were used to measure differences in gray-matter density in cortical and subcortical regions of the brain. We found significant differences in neuronal activity between high- and low-sensitization responders at baseline (before application...... in high-sensitization responders in comparison to low-sensitization responders. These findings suggest that brain-structure and neuronal activation to noxious stimulation differs according to secondary hyperalgesia phenotype. This indicates differences in central sensitization according to phenotype...

  20. Evaluation of heat hyperalgesia and anxiety like-behaviors in a rat model of orofacial cancer.

    Science.gov (United States)

    Gambeta, Eder; Kopruszinski, Caroline Machado; Dos Reis, Renata Cristiane; Zanoveli, Janaina Menezes; Chichorro, Juliana Geremias

    2016-04-21

    Pain and anxiety are commonly experienced by cancer patients and both significantly impair their quality of life. Some authors claim that there is a relationship between pain and anxiety, while others suggest that there is not a direct association. In any case, there is indeed a consensus that anxiety impairs the pain condition beyond be under diagnosed and undertreated in cancer pain patients. Herein we investigated if rats presenting heat hyperalgesia induced by orofacial cancer cell inoculation would display anxiety-like behaviors. In addition, we evaluated if pain blockade would result in alleviation of anxiety behaviors, as well as, if blockade of anxiety would result in pain relief. Orofacial cancer was induced in male Wistar rats by inoculation of Walker-256 cells into the right vibrissal pad. Heat facial hyperalgesia was assessed on day 6 after the inoculation, and on this time point rats were submitted to the elevated plus maze and the light-dark transition tests. The influence of lidocaine and midazolam on heat hyperalgesia and anxiety-like behaviors was assessed. The peak of facial heat hyperalgesia was detected 6 days after cancer cells inoculation, and at this time point, rats exhibited increased anxiety-like behaviors. Local treatment with lidocaine (2%/50μL) caused a marked reduction of heat hyperalgesia, but failed to affect the anxiety-like behaviors, while midazolam (0.5mg/kg, i.p.) treatment failed to change the heat threshold, but induced an anxiolytic-like effect. Altogether, our data demonstrated that rats with orofacial cancer present pain- and anxiety-like behaviors, but brief heat hyperalgesia relief does not affect the anxiety-like behaviors, and vice-versa, in our experimental conditions.

  1. Hyperalgesia in a human model of acute inflammatory pain: a methodological study

    DEFF Research Database (Denmark)

    Pedersen, J L; Kehlet, H

    1998-01-01

    thresholds, (ii) mechanical and heat pain thresholds, (iii) pain to heat (43 degrees C and 45 degrees C, 5 s), (iv) secondary hyperalgesia, and (v) skin erythema were made 1.75 and 0.5 h before, and 0, 1, 2, 4, and 6 h after a burn injury. Sensory thresholds and hyperalgesia to heat and mechanical stimuli...... was demonstrated by significantly higher pain thresholds and lower pain responses on the second and third day of the study. The burn model is a sensitive psychophysical model of acute inflammatory pain, when cross-over designs and within-day comparisons are used, and the model is suitable for double-blind, placebo...

  2. Local and Widespread Hyperalgesia After Isolated Tibial Shaft Fractures Treated with Intramedullary Nailing

    DEFF Research Database (Denmark)

    Larsen, Peter; Elsøe, Rasmus; Graven-Nielsen, Thomas

    2016-01-01

    OBJECTIVES: Knee pain is accepted as a common complication to intramedullary nailing of tibial fractures. However, no studies have systematically studied the pain sequel following tibial fractures. The objective of this study was to assess pain and hyperalgesia from 6 weeks to 12 months postopera......OBJECTIVES: Knee pain is accepted as a common complication to intramedullary nailing of tibial fractures. However, no studies have systematically studied the pain sequel following tibial fractures. The objective of this study was to assess pain and hyperalgesia from 6 weeks to 12 months...

  3. A comprehensive review of opioid-induced hyperalgesia.

    Science.gov (United States)

    Lee, Marion; Silverman, Sanford M; Hansen, Hans; Patel, Vikram B; Manchikanti, Laxmaiah

    2011-01-01

    Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain loss of opioid efficacy in some patients. Findings of the clinical prevalence of OIH are not available. However, several observational, cross-sectional, and prospective controlled trials have examined the expression and potential clinical significance of OIH in humans. Most studies have been conducted using several distinct cohorts and methodologies utilizing former opioid addicts on methadone maintenance therapy, perioperative exposure to opioids in patients undergoing surgery, and healthy human volunteers after acute opioid exposure using human experimental pain testing. The precise molecular mechanism of OIH, while not yet understood, varies substantially in the basic science literature, as well as clinical medicine. It is generally thought to result from neuroplastic changes in the peripheral and central nervous system (CNS) that lead to sensitization of pronociceptive pathways. While there are many proposed mechanisms for OIH, 5 mechanisms involving the central glutaminergic system, spinal dynorphins, descending facilitation, genetic mechanisms, and decreased reuptake and enhanced nociceptive response have been described as the important mechanisms. Of these, the central glutaminergic system is considered the most common possibility. Another is the hypothesis that N-methyl-D-aspartate (NMDA) receptors in OIH include activation, inhibition of the glutamate transporter system, facilitation of calcium regulated intracellular protein kinase C, and cross

  4. Effect of sympathetic nerve block on acute inflammatory pain and hyperalgesia

    DEFF Research Database (Denmark)

    Pedersen, J L; Rung, G W; Kehlet, H

    1997-01-01

    BACKGROUND: Sympathetic nerve blocks relieve pain in certain chronic pain states, but the role of the sympathetic pathways in acute pain is unclear. Thus the authors wanted to determine whether a sympathetic block could reduce acute pain and hyperalgesia after a heat injury in healthy volunteers....

  5. 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....

  6. S-ketamine modulates hyperalgesia in patients with chronic pancreatitis pain

    NARCIS (Netherlands)

    Bouwense, S.A.W.; Buscher, H.C.J.L.; Goor, H. van; Wilder-Smith, O.H.G.

    2011-01-01

    BACKGROUND AND OBJECTIVES: Upper abdominal pain is a dominant feature of chronic pancreatitis. A key phenomenon in this context is hyperalgesia, typically associated with N-methyl-d-aspartate receptor activation. This exploratory study evaluates acute effects of S-ketamine, a noncompetitive N-methyl

  7. Peripheral lidocaine, but not ketamine inhibit capsaicin-induced hyperalgesia in humans

    DEFF Research Database (Denmark)

    Gottrup, Hanne; Bach, Flemming Winther; Arendt-Nielsen, Lars

    2000-01-01

    or lidocaine. Lidocaine produced no side-effects, whereas ketamine produced paraesthesia, dizziness and sleepiness in six out of 24 (25%) cases. Blocking peripheral sodium channels with locally administered lidocaine reduces spontaneous pain and capsaicin-induced hyperalgesia but local block with the NMDA...

  8. Evaluation of antivenoms in the neutralization of hyperalgesia and edema induced by Bothrops jararaca and Bothrops asper snake venoms

    Directory of Open Access Journals (Sweden)

    Picolo G.

    2002-01-01

    Full Text Available Neutralization of hyperalgesia induced by Bothrops jararaca and B. asper venoms was studied in rats using bothropic antivenom produced at Instituto Butantan (AVIB, 1 ml neutralizes 5 mg B. jararaca venom and polyvalent antivenom produced at Instituto Clodomiro Picado (AVCP, 1 ml neutralizes 2.5 mg B. aspar venom. The intraplantar injection of B. jararaca and B. asper venoms caused hyperalgesia, which peaked 1 and 2 h after injection, respectively. Both venoms also induced edema with a similar time course. When neutralization assays involving the independent injection of venom and antivenom were performed, the hyperalgesia induced by B. jararaca venom was neutralized only when bothropic antivenom was administered iv 15 min before venom injection, whereas edema was neutralized when antivenom was injected 15 min or immediately before venom injection. On the other hand, polyvalent antivenom did not interfere with hyperalgesia or edema induced by B. asper venom, even when administered prior to envenomation. The lack of neutralization of hyperalgesia and edema induced by B. asper venom is not attributable to the absence of neutralizing antibodies in the antivenom, since neutralization was achieved in assays involving preincubation of venom and antivenom. Cross-neutralization of AVCP or AVIB against B. jararaca and B. asper venoms, respectively, was also evaluated. Only bothropic antivenom partially neutralized hyperalgesia induced by B. asper venom in preincubation experiments. The present data suggest that hyperalgesia and edema induced by Bothrops venoms are poorly neutralized by commercial antivenoms even when antibodies are administered immediately after envenomation.

  9. Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin.

    Science.gov (United States)

    Ma, Junxiong; Yu, Hailong; Liu, Jun; Chen, Yu; Wang, Qi; Xiang, Liangbi

    2015-10-05

    Painful diabetic neuropathy is a common complication of diabetes mellitus, which often makes the patients suffer from severe hyperalgesia and allodynia. Thus far, the treatment of painful diabetic neuropathy remains unsatisfactory. Metformin, which is the first-line drug for type-2 diabetes, has been proved to attenuate hyperexcitability in sensory neurons linked to chemotherapy-induced neuropathic pain, highlighting its potential in alleviating pain related with painful diabetic neuropathy. The present study was designed to investigate the potential beneficial effect of metformin on hyperalgesia and allodynia in diabetic rats. The mechanical sensitivity, heat nociception, and cold allodynia were examined. The levels of malondialdehyde, superoxide dismutase, and advanced glycation end-products in the blood were measured. The expression of adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and AMPK target genes were examined in the sciatic nerves of the animals. It was found that metformin was capable of attenuating diabetes-induced mechanical hyperalgesia, heat hyperalgesia and cold allodynia. In addition, metformin was capable of decreasing malondialdehyde and glycation end-products levels in blood, as well as increasing superoxide dismutas activity, indicating the inhibitory effect of metformin against diabetes-induced oxidative stress. Further studies showed that metformin could activate AMPK and increase the AMPK target genes in sciatic nerves in diabetic rats. In conclusion, metformin is able to attenuate diabetes-induced hyperalgesia and allodynia, which might be associated its anti-oxidative effect through AMPK pathway. Metformin might be used as an effective drug, especially with fewer side effects, for abnormal sensation in painful diabetic neuropathy.

  10. Electroacupuncture Inhibition of Hyperalgesia in Rats with Adjuvant Arthritis: Involvement of Cannabinoid Receptor 1 and Dopamine Receptor Subtypes in Striatum

    Directory of Open Access Journals (Sweden)

    Yin Shou

    2013-01-01

    Full Text Available Electroacupuncture (EA has been regarded as an alternative treatment for inflammatory pain for several decades. However, the molecular mechanisms underlying the antinociceptive effect of EA have not been thoroughly clarified. Previous studies have shown that cannabinoid CB1 receptors are related to pain relief. Accumulating evidence has shown that the CB1 and dopamine systems sometimes interact and may operate synergistically in rat striatum. To our knowledge, dopamine D1/D2 receptors are involved in EA analgesia. In this study, we found that repeated EA at Zusanli (ST36 and Kunlun (BL60 acupoints resulted in marked improvements in thermal hyperalgesia. Both western blot assays and FQ-PCR analysis results showed that the levels of CB1 expression in the repeated-EA group were much higher than those in any other group (P=0.001. The CB1-selective antagonist AM251 inhibited the effects of repeated EA by attenuating the increases in CB1 expression. The two kinds of dopamine receptors imparted different actions on the EA-induced CB1 upregulation in AA rat model. These results suggested that the strong activation of the CB1 receptor after repeated EA resulted in the concomitant phenomenon of the upregulation of D1 and D2 levels of gene expression.

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

    Directory of Open Access Journals (Sweden)

    Chen J

    2012-11-01

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

  12. Peripheral mechanisms underlying the essential role of P2X7 receptors in the development of inflammatory hyperalgesia.

    Science.gov (United States)

    Teixeira, Juliana Maia; Oliveira, Maria Cláudia G; Parada, Carlos Amílcar; Tambeli, Cláudia Herrera

    2010-10-10

    Activation of P2X7 receptors by endogenous ATP contributes to the development of inflammatory hyperalgesia. Given the clinical importance of mechanical hyperalgesia in inflammatory states, we hypothesized that the activation of the P2X7 receptor by endogenous ATP contributes to carrageenan-induced mechanical hyperalgesia, and that this contribution is mediated by an indirect sensitization of the primary afferent nociceptors. Co-administration of the selective P2X7 receptor antagonist, A-438079, or the P2X7 receptor antagonist, oATP, with carrageenan blocked the mechanical hyperalgesia induced by carrageenan and significantly reduced the increased concentration of TNF-alpha, IL-6 and CINC-1, but not of IL-1beta induced by carrageenan in the subcutaneous tissue of the rat's hind paw. We concluded that the activation of P2X7 receptors by endogenous ATP is essential to the development of the mechanical hyperalgesia induced by carrageenan in the subcutaneous tissue. It is suggested that this essential role of P2X7 receptors in the development of carrageenan-induced mechanical hyperalgesia is mediated by an indirect sensitization of the primary afferent nociceptors dependent on the previous release of TNF-alpha, IL-6 and CINC-1, but not of IL-1beta.

  13. MicroRNA-124 as a novel treatment for persistent hyperalgesia

    Directory of Open Access Journals (Sweden)

    Willemen Hanneke LDM

    2012-06-01

    Full Text Available Abstract Background Chronic pain is often associated with microglia activation in the spinal cord. We recently showed that microglial levels of the kinase G protein–coupled receptor kinase (GRK2 are reduced in models of chronic pain. We also found that mice with a cell-specific reduction of around 50% in GRK2 level in microglia/macrophages (LysM-GRK2+/− mice develop prolonged inflammatory hyperalgesia concomitantly with ongoing spinal microglia/macrophage activation. The microRNA miR-124 is thought to keep microglia/macrophages in brain and spinal cord in a quiescent state. In the present study, we investigated the contribution of miR-124 to regulation of hyperalgesia and microglia/macrophage activation in GRK2-deficient mice. In addition, we investigated the effect of miR-124 on chronic inflammatory and neuropathic pain in wild-type (WT mice. Methods Hyperalgesia was induced by intraplantar IL-1β in WT and LysM-GRK2+/− mice. We determined spinal cord microglia/macrophage miR-124 expression and levels of pro-inflammatory M1 and anti-inflammatory M2 activation markers. The effect of intrathecal miR-124 treatment on IL-1β-induced hyperalgesia and spinal M1/M2 phenotype, and on carrageenan-induced and spared nerve injury-induced chronic hyperalgesia in WT mice was analyzed. Results Transition from acute to persistent hyperalgesia in LysM-GRK2+/− mice is associated with reduced spinal cord microglia miR-124 levels. In our LysM-GRK2+/− mice, there was a switch towards a pro-inflammatory M1 phenotype together with increased pro-inflammatory cytokine production. Intrathecal administration of miR-124 completely prevented the transition to persistent pain in response to IL-1β in LysM-GRK2+/− mice. The miR-124 treatment also normalized expression of spinal M1/M2 markers of LysM-GRK2+/− mice. Moreover, intrathecal miR-124 treatment reversed the persistent hyperalgesia induced by carrageenan in WT mice and prevented development of

  14. Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin.

    Science.gov (United States)

    Stoicea, Nicoleta; Russell, Daric; Weidner, Greg; Durda, Michael; Joseph, Nicholas C; Yu, Jeffrey; Bergese, Sergio D

    2015-01-01

    Chronic pain patients receiving opioid drugs are at risk for opioid-induced hyperalgesia (OIH), wherein opioid pain medication leads to a paradoxical pain state. OIH involves central sensitization of primary and secondary afferent neurons in the dorsal horn and dorsal root ganglion, similar to neuropathic pain. Gabapentin, a gamma-aminobutyric acid (GABA) analog anticonvulsant used to treat neuropathic pain, has been shown in animal models to reduce fentanyl hyperalgesia without compromising analgesic effect. Chronic pain patients have also exhibited lower opioid consumption and improved pain response when given gabapentin. However, few human studies investigating gabapentin use in OIH have been performed in recent years. In this review, we discuss the potential mechanisms that underlie OIH and provide a critical overview of interventional therapeutic strategies, especially the clinically-successful drug gabapentin, which may reduce OIH.

  15. Caspase Inhibitors may Attenuate Opioid-induced Hyperalgesia and Tolerance via Inhibiting Microglial Activation and Neuroinflammation

    Directory of Open Access Journals (Sweden)

    Jiancheng Zhang

    2013-07-01

    Full Text Available Prolonged exposure to an opioid induces hyperalgesia and tolerance, which negatively affect pain management in turn and significantly hamper the application of opioids. A growing body of evidence has demonstrated that glial activation contributes to the development of these two side effects. Recent studies have demonstrated that morphine, binding to an accessory protein of Toll-like receptor 4 (TLR4, activates microglia and produces neuroinflammation in amanner parallel to lipopolysaccharide. Meanwhile, lipopolysaccharide activates microglia through TLR4/caspase signalling. Therefore, we hypothesise that morphine may activate microglia throughTLR4/caspase signalling and that caspase inhibitors may attenuate opioid-induced hyperalgesia and tolerance via inhibiting microglial activation and neuroinflammation

  16. PLGA-Curcumin Attenuates Opioid-Induced Hyperalgesia and Inhibits Spinal CaMKIIα.

    Directory of Open Access Journals (Sweden)

    Xiaoyu Hu

    Full Text Available Opioid-induced hyperalgesia (OIH is one of the major problems associated with prolonged use of opioids for the treatment of chronic pain. Effective treatment for OIH is lacking. In this study, we examined the efficacy and preliminary mechanism of curcumin in attenuating OIH. We employed a newly developed PLGA-curcumin nanoformulation (PLGA-curcumin in order to improve the solubility of curcumin, which has been a major obstacle in properly characterizing curcumin's mechanism of action and efficacy. We found that curcumin administered intrathecally or orally significantly attenuated hyperalgesia in mice with morphine-induced OIH. Furthermore, we demonstrated that the effects of curcumin on OIH correlated with the suppression of chronic morphine-induced CaMKIIα activation in the superficial laminae of the spinal dorsal horn. These data suggest that PLGA-curcumin may reverse OIH possibly by inhibiting CaMKIIα and its downstream signaling.

  17. Opioid-Induced Hyperalgesia in Chronic Pain Patients and the Mitigating Effects of Gabapentin

    Directory of Open Access Journals (Sweden)

    Nicoleta eStoicea

    2015-05-01

    Full Text Available Chronic pain patients receiving opioid drugs are at risk for opioid-induced hyperalgesia (OIH, wherein opioid pain medication leads to a paradoxical pain state. OIH involves central sensitization of primary and secondary afferent neurons in the dorsal horn and dorsal root ganglion, similar to neuropathic pain. Gabapentin, a gamma-aminobutyric acid (GABA analogue anticonvulsant used to treat neuropathic pain, has been shown in animal models to reduce fentanyl hyperalgesia without compromising analgesic effect. Chronic pain patients have also exhibited lower opioid consumption and improved pain response when given gabapentin. However, few human studies investigating gabapentin use in OIH have been performed in recent years. In this review, we discuss the potential mechanisms that underlie OIH and provide a critical overview of interventional therapeutic strategies, especially the clinically-successful drug gabapentin, which may reduce OIH.

  18. PLGA-Curcumin Attenuates Opioid-Induced Hyperalgesia and Inhibits Spinal CaMKIIα.

    Science.gov (United States)

    Hu, Xiaoyu; Huang, Fang; Szymusiak, Magdalena; Tian, Xuebi; Liu, Ying; Wang, Zaijie Jim

    2016-01-01

    Opioid-induced hyperalgesia (OIH) is one of the major problems associated with prolonged use of opioids for the treatment of chronic pain. Effective treatment for OIH is lacking. In this study, we examined the efficacy and preliminary mechanism of curcumin in attenuating OIH. We employed a newly developed PLGA-curcumin nanoformulation (PLGA-curcumin) in order to improve the solubility of curcumin, which has been a major obstacle in properly characterizing curcumin's mechanism of action and efficacy. We found that curcumin administered intrathecally or orally significantly attenuated hyperalgesia in mice with morphine-induced OIH. Furthermore, we demonstrated that the effects of curcumin on OIH correlated with the suppression of chronic morphine-induced CaMKIIα activation in the superficial laminae of the spinal dorsal horn. These data suggest that PLGA-curcumin may reverse OIH possibly by inhibiting CaMKIIα and its downstream signaling.

  19. Duration and distribution of experimental muscular hyperalgesia in humans following combined infusions of serotonin and bradykinin

    DEFF Research Database (Denmark)

    Babenko, Victor; Svensson, Peter; Graven-Nielsen, Thomas;

    2000-01-01

    -infusions interval of 3 min. Infusions of isotonic saline (NaCl, 0.9%) were given as control. Pain intensity was continuously scored on a visual analogue scale (VAS), and subjects drew the distribution of the pain areas on an anatomical map. Pressure pain thresholds (PPTs) were assessed with an electronic algometer....... In addition, PPTs were significantly decreased (Peffect of bradykinin in producing experimental muscle pain and muscle hyperalgesia to mechanical stimuli. The combination of serotonin and bradykinin can produce muscle...

  20. Opioid-Induced Hyperalgesia - Worsening Pain in Opioid-Dependent Patients

    Science.gov (United States)

    2013-02-01

    shown to reduce pain . Amantadine is an NMDA receptor antagonist that may mitigate central sensitization. Adjuvant analgesics may lessen nociceptive ...FEB 2013 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Opioid-induced hyperalgesia--worsening pain in opioid-dependent...Report Opioid-induced hyperalgesia—worsening pain in opioid-dependent patients☆ Abstract Patients with chronic opioid use are commonly treated in the

  1. Increased capsaicin-induced secondary hyperalgesia in patients with multiple chemical sensitivity

    DEFF Research Database (Denmark)

    Holst, Helle; Arendt-Nielsen, Lars; Mosbech, Holger;

    2011-01-01

    in experimental pain models to provoke peripheral and central sensitization. In patients with symptoms elicited by odorous chemicals capsaicin-induced secondary hyperalgesia and temporal summation were assessed as markers for abnormal central nociceptive processing together with neurogenic inflammation (flare).......the underlying cause of pathophysiological mechanisms triggering multiple chemical sensitivity (MCS) remains disputed.Recently, alterations in the central nervous system, for example,central sensitization, similar to various chronic pain disorders, have been suggested. Capsaicin is used...

  2. Nocebo hyperalgesia: contributions of social observation and body-related cognitive styles

    OpenAIRE

    2016-01-01

    Elisabeth Vögtle,1 Birgit Kröner-Herwig,1 Antonia Barke21Department of Clinical Psychology and Psychotherapy, Georg-Elias-Müller-Institute for Psychology, University of Göttingen, Göttingen, 2Department of Psychology, Division of Clinical Psychology and Psychotherapy, Philipps University Marburg, Marburg, Germany Purpose: Recently, it has been shown that nocebo hyperalgesia can be acquired through observational learning. The aim of this study was ...

  3. Hyperalgesia in Heroin Dependent Patients and the Effects of Opioid Substitution Therapy

    OpenAIRE

    2012-01-01

    Evidence suggests that patients on opiate maintenance therapy for the treatment of addiction present with opioid-induced hyperalgesia (OIH). This study compared the experimental (cold-pressor, electrical stimulation) pain responses of 82 treatment-seeking heroin-dependent adults randomized to methadone (METH, n = 11) or buprenorphine (BUP, n = 64) therapy, with matched drug free controls (n = 21). Heroin-dependent participants were evaluated at baseline (treatment entry), medication (METH or ...

  4. Influence of repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants.

    Science.gov (United States)

    Taddio, Anna; Shah, Vibhuti; Atenafu, Eshetu; Katz, Joel

    2009-07-01

    This study determined the effects of cumulative exposure to painful needle procedures and sucrose analgesia on the development of remote hyperalgesia in newborn infants, defined as an increase in response to a normally painful stimulus at a site distal from the site of injury. One-hundred and twenty healthy newborns and 120 healthy newborn infants of diabetic mothers equally randomized to sucrose analgesia or placebo prior to all needle procedures in the first two days after birth were divided into two exposure groups according to number of needle procedures they had undergone [high (> or =5) or low (pain response during a subsequent venipuncture distal to the site of previous injury, assessed by the Premature Infant Pain Profile (PIPP) [7.1 vs. 8.4; p=0.012] and Visual Analog Scale (VAS) [2.5 cm vs. 3.2 cm; p=0.047], and a trend for longer cry duration [25.7 s vs. 33.8 s; p=0.171]. PIPP scores did not differ during a routine diaper change, suggesting a nociceptive specific mechanism for the remote hyperalgesia to venipuncture. Sucrose reduced PIPP, VAS, and cry duration scores during venipuncture, but did not prevent hyperalgesia (p>0.05). There was a preponderance of infants of diabetic mothers in the high exposure group; however, the analysis did not demonstrate this to be a confounding factor. In conclusion, sucrose analgesia for repeated painful procedures in the first day of life does not prevent development of remote hyperalgesia in newborns.

  5. Model of methadone-induced hyperalgesia in rats and effect of memantine.

    Science.gov (United States)

    Hay, Justin L; Kaboutari, Jahangir; White, Jason M; Salem, Abdallah; Irvine, Rod

    2010-01-25

    Methadone used for opioid dependence therapy is associated with increased pain sensitivity. This study aimed to investigate whether methadone administration lowers nociceptive threshold in adult male Sprague-Dawley (SD) rats, and if this threshold could be altered by the NMDA receptor antagonist memantine. Rats were implanted with osmotic pumps delivering 1mg/kg/day methadone (n=6), or saline placebo (n=6) (0.51 microl/h). A separate cohort of rats received either methadone 1mg/kg/day (n=8) or methadone 1mg/kg/day with 20mg/kg/day memantine (n=8). Nociception was measured by the Hargreave's paw withdrawal test. Baseline nociception was measured on day 0 prior to osmotic pump implantation and was measured daily for the following 21 days. Osmotic pumps were removed following nociceptive testing on day 14. Methadone only treated rats had a mean paw withdrawal latency significantly lower than the corresponding values for saline on days 8, 9, 10, 11, 12, 14, and 17 (P0.05). Paw withdrawal latency of rats treated with methadone co-administered with memantine did not differ significantly compared to methadone only (P>0.05). This demonstrates that methadone induces hyperalgesia in the SD rat yet this hyperalgesia resolves following discontinuation of methadone administration. Furthermore, memantine does not alter the development of methadone-induced hyperalgesia.

  6. Pharmacological treatment of opioid-induced hyperalgesia: a review of the evidence.

    Science.gov (United States)

    Ramasubbu, Chitra; Gupta, Anita

    2011-01-01

    Opioids are commonly used to treat moderate to severe pain. Opioid-induced hyperalgesia is a paradoxical response to opioid agonists resulting in an increased perception of pain rather than an antinociceptive effect. Even though there is a debate regarding its clinical relevance, it is becoming a challenge in both acute and chronic pain settings. The study of opioid-induced hyperalgesia is an emerging field with multiple challenges faced by investigators with regard to defining the diagnosis and characterizing the findings. The objective of this study was to review the preliminary evidence related to the treatment and management of opioid-induced hyperalgesia. Lack of data, small patient numbers, short-term follow-up, and variations in study design limited the review. With the literature on this subject being sparse, this study attempts to provide a preliminary look at the available data and to set the stage for an eventual meta-analysis. Case reports in the literature have shown success with various pharmacological interventions. Possible treatment regimens include ketamine, dextromethorphan, and nonsteroidal anti-inflammatory drugs (NSAIDs), opioid switching, amantadine, buprenorphine, α(2) agonists, and methadone. These agents are briefly discussed in this paper. Further well-designed, placebo-controlled trials are needed to assess the effectiveness of the interventions investigated in this review.

  7. Chronic CRF1 receptor blockade reduces heroin intake escalation and dependence-induced hyperalgesia.

    Science.gov (United States)

    Park, Paula E; Schlosburg, Joel E; Vendruscolo, Leandro F; Schulteis, Gery; Edwards, Scott; Koob, George F

    2015-03-01

    Opioids represent effective drugs for the relief of pain, yet chronic opioid use often leads to a state of increased sensitivity to pain that is exacerbated during withdrawal. A sensitization of pain-related negative affect has been hypothesized to closely interact with addiction mechanisms. Neuro-adaptive changes occur as a consequence of excessive opioid exposure, including a recruitment of corticotropin-releasing factor (CRF) and norepinephrine (NE) brain stress systems. To better understand the mechanisms underlying the transition to dependence, we determined the effects of functional antagonism within these two systems on hyperalgesia-like behavior during heroin withdrawal utilizing models of both acute and chronic dependence. We found that passive or self-administered heroin produced a significant mechanical hypersensitivity. During acute opioid dependence, systemic administration of the CRF1 receptor antagonist MPZP (20 mg/kg) alleviated withdrawal-induced mechanical hypersensitivity. In contrast, several functional adrenergic system antagonists (clonidine, prazosin, propranolol) failed to alter mechanical hypersensitivity in this state. We then determined the effects of chronic MPZP or clonidine treatment on extended access heroin self-administration and found that MPZP, but not clonidine, attenuated escalation of heroin intake, whereas both drugs alleviated chronic dependence-associated hyperalgesia. These findings suggest that an early potentiation of CRF signaling occurs following opioid exposure that begins to drive both opioid-induced hyperalgesia and eventually intake escalation.

  8. Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents

    Directory of Open Access Journals (Sweden)

    Mercado Ramon

    2011-01-01

    Full Text Available Abstract Background Tissue injury elicits both hypersensitivity to evoked stimuli and ongoing, stimulus-independent pain. We previously demonstrated that pain relief elicits reward in nerve-injured rats. This approach was used to evaluate the temporal and mechanistic features of inflammation-induced ongoing pain. Results Intraplantar Complete Freund's Adjuvant (CFA produced thermal hyperalgesia and guarding behavior that was reliably observed within 24 hrs and maintained, albeit diminished, 4 days post-administration. Spinal clonidine produced robust conditioned place preference (CPP in CFA treated rats 1 day, but not 4 days following CFA administration. However, spinal clonidine blocked CFA-induced thermal hyperalgesia at both post-CFA days 1 and 4, indicating different time-courses of ongoing and evoked pain. Peripheral nerve block by lidocaine administration into the popliteal fossa 1 day following intraplantar CFA produced a robust preference for the lidocaine paired chamber, indicating that injury-induced ongoing pain is driven by afferent fibers innervating the site of injury. Pretreatment with resiniferatoxin (RTX, an ultrapotent capsaicin analogue known to produce long-lasting desensitization of TRPV1 positive afferents, fully blocked CFA-induced thermal hypersensitivity and abolished the CPP elicited by administration of popliteal fossa lidocaine 24 hrs post-CFA. In addition, RTX pretreatment blocked guarding behavior observed 1 day following intraplantar CFA. In contrast, administration of the selective TRPV1 receptor antagonist, AMG9810, at a dose that reversed CFA-induced thermal hyperalgesia failed to reduce CFA-induced ongoing pain or guarding behavior. Conclusions These data demonstrate that inflammation induces both ongoing pain and evoked hypersensitivity that can be differentiated on the basis of time course. Ongoing pain (a is transient, (b driven by peripheral input resulting from the injury, (c dependent on TRPV1 positive

  9. Effect of preemptive nerve block on inflammation and hyperalgesia after human thermal injury

    DEFF Research Database (Denmark)

    Pedersen, J L; Crawford, M E; Dahl, J B;

    1996-01-01

    BACKGROUND: Postoperative pain relief may be improved by reducing sensitization of nociceptive pathways caused by surgical trauma. Such a reduction may depend on the timing and efficacy of analgesia and the duration of the nociceptive block versus the duration of the nociceptive input. We examine...

  10. Kinin B1 receptor antagonists inhibit diabetes-induced hyperalgesia in mice.

    Science.gov (United States)

    Gabra, Bichoy H; Sirois, Pierre

    2003-02-01

    Insulin-dependent diabetes mellitus (type 1 diabetes) is an inflammatory autoimmune disease associated with vascular permeability changes leading to many complications including nephropathy, retinopathy, neuropathy, hypertension and hyperalgesia. The bradykinin B(1) receptors (BKB(1)-R) were recently found to be upregulated alongside the development of type 1 diabetes and to be involved in its complications. Kinins are important mediators of a variety of biological effects including cardiovascular homeostasis, inflammation and nociception. In the present study, we studied the effect of a selective BKB(1)-R agonist desArg(9)-BK (DBK) and two selective receptor antagonists, the R-715 (Ac-Lys-[D-beta Nal(7), Ile(8)] desArg(9)-BK) and the R-954 (Ac-Orn-[Oic(2), alphaMe Phe(5), D-beta Nal(7), Ile(8)] desArg(9)-BK) on diabetic hyperalgesia. Type 1 diabetes was induced in male CD-1 mice via a single injection of streptozotocin (STZ, 200mg/kg, i.p.), one week before the test. Nociception, a measure of hyperalgesia, was assessed using the plantar stimulation (Hargreaves) and the tail-immersion tests. The induction of type 1 diabetes provoked a significant hyperalgesic activity in diabetic mice, causing an 11% decrease in plantar stimulation reaction time and 13% decrease in tail-immersion reaction time, compared to normal mice. Following acute administration of R-715 (100-600 microg/kg, i.p.), or R-954 (50-400 microg/kg, i.p.), the STZ-induced hyperalgesic activity was blocked in a dose-dependent manner and the hot plate and tail-immersion latencies of diabetic mice returned to normal values observed in control healthy mice. In addition, the acute administration of DBK (400 microg/kg, i.p.) significantly potentiated diabetes-induced hyperalgesia, an effect that was totally reversed by R-715 (1.6-2.4 mg/kg, i.p.) and R-954 (0.8-1.2mg/kg, i.p.). These results provide further evidence for the implication of the BKB(1)-R in type 1 diabetic hyperalgesia and suggest a novel

  11. Protective effects of dexmedetomidine combined with flurbiprofen axetil on remifentanil-induced hyperalgesia: A randomized controlled trial

    Science.gov (United States)

    Yu, Zenggui; Wu, Weilan; Wu, Xiaodan; Lei, Hongyi; Gong, Cansheng; Xu, Shiyuan

    2016-01-01

    High dosages of intra-operative remifentanil are associated with opioid-induced hyperalgesia (OIH). The aim of the present study was to investigate the effect of combined dexmedetomidine and flurbiprofen axetil treatment on remifentanil-induced hyperalgesia. Patients with an American Society of Anesthesiologists physical status of I–II who were diagnosed with hysteromyoma and scheduled for laparoscopic assisted vaginal hysterectomy (LAVH) were randomly divided into three groups. Group hyperalgesia (Group H, n=29) received intra-operative remifentanil, Group hyperalgesia and dexmedetomidine (Group HD, n=28) received remifentanil and a continuous infusion of dexmedetomidine, and Group hyperalgesia, dexmedetomidine and flurbiprofen axetil (Group HDF, n=29) received remifentanil, flurbiprofen axetil and dexmedetomidine. Mechanical pain thresholds were measured during the preoperative visit and postoperatively at 1, 6 and 24-h time points. Visual analog scale (VAS) scores, time to analgesic requirement, total sufentanil consumption and side effects were assessed postoperatively. Mechanical pain threshold at the incision site was significantly lower in Group H compared with Groups HD and HDF (both P<0.05), and significantly higher in Group HDF than in Group HD (P<0.05). The area of secondary hyperalgesia at the incision site was greater in Group H than in the other two groups (both P<0.05), and significantly smaller in Group HDF compared with Group HD (P<0.05). VAS scores and total sufentanil consumption were significantly higher in Group H compared with the other two groups (both P<0.05), and were significantly lower in Group HDF compared with Group HD (P<0.05). Dexmedetomidine combined with flurbiprofen axetil exhibits synergetic effects in the prevention of remifentanil-induced hyperalgesia in patients undergoing LAVH. PMID:27698764

  12. 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.

  13. Patients with chronic pain after abdominal surgery show less preoperative endogenous pain inhibition and more postoperative hyperalgesia: a pilot study.

    Science.gov (United States)

    Wilder-Smith, Oliver Hamilton; Schreyer, Tobias; Scheffer, Gert Jan; Arendt-Nielsen, Lars

    2010-06-01

    Chronic pain is common and undesirable after surgery. Progression from acute to chronic pain involves altered pain processing. The authors studied relationships between presence of chronic pain versus preoperative descending pain control (diffuse noxious inhibitory controls; DNICs) and postoperative persistence and spread of skin and deep tissue hyperalgesia (change in electric/pressure pain tolerance thresholds; ePTT/pPTT) up to 6 months postoperatively. In 20 patients undergoing elective major abdominal surgery under standardized anesthesia, we determined ePTT/pPTT (close to [abdomen] and distant from [leg] incision), eDNIC/pDNIC (change in ePTT/pPTT with cold pressor pain task; only preoperatively), and a 100 mm long pain visual analogue scale (VAS) (0 mm = no pain, 100 mm = worst pain imaginable), both at rest and on movement preoperatively, and 1 day and 1, 3, and 6 months postoperatively. Patients reporting chronic pain 6 months postoperatively had more abdominal and leg skin hyperalgesia over the postoperative period. More inhibitory preoperative eDNIC was associated with less late postoperative pain, without affecting skin hyperalgesia. More inhibitory pDNIC was linked to less postoperative leg deep tissue hyperalgesia, without affecting pain VAS. This pilot study for the first time links chronic pain after surgery, poorer preoperative inhibitory pain modulation (DNIC), and greater postoperative degree, persistence, and spread of hyperalgesia. If confirmed, these results support the potential clinical utility of perioperative pain processing testing.

  14. Sprouted innervation into uterine transplants contributes to the development of hyperalgesia in a rat model of endometriosis.

    Science.gov (United States)

    McAllister, Stacy L; Dmitrieva, Natalia; Berkley, Karen J

    2012-01-01

    Endometriosis is an enigmatic painful disorder whose pain symptoms remain difficult to alleviate in large part because the disorder is defined by extrauteral endometrial growths whose contribution to pain is poorly understood. A rat model (ENDO) involves autotransplanting on abdominal arteries uterine segments that grow into vascularized cysts that become innervated with sensory and sympathetic fibers. ENDO rats exhibit vaginal hyperalgesia. We used behavioral, physiological, and immunohistochemical methods to test the hypothesis that cyst innervation contributes to the development of this hyperalgesia after transplant. Rudimentary sensory and sympathetic innervation appeared in the cysts at two weeks, sprouted further and more densely into the cyst wall by four weeks, and matured by six weeks post-transplant. Sensory fibers became abnormally functionally active between two and three weeks post-transplant, remaining active thereafter. Vaginal hyperalgesia became significant between four and five weeks post-transplant, and stabilized after six to eight weeks. Removing cysts before they acquired functional innervation prevented vaginal hyperalgesia from developing, whereas sham cyst removal did not. Thus, abnormally-active innervation of ectopic growths occurs before hyperalgesia develops, supporting the hypothesis. These findings suggest that painful endometriosis can be classified as a mixed inflammatory/neuropathic pain condition, which opens new avenues for pain relief. The findings also have implications beyond endometriosis by suggesting that functionality of any transplanted tissue can be influenced by the innervation it acquires.

  15. Sprouted innervation into uterine transplants contributes to the development of hyperalgesia in a rat model of endometriosis.

    Directory of Open Access Journals (Sweden)

    Stacy L McAllister

    Full Text Available Endometriosis is an enigmatic painful disorder whose pain symptoms remain difficult to alleviate in large part because the disorder is defined by extrauteral endometrial growths whose contribution to pain is poorly understood. A rat model (ENDO involves autotransplanting on abdominal arteries uterine segments that grow into vascularized cysts that become innervated with sensory and sympathetic fibers. ENDO rats exhibit vaginal hyperalgesia. We used behavioral, physiological, and immunohistochemical methods to test the hypothesis that cyst innervation contributes to the development of this hyperalgesia after transplant. Rudimentary sensory and sympathetic innervation appeared in the cysts at two weeks, sprouted further and more densely into the cyst wall by four weeks, and matured by six weeks post-transplant. Sensory fibers became abnormally functionally active between two and three weeks post-transplant, remaining active thereafter. Vaginal hyperalgesia became significant between four and five weeks post-transplant, and stabilized after six to eight weeks. Removing cysts before they acquired functional innervation prevented vaginal hyperalgesia from developing, whereas sham cyst removal did not. Thus, abnormally-active innervation of ectopic growths occurs before hyperalgesia develops, supporting the hypothesis. These findings suggest that painful endometriosis can be classified as a mixed inflammatory/neuropathic pain condition, which opens new avenues for pain relief. The findings also have implications beyond endometriosis by suggesting that functionality of any transplanted tissue can be influenced by the innervation it acquires.

  16. Withania somnifera root extract prolongs analgesia and suppresses hyperalgesia in mice treated with morphine.

    Science.gov (United States)

    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.

  17. Antagonists of toll like receptor 4 maybe a new strategy to counteract opioid-induced hyperalgesia and opioid tolerance.

    Science.gov (United States)

    Li, Qian

    2012-12-01

    Long term opioid treatment results in hyperalgesia and tolerance, which is a troublesome phenomenon in clinic application. Recent studies have revealed a critical role of toll-like receptor 4 (TLR4) in the neuropathological process of opioid-induced hyperalgesia and tolerance. TLR4 is predominantly expressed by microglial cells and is a key modulator in the activation of the innate immune system. Activation of TLR4 may initiate the activation of microglia and hence a number of neurotransmitters and neuromodulators that could enhance neuronal excitability are released. Blockade of TLR4 activation by its antagonists alleviate neuropathic pain. We hypothesized that opioid antagonists such as naloxone and naltrexone, which were also demonstrated to be TLR4 antagonist, may have clinic application value in attenuation of opioid-induced hyperalgesia and tolerance.

  18. Optokinetic stimulation increases limb pain and forehead hyperalgesia in complex regional pain syndrome

    DEFF Research Database (Denmark)

    Knudsen, Lone F.; Drummond, Peter D.

    2015-01-01

    to investigate the mechanisms underlying the link between sensory conflicts and pain in CRPS using optokinetic stimulation (OKS) - a method known to induce motion sickness. METHODS: Twenty-one CRPS patients underwent OKS and rated symptoms of motion sickness. Patients also rated limb pain and pain....... In a subgroup of nauseated patients who withdrew early from OKS, hyperalgesia to pressure in the ipsilateral forehead persisted longer than in the remaining participants. Sharpness sensations remained constant at all sites. CONCLUSIONS: Sensory conflicts may facilitate pain in CRPS by activating the mechanisms...

  19. [MORPHOLOGICAL CHANGES OF SKIN IN OPERATIVE WOUND IN SYNDROME OF OPIOID-INDUCED HYPERALGESIA].

    Science.gov (United States)

    Dmytriyev, D V; Konoplytskyi, V S

    2015-10-01

    Morphological changes of skin in region of operative wound were investigated. There was established, that while application of fentanyl in high doses, using constant infusion for anesthesia in early postoperative period in children, operated for abdominal cavity tumors, the opioid-induced hyperalgesia occurrence is possible, what is accompanied by morphological changes in skin around operative wound, necrosis in centre of focus, pronounced perifocal reactive changes in a kind of significant inflammation and essential disorder of microcirculation with formation of small neural fibers on the 14th day. Pronounced fibrosis of derma, formation of big quantity of collagen fibers with edema, stratification.

  20. Opioid-induced hyperalgesia: a review of epidemiology, mechanisms and management.

    Science.gov (United States)

    Low, Yinghui; Clarke, Collin F; Huh, Billy K

    2012-05-01

    There has been a growing interest in opioid-induced hyperalgesia (OIH), which is an increased sensitivity to pain caused by opioid exposure. Multiple underlying pathways may contribute to the development of OIH, and the mechanism may vary with the duration of opioid exposure, dose, type and route of administration. In addition, the distinction between OIH, tolerance and withdrawal should be made in both the basic and clinical science literature so as to help translate findings to the clinical phenomenon and to help determine the best strategies to prevent or treat OIH.

  1. A Rat Model of Full Thickness Thermal Injury Characterized by Thermal Hyperalgesia, Mechanical Allodynia, Pronociceptive Peptide Release and Tramadol Analgesia

    Science.gov (United States)

    2014-01-01

    Zhang L, Ma Y, Chen L, Tian Y, Mao J, et al. Nociceptive behavior following hindpaw burn injury in young rats: response to systemic morphine. Pain ...18 system in need of optimal pain control, reduced incidence of chronic pain and reduced risk of tolerance and addiction [4]. Opioid based narcotics...are the most prevalent therapeutics for the management of severe pain in civilian and military inpatient settings [5]. Because traumatic injuries

  2. Development of a peptidomimetic antagonist of neuropeptide FF receptors for the prevention of opioid-induced hyperalgesia.

    Science.gov (United States)

    Bihel, Frédéric; Humbert, Jean-Paul; Schneider, Séverine; Bertin, Isabelle; Wagner, Patrick; Schmitt, Martine; Laboureyras, Emilie; Petit-Demoulière, Benoît; Schneider, Elodie; Mollereau, Catherine; Simonnet, Guy; Simonin, Frédéric; Bourguignon, Jean-Jacques

    2015-03-18

    Through the development of a new class of unnatural ornithine derivatives as bioisosteres of arginine, we have designed an orally active peptidomimetic antagonist of neuropeptide FF receptors (NPFFR). Systemic low-dose administration of this compound to rats blocked opioid-induced hyperalgesia, without any apparent side-effects. Interestingly, we also observed that this compound potentiated opioid-induced analgesia. This unnatural ornithine derivative provides a novel therapeutic approach for both improving analgesia and reducing hyperalgesia induced by opioids in patients being treated for chronic pain.

  3. Evidence for an inhibitory role of central histamine on carrageenin-induced hyperalgesia.

    Science.gov (United States)

    Netti, C; Sibilia, V; Guidobono, F; Villani, P; Pecile, A; Braga, P C

    1994-02-01

    The effects of intracerebroventricular (i.c.v.) injection of histamine, the H1 agonist 2-methyl-histamine and the H2 agonist dimaprit were tested on carrageenin induced hyperalgesia by the Randall-Selitto paw pressure test in the rat. Treatment with histamine (0.1, 0.2, 0.4 mumol/rat, i.c.v.) 150 min after intraplantar carrageenin (0.1 ml of 1% solution) caused a significant increase of paw pressure thresholds in inflamed (but not in non-inflamed) paws. The magnitude and the duration of the antinociceptive effects of histamine were dose-dependent. Administration of 2-methyl-histamine (0.2, 0.4, 0.8, 1.0 mumol/rat, i.c.v.) and dimaprit (0.1, 0.2, 0.4, 0.8 mumol/rat, i.c.v.) also displayed dose-dependent blockade of carrageenin-induced hyperalgesia. Antinociceptive ED50 values calculated 30 min after drug treatments were: histamine 0.18 mumol/rat; 2-methyl-histamine 0.65 mumol/rat; dimaprit 0.33 mumol/rat. These data indicate that histamine through central H1 and H2 receptors exerts an inhibitory role in the control of nociception in pain resulting from inflammation.

  4. Detection of cold pain, cold allodynia and cold hyperalgesia in freely behaving rats

    Directory of Open Access Journals (Sweden)

    Woolf Clifford J

    2005-12-01

    Full Text Available Abstract Background Pain is elicited by cold, and a major feature of many neuropathic pain states is that normally innocuous cool stimuli begin to produce pain (cold allodynia. To expand our understanding of cold induced pain states we have studied cold pain behaviors over a range of temperatures in several animal models of chronic pain. Results We demonstrate that a Peltier-cooled cold plate with ± 1°C sensitivity enables quantitative measurement of a detection withdrawal response to cold stimuli in unrestrained rats. In naïve rats the threshold for eliciting cold pain behavior is 5°C. The withdrawal threshold for cold allodynia is 15°C in both the spared nerve injury and spinal nerve ligation models of neuropathic pain. Cold hyperalgesia is present in the spared nerve injury model animals, manifesting as a reduced latency of withdrawal response threshold at temperatures that elicit cold pain in naïve rats. We also show that following the peripheral inflammation produced by intraplantar injection of complete Freund's adjuvant, a hypersensitivity to cold occurs. Conclusion The peltier-cooled provides an effective means of assaying cold sensitivity in unrestrained rats. Behavioral testing of cold allodynia, hyperalgesia and pain will greatly facilitate the study of the neurobiological mechanisms involved in cold/cool sensations and enable measurement of the efficacy of pharmacological treatments to reduce these symptoms.

  5. Remifentanil-acute opioid tolerance and opioid-induced hyperalgesia: a systematic review.

    Science.gov (United States)

    Kim, Sang Hun; Stoicea, Nicoleta; Soghomonyan, Suren; Bergese, Sergio D

    2015-01-01

    The use of opioids may seem to be a double-edged sword; they provide straight analgesic and antihyperalgesic effects initially, but subsequently are associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) that have been reported in experimental studies and clinical observations. It has been suggested that opioids can induce an acute tolerance and hyperalgesia in dose- and/or time-dependent manners even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management in clinical anesthesia and in the intensive care units because of its rapid onset and offset. We reviewed articles analyzing AOT and/or OIH by remifentanil and focused on the following issues: (1) evidence of remifentanil inducing AOT and/or OIH and (2) importance of AOT and/or OIH in considering the reduction of remifentanil dosage or adopting preventive modulations. Twenty-four experimental and clinical studies were identified using electronic searches of MEDLINE (PubMed, Ovid, Springer, and Elsevier). However, the development of AOT and OIH by remifentanil administration remains controversial. There is no sufficient evidence to support or refute the existence of OIH in humans.

  6. Self-reported Recovery is Associated with Improvement in Localised Hyperalgesia Among Adolescent Females with Patellofemoral Pain

    DEFF Research Database (Denmark)

    Rathleff, Michael Skovdal; Roos, Ewa M.; Olesen, Jens Lykkegaard;

    2016-01-01

    to the manifestations of pain. The objective of this study was to compare the change in localised and distal hyperalgesia among female adolescents with Patellofemoral Pain (PFP) deeming themselves recovered compared to those not recovered 3 months after patient education with or without exercise therapy. METHODS...

  7. Toll-like receptor 4 mutant and null mice retain morphine-induced tolerance, hyperalgesia, and physical dependence.

    Directory of Open Access Journals (Sweden)

    Theresa Alexandra Mattioli

    Full Text Available The innate immune system modulates opioid-induced effects within the central nervous system and one target that has received considerable attention is the toll-like receptor 4 (TLR4. Here, we examined the contribution of TLR4 in the development of morphine tolerance, hyperalgesia, and physical dependence in two inbred mouse strains: C3H/HeJ mice which have a dominant negative point mutation in the Tlr4 gene rendering the receptor non-functional, and B10ScNJ mice which are TLR4 null mutants. We found that neither acute antinociceptive response to a single dose of morphine, nor the development of analgesic tolerance to repeated morphine treatment, was affected by TLR4 genotype. Likewise, opioid induced hyperalgesia and opioid physical dependence (assessed by naloxone precipitated withdrawal were not altered in TLR4 mutant or null mice. We also examined the behavioural consequence of two stereoisomers of naloxone: (- naloxone, an opioid receptor antagonist, and (+ naloxone, a purported antagonist of TLR4. Both stereoisomers of naloxone suppressed opioid induced hyperalgesia in wild-type control, TLR4 mutant, and TLR4 null mice. Collectively, our data suggest that TLR4 is not required for opioid-induced analgesic tolerance, hyperalgesia, or physical dependence.

  8. Paclitaxel-induced hyperalgesia modulates negative affective component of pain and NR1 receptor expression in the frontal cortex in rats.

    Science.gov (United States)

    Noda, Kazuko; Akita, Hisanao; Ogata, Masanori; Saji, Makoto

    2014-03-01

    Paclitaxel, one of the chemotherapeutic agents clinically used to treat several types of cancer, produces side effects such as peripheral neuropathy, sensory abnormalities, and hyperalgesia. Since hyperalgesia remains after cessation of paclitaxel therapy and becomes chronic, we hypothesize that alteration in memory and the cognitive process of pain underlies hyperalgesia. To test this hypothesis, we examined whether drug-induced hyperalgesia alters the affective component of pain and the NMDA-NR1 and mGluR1 receptors as a mediator for signal transmission and memory of pain. Mechanical sensitivity was measured by von Frey filament test after intraperitoneal injection of paclitaxel in rats. Paclitaxel-induced hyperalgesia was confirmed over almost the entire 14-day period of observation after the treatment. The effect of paclitaxel-induced hyperalgesia on the affective component of pain was assessed using pain-induced place aversion. The formalin-induced conditioned place aversion was completely abolished in the paclitaxel-treated rats. Immunoblot analysis of NR1 and mGluR1 protein levels in various brain regions was performed after paclitaxel treatment. Treatment reduced only the NR1 expression within the frontal cortex. These results suggest that the hypofunction of memory processes with the reduced NMDA receptors in the frontal cortex might be involved in the expression of abnormal emotional behaviors accompanied by hyperalgesia.

  9. Differential activation of p38 and extracellular signal-regulated kinase in spinal cord in a model of bee venom-induced inflammation and hyperalgesia

    Directory of Open Access Journals (Sweden)

    Kobayashi Kimiko

    2008-04-01

    Full Text Available Abstract Background Honeybee's sting on human skin can induce ongoing pain, hyperalgesia and inflammation. Injection of bee venom (BV into the intraplantar surface of the rat hindpaw induces an early onset of spontaneous pain followed by a lasting thermal and mechanical hypersensitivity in the affected paw. The underlying mechanisms of BV-induced thermal and mechanical hypersensitivity are, however, poorly understood. In the present study, we investigated the role of mitogen-activated protein kinase (MAPK in the generation of BV-induced pain hypersensitivity. Results We found that BV injection resulted in a quick activation of p38, predominantly in the L4/L5 spinal dorsal horn ipsilateral to the inflammation from 1 hr to 7 d post-injection. Phosphorylated p38 (p-p38 was expressed in both neurons and microglia, but not in astrocytes. Intrathecal administration of the p38 inhibitor, SB203580, prevented BV-induced thermal hypersensitivity from 1 hr to 3 d, but had no effect on mechanical hypersensitivity. Activated ERK1/2 was observed exclusively in neurons in the L4/L5 dorsal horn from 2 min to 1 d, peaking at 2 min after BV injection. Intrathecal administration of the MEK inhibitor, U0126, prevented both mechanical and thermal hypersensitivity from 1 hr to 2 d. p-ERK1/2 and p-p38 were expressed in neurons in distinct regions of the L4/L5 dorsal horn; p-ERK1/2 was mainly in lamina I, while p-p38 was mainly in lamina II of the dorsal horn. Conclusion The results indicate that differential activation of p38 and ERK1/2 in the dorsal horn may contribute to the generation and development of BV-induced pain hypersensitivity by different mechanisms.

  10. Comparison of Blood Pressure and Thermal Responses in Rats Exposed to Millimeter Wave Energy or Environmental Heat

    Science.gov (United States)

    2005-12-22

    nerve injury rats exhibit millimeter wave length: potential occupational safety issues relating to surface thermal hyperalgesia on an automated...May 2006 1 Journal Article I Aug 2005 - May 2006 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Comparison of Blood Pressure and Thermal Responses in Rats...Z39.18 5-1 •ATEThENTA SHOCK, Vol. 25, No. 6, pp. 625-632, 2006 Approved for Public Release Distribution Unlimited COMPARISON OF BLOOD PRESSURE AND THERMAL

  11. Thermal hypersensitivity in a subset of irritable bowel syndrome patients

    Institute of Scientific and Technical Information of China (English)

    QiQi Zhou; Roger B Fillingim; Joseph L Riley III; G Nicholas Verne

    2009-01-01

    AIM: To characterize thermal hypersensitivity in patients with constipation- and diarrhea-predominant irritable bowel syndrome (IBS). METHODS: Thermal pain sensitivity was tested among patients with diarrhea-predominant IBS (D-IBS) and constipation-predominant IBS (C-IBS) compared to healthy subjects. A total of 42 patients (29 female and patients (16 female and eight male; mean age 32.5participated in the study. Thermal stimuli were delivered using a Medoc Thermal Sensory Analyzer with a 3 cm heat pain tolerance (HPTo) were assessed on the left ventral forearm and left calf using an ascending method of limits. The Functional Bowel Disease Severity Index (FBDSI) was also obtained for all subjects. RESULTS: Controls were less sensitive than C-IBS and D-IBS (both at P < 0.001) with no differences between C-IBS and D-IBS for HPTh and HPTo. Thermal hyperalgesia was present in both groups of IBS patients relative to controls, with IBS patients reporting significantly lower pain threshold and pain tolerance at both test sites. Cluster analysis revealed the presence of subgroups of IBS patients based on thermal hyperalgesia. One cluster (17% of the sample) showed a profile of heat pain sensitivity very similar to that of healthy controls; a second cluster (47% of the sample) showed moderate heat pain sensitivity; and a third cluster (36% of the sample) showed a very high degree of thermal hyperalgesia.CONCLUSION: A subset of IBS patients had thermal hypersensitivity compared to controls, who reported significantly lower HPTh and HPTo. All IBS patients had a higher score on the FBDSI than controls. Interestingly, the subset of IBS patients with high thermal sensitivity (36%) had the highest FBDSI score compared to the other two groups of IBS patients.

  12. Is mechanism and symptom-based analgesia an answer to opioid-Induced hyperalgesia?

    Directory of Open Access Journals (Sweden)

    Mayank Gupta

    2015-01-01

    Full Text Available "Cancer Pain" and "Pain in cancer patient" are not synonymous. Opioid-induced Hyperalgesia (OIH is a paradoxical state of nociceptive sensitization caused by exposure to opioids. Neuropathic pain is only partially responsive to opioids; injudicious increase in dose of opioids in neuropathic pain may not only result in inadequate pain relief but also OIH. Majority of literature on OIH is in non-cancer pain with systemic use of opioids. We describe the development and successful treatment of OIH in a 55-year-old male patient with Small cell Carcinoma Lung. Opioid tapering, rotation, systemic desensitization helps in combatting OIH. The use of anti-neuropathic adjuvant analgesics helps not only in preventing and treating OIH but also in understanding putative mechanisms underlying neuropathic pain and OIH.

  13. Pharmacological inhibition of eicosanoid synthesis and hyperalgesia in yeast-injected rat paws

    Energy Technology Data Exchange (ETDEWEB)

    Opas, E.E.; Dallob, A.; Herold, E.; Luell, S.; Humes, J.L.

    1986-03-01

    Brewer's yeast caused an inflammation characterized by edema and hyperalgesia when injected into the hindpaw of a rat. These events were temporally distinct and each was associated with increases of specific arachidonic and oxygenation products. As determined by radioimmunoassay (RIA) on whole paw lipid extracts, the 5-lipoxygenase (5-LO) products, leukotrienes C/sub 4/ and D/sub 4/ and 5-hydroxyeicosatetraendic acid (5-HETE) were synthesized concurrently with the onset of edema (maximal at 15 minutes after yeast injection). The hyperalgesic phase of the inflammation (3-4 hr after yeast injection) was associated with increased tissue levels of the cyclooxygenase (CO) products, prostaglandin E/sub 2/ and thromboxane B/sub 2/ (TXB/sub 2/) as well as increases in levels of the 5-LO products, leukotriene B/sub 4/ (LTB/sub 4/) and 5-HETE. Pharmacological agents modulated the synthesis of eicosanoids and suppressed the hyperalgesic response.

  14. Acute-onset opioid-induced hyperalgesia in a child with juvenile idiopathic arthritis.

    Science.gov (United States)

    Vijayan, Vini; Moran, Ryan; Elder, Melissa E; Sukumaran, Sukesh

    2012-10-01

    We describe a child with polyarticular juvenile idiopathic arthritis (JIA) presenting with severe diffuse pain refractory to nonsteroidal anti-inflammatory agents and high-dose opioids. Her JIA involved her knees and ankles and was mildly active on etanercept and nonsteroidal anti-inflammatory agents. At presentation, she complained of hip pain progressing to severe diffuse pain and allodynia involving her extremities. No abnormalities were seen in her laboratory parameters and imaging of her lower extremities. After appreciating no substantial benefit by increasing her opioids, her opioids were tapered and discontinued, and this was followed by significant alleviation in her pain, and a diagnosis of opioid-induced hyperalgesia (OIH) was made. Despite reports in adults, the phenomenon of OIH has been reported infrequently in children. To our knowledge, OIH has not been described in children with rheumatologic conditions. We recommend investigating the possibility of OIH when treating a child with JIA and severe refractory pain.

  15. Opioid-induced hyperalgesia (OIH): a real clinical problem or just an experimental phenomenon?

    Science.gov (United States)

    Eisenberg, Elon; Suzan, Erica; Pud, Dorit

    2015-03-01

    Although opioid-induced hyperalgesia (OIH) is mentioned as a potential cause of opioid dose escalation without adequate analgesia, true evidence in support of this notion is relatively limited. Most studies conducted in the context of acute and experimental pain, which seemingly demonstrated evidence for OIH, actually might have measured other phenomena such as acute opioid withdrawal or tolerance. OIH studies in patients with chronic pain have used various experimental pain models (such as cold pain tolerance or heat pain intensity). Therefore, the fact that they have yielded inconsistent results is hard to interpret. Thus far, with the exception of a few clinical case reports on OIH in patients with cancer pain and one prospective study in patients with chronic neuropathic pain, evidence for OIH in patients with chronic or cancer-related pain is lacking. Whether experimental pain models are necessary for establishing the clinical diagnosis of OIH, and which specific model is preferred, are yet to be determined.

  16. Is mechanism and symptom-based analgesia an answer to opioid-induced hyperalgesia?

    Science.gov (United States)

    Gupta, Mayank; Gupta, Priyanka

    2015-01-01

    "Cancer Pain" and "Pain in cancer patient" are not synonymous. Opioid-induced Hyperalgesia (OIH) is a paradoxical state of nociceptive sensitization caused by exposure to opioids. Neuropathic pain is only partially responsive to opioids; injudicious increase in dose of opioids in neuropathic pain may not only result in inadequate pain relief but also OIH. Majority of literature on OIH is in non-cancer pain with systemic use of opioids. We describe the development and successful treatment of OIH in a 55-year-old male patient with Small cell Carcinoma Lung. Opioid tapering, rotation, systemic desensitization helps in combatting OIH. The use of anti-neuropathic adjuvant analgesics helps not only in preventing and treating OIH but also in understanding putative mechanisms underlying neuropathic pain and OIH.

  17. Hyperbaric oxygen therapy attenuates central sensitization induced by a thermal injury in humans

    DEFF Research Database (Denmark)

    Rasmussen, V M; Borgen, A E; Jansen, E C

    2015-01-01

    BACKGROUND: Hyperbaric oxygen (HBO2 ) treatment has in animal experiments demonstrated antinociceptive effects. It was hypothesized that these effects would attenuate secondary hyperalgesia areas (SHAs), an expression of central sensitization, after a first-degree thermal injury in humans. METHODS......, compared with control. These new and original findings in humans corroborate animal experimental data. The thermal injury model may give impetus to future human neurophysiological studies exploring the central effects of hyperbaric oxygen treatment....

  18. Amitriptyline reverses hyperalgesia and improves associated mood-like disorders in a model of experimental monoarthritis.

    Science.gov (United States)

    Amorim, D; David-Pereira, A; Pertovaara, A; Almeida, A; Pinto-Ribeiro, F

    2014-05-15

    Affective disorders are common comorbidities of chronic inflammatory pain that are often overlooked in primary care. As the impact of inflammatory pain upon mood-like disorders in animal models is not well known, our objective was to assess whether prolonged experimental monoarthritis (ARTH) induced the development of anxiety and depressive-like behaviours in rodents and if amitriptyline, an antidepressant commonly used in the treatment of chronic pain, could reverse both nociceptive and mood-like impairments. Experimental ARTH was induced through an injection of kaolin/carrageenan into the right knee joint with control (SHAM) animals injected with saline. Four weeks after induction, ARTH animals displayed mechanical hyperalgesia and a depressive-like phenotype as they showed a significant increase in immobility and a decrease in the latency to immobility in the forced-swimming test at the expense of the time spent climbing/swimming. ARTH animals also displayed a decreased sucrose preference, an index of anhedonia and anxiety-like behaviour as time spent exploring the open arms of the elevated-plus-maze was decreased when compared to controls. The anxiety-like phenotype was also supported by an increase in the number of fecal boli left in the open field. In ARTH animals, the administration of amitriptyline decreased mechanical hyperalgesia and increased sucrose preference and the time spent climbing, although it had a deleterious effect in the performance of control animals. Our data show that this model of ARTH can be useful for the study of chronic pain-mood disorders comorbidities and that amitriptyline is able to partly reverse the associated nociceptive and emotional impairments.

  19. Effect of painless diabetic neuropathy on pressure pain hypersensitivity (hyperalgesia after acute foot trauma

    Directory of Open Access Journals (Sweden)

    Tobias Wienemann

    2014-11-01

    Full Text Available Introduction and objective: Acute injury transiently lowers local mechanical pain thresholds at a limb. To elucidate the impact of painless (diabetic neuropathy on this post-traumatic hyperalgesia, pressure pain perception thresholds after a skeletal foot trauma were studied in consecutive persons without and with neuropathy (i.e. history of foot ulcer or Charcot arthropathy. Design and methods: A case–control study was done on 25 unselected clinical routine patients with acute unilateral foot trauma (cases: elective bone surgery; controls: sprain, toe fracture. Cases were 12 patients (11 diabetic subjects with severe painless neuropathy and chronic foot pathology. Controls were 13 non-neuropathic persons. Over 1 week after the trauma, cutaneous pressure pain perception threshold (CPPPT and deep pressure pain perception threshold (DPPPT were measured repeatedly, adjacent to the injury and at the opposite foot (pinprick stimulators, Algometer II®. Results: In the control group, post-traumatic DPPPT (but not CPPPT at the injured foot was reduced by about 15–25%. In the case group, pre- and post-operative CPPPT and DPPPT were supranormal. Although DPPPT fell post-operatively by about 15–20%, it remained always higher than the post-traumatic DPPPT in the control group: over musculus abductor hallucis 615 kPa (kilopascal versus 422 kPa, and over metatarsophalangeal joint 518 kPa versus 375 kPa (medians; case vs. control group; CPPPT did not decrease post-operatively. Conclusion: Physiological nociception and post-traumatic hyperalgesia to pressure are diminished at the foot with severe painless (diabetic neuropathy. A degree of post-traumatic hypersensitivity required to ‘pull away’ from any one, even innocuous, mechanical impact in order to avoid additional damage is, therefore, lacking.

  20. Intraoperative Use of Remifentanil and Opioid Induced Hyperalgesia/Acute Opioid Tolerance - Systematic review

    Directory of Open Access Journals (Sweden)

    Sang Hun eKim

    2014-05-01

    Full Text Available IntroductionThe use of opioids has been increasing in operating room and intensive care unit to provide perioperative analgesia as well as stable hemodynamics. However, many authors have suggested that the use of opioids is associated with the expression of acute opioid tolerance (AOT and opioid-induced hyperalgesia (OIH in experimental studies and clinical observations in dose and/or time dependent exposure even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management during anesthesia as well as in the intensive care units because of its rapid onset and offset. ObjectivesSearch of the available literature to assess remifentanil AOT and OIH based on available published data.MethodsWe reviewed articles analyzing remifentanil AOT and OIH, and focused our literature search on evidence based information. Experimental and clinical studies were identified using electronic searches of Medline (PubMed, Ovid, Springer, and Elsevier, ClinicalKey. ResultsOur results showed that the development of remifentanil AOT and OIH is a clinically significant phenomenon requiring further research.Discussions and ConclusionsAOT - defined as an increase in the required opioid dose to maintain adequate analgesia, and OIH - defined as decreased pain threshold, should be suspected with any unexplained pain report unassociated with the disease progression.The clinical significance of these findings was evaluated taking into account multiple methodological issues including the dose and duration of opioids administration, the different infusion mode, the co-administrated anesthetic drug’s effect, method assessing pain sensitivity, and the repetitive and potentially tissue damaging nature of the stimuli used to determine the threshold during opioid infusion.Future studies need to investigate the contribution of remifentanil induced hyperalgesia to chronic pain and the role of pharmacological modulation to reverse this process.

  1. Induction of Hyperalgesia in Pigs through Blocking Low Hydraulic Resistance Channels and Reduction of the Resistance through Acupuncture: A Mechanism of Action of Acupuncture

    Directory of Open Access Journals (Sweden)

    Wei-Bo Zhang

    2013-01-01

    Full Text Available According to the classic theory of Chinese medicine, pain is due to the blockage in meridian channels, and acupuncture was invented to treat pain by “dredging” the channels. To test the theory, a hyperalgesia model was made by injecting hydrogel into low hydraulic resistance channel (LHRC in 12 anaesthetized minipigs. Tail-flick threshold and ear-flick threshold were measured using a thermal radiation dolorimeter, and relative flick threshold (RFT was calculated. Hydraulic resistance (HR was measured with a biological HR measuring instrument on low HR points on LHRC and on control points with higher HR located outside LHRC; readings were recorded before, during, and after acupuncture treatment. RFT decreased after blocking the LRHC and was still significantly decreased 2 days and 4 days afterwards. No significant changes occurred when injecting saline into the same points or injecting gel into points outside the channel. Subsequent acupuncture reduced HR on LRHC along meridians but had no significant effect on sites with higher HR located outside LHRC. One of the mechanisms of action of acupuncture treatment for chronic pain may be that acupuncture affects peripheral tissue by reducing the HR in LHRC along meridians, improving the flow of interstitial fluid and removing algogenic substances and thereby relieving pain.

  2. Periodate oxidized ATP (oATP) reduces hyperalgesia in mice: involvement of P2X7 receptors and implications for therapy.

    Science.gov (United States)

    Fulgenzi, A; Ticozzi, P; Gabel, C A; Dell'Antonio, G; Quattrini, A; Franzone, J S; Ferrero, M E

    2008-01-01

    Some inflammatory mediators play an important role not only in the pathogenesis of the inflammatory pain, but also in that of neuropathic and visceral pain. We previously showed the antihyperalgesic effect of oATP, the inhibitor of the P2X7 receptors for the pro-nociceptive ATP, in experimental inflammation. Here we show the antihyperalgesic effect of oATP in mouse models of neuropathic and visceral pain, other than in a model of arthritic pain mimicking rheumatoid arthritis in humans. We also show that mice lacking P2X7 receptors (KO) are resistant to hyperalgesic thermal stimuli following the induction of arthritic, neuropathic and visceral pain. Local (injection into the right hind paw) pre-treatment with oATP is able to prevent the successive induction of ATP-dependent hyperalgesia in wild type mice. In addition, KO mice are not insensitive to intraplantar treatment with ATP. Our data suggest that, even if oATP is able to inhibit purinoceptors different from P2X7, the latter are the more important involved in pain transmission.

  3. Mild moxibustion at Tianshu (ST 25) decreases expression of prokineticin-1 and prokineticin receptor-1 in colon tissue of rats with chronic visceral hyperalgesia

    Institute of Scientific and Technical Information of China (English)

    Luyi Wu; Chunhui Bao; Linbao Ge; Cili Zhou; Huirong Liu; Li Qi; Tao Yi; Huangan Wu; Xiaomei Wang

    2011-01-01

    Prokineticin-1 and prokineticin receptor-1 play important roles in visceral hypersensitivity and in-flammatory pain. Visceral hypersensitivity is closely associated with irritable bowel syndrome. Mild moxibustion can relieve chronic visceral hyperalgesia in rats with irritable bowel syndrome. We hypothesized that prokineticin-1 and prokineticin receptor-1 is the key target in the mechanism. This study established chronic visceral hyperalgesia rat models by colorectal distention. Protein and mRNA expression of prokineticin-1 and prokineticin receptor-1 were determined by immunohisto-chemical method and fluorescence quantitative-PCR, respectively, and were found to be signifi-cantly increased in visceral hyperalgesic rats. Mild moxibustion at Tianshu (ST 25) decreased prokineticin-1 and prokineticin receptor-1 expression in chronic visceral hyperalgesia rats and lessen the chronic visceral hyperalgesia in rats with irritable bowel syndrome at different levels of colorectal distention pressure.

  4. Mechanisms of opioid-induced hyperalgesia in the spinal cord level%阿片类药物引起痛觉过敏的脊髓机制

    Institute of Scientific and Technical Information of China (English)

    雷洪伊; 徐世元

    2012-01-01

    Background Opioid-induced hyperalgesia has received increasing attention,and the mechanisms need further investigation.Objective To expound some possible mechanisms of opioid-induced hyperalgesia in the spinal cord level,which may offer some methods for prevention of the hyperalgesia in clinic.Content This review provides some information about opioidinduced hyperalgesia in the spinal cord level,such as the receptors pathway,signal transduction pathway,neuropeptide and so on.Trend The detailed mechanism of opioid-induced hyperalgesia in the spinal cord level needs further study.%背景 阿片类药物引起的痛觉过敏(opioid-induced hyperalgesia,OIH)日益引起关注,其机制有待深入研究.目的 论述脊髓水平OIH的机制,以供临床研究防治此类痛觉过敏参考.内容 就脊髓水平受体通路、信号转导路径及神经肽等方面,论述OIH的机制.趋向 脊髓水平多种途径参与OIH,值得进一步研究.

  5. Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters

    OpenAIRE

    2008-01-01

    Diabetic rats show behavioral indices of painful neuropathy that may model the human condition. Hyperalgesia during the formalin test in diabetic rats is accompanied by the apparently paradoxical decrease in spinal release of excitatory neurotransmitters and increase in the inhibitory neurotransmitter GABA. Decreased expression of the potassium-chloride co-transporter, KCC2, in the spinal cord promotes excitatory properties of GABA. We therefore measured spinal KCC2 expression and explored th...

  6. Transcutaneous Electrical Nerve Stimulation (TENS) reduces pain, fatigue, and hyperalgesia while restoring central inhibition in primary fibromyalgia

    OpenAIRE

    Dailey, Dana L.; Rakel, Barbara A; Vance, Carol GT; Richard E. Liebano; Anand, Amrit S; Bush, Heather M.; Lee, Kyoung S; Lee, Jennifer E.; Sluka, Kathleen A.

    2013-01-01

    Because TENS works by reducing central excitability and activating central inhibition pathways, we tested the hypothesis that TENS would reduce pain and fatigue and improve function and hyperalgesia in people with fibromyalgia who have enhanced central excitability and reduced inhibition. The current study used a double-blinded randomized, placebo controlled cross-over design to test effects of a single treatment of TENS in people with fibromyalgia. Three treatments were assessed in random or...

  7. Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters

    Science.gov (United States)

    Jolivalt, Corinne G.; Lee, Corinne A.; Ramos, Khara M.; Calcutt, Nigel A.

    2008-01-01

    Diabetic rats show behavioral indices of painful neuropathy that may model the human condition. Hyperalgesia during the formalin test in diabetic rats is accompanied by the apparently paradoxical decrease in spinal release of excitatory neurotransmitters and increase in the inhibitory neurotransmitter GABA. Decreased expression of the potassium-chloride co-transporter, KCC2, in the spinal cord promotes excitatory properties of GABA. We therefore measured spinal KCC2 expression and explored the role of the GABAA receptor in rats with painful diabetic neuropathy. KCC2 protein levels were significantly reduced in the spinal cord of diabetic rats while levels of NKCC1 and the GABAA receptor were unchanged. Spinal delivery of the GABAA receptor antagonist bicuculline reduced formalin-evoked flinching in diabetic rats and also dose-dependently alleviated tactile allodynia. GABAA receptor-mediated rate-dependent depression of the spinal H reflex was absent in the spinal cord of diabetic rats. Control rats treated with the KCC2 blocker DIOA, mimicked diabetes by showing increased formalin-evoked flinching and diminished rate dependent depression. The ability of bicuculline to alleviate allodynia and formalin-evoked hyperalgesia in diabetic rats is consistent with a reversal of the properties of GABA predicted by reduced spinal KCC2 and suggests that reduced KCC2 expression and increased GABA release contribute to spinally-mediated hyperalgesia in diabetes. PMID:18755547

  8. Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters.

    Science.gov (United States)

    Jolivalt, Corinne G; Lee, Corinne A; Ramos, Khara M; Calcutt, Nigel A

    2008-11-15

    Diabetic rats show behavioral indices of painful neuropathy that may model the human condition. Hyperalgesia during the formalin test in diabetic rats is accompanied by the apparently paradoxical decrease in spinal release of excitatory neurotransmitters and increase in the inhibitory neurotransmitter GABA. Decreased expression of the potassium-chloride co-transporter, KCC2, in the spinal cord promotes excitatory properties of GABA. We therefore measured spinal KCC2 expression and explored the role of the GABA(A) receptor in rats with painful diabetic neuropathy. KCC2 protein levels were significantly reduced in the spinal cord of diabetic rats, while levels of NKCC1 and the GABA(A) receptor were unchanged. Spinal delivery of the GABA(A) receptor antagonist bicuculline reduced formalin-evoked flinching in diabetic rats and also dose-dependently alleviated tactile allodynia. GABA(A) receptor-mediated rate-dependent depression of the spinal H reflex was absent in the spinal cord of diabetic rats. Control rats treated with the KCC2 blocker DIOA, mimicked diabetes by showing increased formalin-evoked flinching and diminished rate- dependent depression. The ability of bicuculline to alleviate allodynia and formalin-evoked hyperalgesia in diabetic rats is consistent with a reversal of the properties of GABA predicted by reduced spinal KCC2 and suggests that reduced KCC2 expression and increased GABA release contribute to spinally mediated hyperalgesia in diabetes.

  9. Nocebo hyperalgesia: contributions of social observation and body-related cognitive styles

    Directory of Open Access Journals (Sweden)

    Vögtle E

    2016-04-01

    Full Text Available Elisabeth Vögtle,1 Birgit Kröner-Herwig,1 Antonia Barke21Department of Clinical Psychology and Psychotherapy, Georg-Elias-Müller-Institute for Psychology, University of Göttingen, Göttingen, 2Department of Psychology, Division of Clinical Psychology and Psychotherapy, Philipps University Marburg, Marburg, Germany Purpose: Recently, it has been shown that nocebo hyperalgesia can be acquired through observational learning. The aim of this study was to investigate socially induced nocebo hyperalgesia and its relationship with pain catastrophizing, somatic complaints, hypochondriacal concerns, and empathy. Participants and methods: Ninety-seven women (43.1±15.5 years were randomly assigned to one of the two conditions. Participants in the nocebo condition (NC watched a video in which a female model displayed more pain when an ointment was applied and less pain when no ointment was applied. In the control condition (CC, the model demonstrated low pain with and without the ointment. Subsequently, all participants received three pressure pain stimuli (60 seconds on each hand. On one hand, the ointment was applied prior to the stimulation. The order of the stimulation of the fingers (middle, index, or ring finger, the side of ointment application (left or right hand, and the side with which the stimulation began were randomized within each group and balanced across the groups. Depending on the randomization, the pressure pain application started with or without ointment and on the left or right hand. Pain ratings on a numerical rating scale (0–10 were collected. In addition, the participants completed questionnaires regarding body-related cognitive styles and empathy. Results: There was a significant difference in the pain ratings between the CC and the NC. The effect of ointment application was also significant, but no interaction between condition and ointment application was found. Only in the CC did the nocebo response correlate with

  10. GABAA receptor partially mediated propofol-induced hyperalgesia at superspinal level and analgesia at spinal cord level in rats

    Institute of Scientific and Technical Information of China (English)

    Qin-yun WANG; Jun-li CAO; Yin-ming ZENG; Ti-jun DAI

    2004-01-01

    AIM: To observe effects of propofol on nociceptive response at superspinal and spinal level in rats. METHODS:Two hundreds and fifty-eight Sprague-Dawley male rats were randomized into thirty-two groups. Propofol and bicuculline were microinjected into lateral ventricle (icv), ventrolateral periaqueductal gray (vlPAG), intrathecal (ith), and intraperitoneal (ip). The noxious responses were evaluated by hot plate and formalin test. RESULTS: In hot-plate test, systemic and superspinal administration of propofol (40 mg·kg-1 ip, 100μg in 10μL, icy, and 4μg in 0.4μL vlPAG microinjection) produced hyperalgesia (P<0.01). Hyperalgesia induced by vlPAG microinjection of propofol was significantly antagonized by 69.8%, 71.2%, 98.8% at 10, 20, and 30 min by microinjection of bicuculline (10 ng in 0.4μL, vlPAG) (P<0.01). Analgesia induced by ith propofol (100μg·10μL-1) was antagonized about 81.3%, 54.8%, 80.8%, and 97.4% at 10, 20, 30 and 40 min by ith bicuculline (P<0.05). In formalin test,systemic and superspinal administration of propofol (40 mg·kg-1 ip, 4μg in 0.4μL, vlPAG) also produced hyperalgesia (P<0.01). The increased formalin pain scores were antagonized about 57.1% by bicuculline (10ng, vlPAG)(P<0.05) at 60 min after formalin injection. The decreased formalin pain scores induced by ith propofol (100μg in 10μL) were antagonized about 66.7% at 30 min by ith bicuculline (P<0.05) after formalin injection. Hyperalgesia produced by ip propofol in both hot plate and formalin test could not be antagonized by vlPAG administration of bicuculline. CONCLUSION: GABAA receptor partly mediated propofol-induced hyperalgesia at superspinal and analgesia at spinal cord in rats.

  11. An investigation of the antinociceptive effects of Riluzole in hyperalgesia models of mice

    Institute of Scientific and Technical Information of China (English)

    Xiaoping Xia; Zhenliang Ma; Yinming Zeng

    2006-01-01

    Objective: To investigate the antinociceptive effects of Riluzole administered intraperitoneally in three hyperalgesia model of mice. Methods: Antinociceptive tests in C57BL mice were investigated with formalin test、acetic acid induced writhing test and tail-immersion test. The effects of intraperitoneally Riluzole 2 mg/kg、4 mg/kg and 8 mg/kg on the pain threshold were observed. Result: We found that i.p. treatment with Riluzole (4 mg/kg and 8 mg/kg) blocked the second phase flinching behavior compared with vehicle (P < 0.05), but not during the first phase in the formalin test. In addition to the formalin test, Riluzole at different dose (from 2 to 8 mg/kg) attenuated acetic acid induced writhing response when compared to vehicle group (P < 0.05). In the tail-immersion test, Riluzole at the highest dose (8 mg/kg) caused significant increase in tail flick response latency as compared to vehicle animals or compared with Baseline (P < 0.05). Conclusion: Our results suggest that glutamate release inhibitor Riluzole can attenuate nociceptive behavior and has differrent antinociceptive characteristic according to the various pain models.

  12. Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia.

    Science.gov (United States)

    Hua, Zhen; Liu, LiPing; Shen, Jun; Cheng, Katherine; Liu, Aijun; Yang, Jing; Wang, Lina; Qu, Tingyu; Yang, HongNa; Li, Yan; Wu, Haiyan; Narouze, John; Yin, Yan; Cheng, Jianguo

    2016-08-24

    More than 240 million opioid prescriptions are dispensed annually to treat pain in the US. The use of opioids is commonly associated with opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), which limit efficacy and compromise safety. The dearth of effective way to prevent or treat OT and OIH is a major medical challenge. We hypothesized that mesenchymal stem cells (MSCs) attenuate OT and OIH in rats and mice based on the understanding that MSCs possess remarkable anti-inflammatory properties and that both OT and chronic pain are associated with neuroinflammation in the spinal cord. We found that the development of OT and OIH was effectively prevented by either intravenous or intrathecal MSC transplantation (MSC-TP), which was performed before morphine treatment. Remarkably, established OT and OIH were significantly reversed by either intravenous or intrathecal MSCs when cells were transplanted after repeated morphine injections. The animals did not show any abnormality in vital organs or functions. Immunohistochemistry revealed that the treatments significantly reduced activation level of microglia and astrocytes in the spinal cord. We have thus demonstrated that MSC-TP promises to be a potentially safe and effective way to prevent and reverse two of the major problems of opioid therapy.

  13. Auraptenol attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors.

    Science.gov (United States)

    Wang, Yunfei; Cao, Shu-e; Tian, Jianmin; Liu, Guozhe; Zhang, Xiaoran; Li, Pingfa

    2013-11-29

    Common chemotherapeutic agents such as vincristine often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is refractory to common analgesics and represents a challenging clinical issue. Angelicae dahuricae radix is an old traditional Chinese medicine with demonstrated analgesic efficacy in humans. However, the active component(s) that attribute to the analgesic action have not been identified. This work described the anti-hyperalgesic effect of one coumarin component, auraptenol, in a mouse model of chemotherapeutic agent vincristine-induced neuropathic pain. We reported that auraptenol dose-dependently reverted the mechanical hyperalgesia in mice within the dose range of 0.05-0.8 mg/kg. In addition, the anti-hyperalgesic effect of auraptenol was significantly blocked by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). Within the dose range studied, auraptenol did not significantly alter the general locomotor activity in mice. Taken together, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust analgesic efficacy in mice. These data support further studies to assess the potential of auraptenol as a novel analgesic for the management of neuropathic pain.

  14. Topical ketorolac has no antinociceptive or anti-inflammatory effect in thermal injury

    DEFF Research Database (Denmark)

    Møiniche, S; Pedersen, J L; Kehlet, H

    1994-01-01

    detection thresholds (MPDT) and the intensity of burn-induced erythema (erythema index, EI) were assessed in the area of the thermal injury, and areas of hyperalgesia to pin prick were determined outside the injury before and 3, 6 and 24 h after the burn injury. Burn injury led to a decrease in HPDT, HPT......This study investigated the antinociceptive and anti-inflammatory effect of a topical non-steroidal anti-inflammatory drug in human thermal injury. Twelve healthy unmedicated volunteers had identical burn injuries produced on the medial side of both calves with a 49 degrees C 15 x 25 mm thermode...... and MPDT, an increase in EI and development of mechanical hyperalgesia (P 0.2)....

  15. Role of glycine transporter-1 in fentanyl-induced hyperalgesia%甘氨酸转运体-1对芬太尼诱导的切口痛觉敏化作用

    Institute of Scientific and Technical Information of China (English)

    陈蕾; 姜慧丽; 薛庆生; 陈利海; 于布为

    2012-01-01

    Objective To investigate the roles of glycine transpoter-l(GlyT-l) on fentanyl-induced hyperalgesia on a rat model of incision pain and its mechanism. Methods Forty male Sprague-Dawley rats weighting 190-230 g were randomly allocated into 4 groups (n=10/group): subcutaneous normal saline+ intrathecal normal saline (NS+NS) group, subcutaneous normal saline + intrathecal sarcosine(NS+Sar) group, subcutaneous fentanyl +intrathecal normal saline (Fen+NS) group and subcutaneous fentanyl + intrathecal sarcosine (Fen+Sar) group. The mechanical and thermal threshold were detected with thermal radiation and von Frey filaments of rats from pre-operation to the postoperative 7th day. Results Compared with the baseline, the values of mechanical and thermal threshold in the next day of incision operation were significantly lower in all the groups. Tendency of increment of the threshold was found during the next 6 days. The decrease in thermal threshold was most extent in the Fen+NS group. No significant difference existed between Fen+Sar group and NS+NS group. The mechanical and thermal thresholds were the highest in the NS+Sar group. Conclusions Fentanyl increased hyperalgesia of incision pain in rats. This effect tends to decrease by GlyT-1 inhibitors sarcosine. It is suggested that changes of GlyT-1 function may be involved in the fentanyl induced hyperalgesia.%目的:探讨甘氨酸转运体-1在芬太尼诱导的切口痛觉敏化中的作用和机制.方法:鞘内成功埋管2周后的雄性SD大鼠40只,体重为190~230 g,以Brennan法制作动物切口痛模型,并随机分为4组,NS+NS(皮下生理盐水+鞘内生理盐水)组、NS+Sar(皮下生理盐水+鞘内肌氨酸)组、Fen+NS(皮下芬太尼+鞘内生理盐水)组和Fen+Sar(皮下芬太尼+鞘内肌氨酸)组.每组各10只大鼠,通过热辐射刺激和von Frey机械刺激进行痛行为测定,记录手术前(基础值),术后第1、2、3、4、5、6、7天大鼠的热痛和机械痛阈值,分别作统计学

  16. The effect of nicotine withdrawal on hyperalgesia in CCI rats%尼古丁戒断对CCI大鼠痛觉过敏的影响

    Institute of Scientific and Technical Information of China (English)

    张彦伟; 逯素芬; 李长营; 张宗旺

    2015-01-01

    目的 探讨尼古丁戒断慢性压迫性损伤(chronic constriction injury,CCI)大鼠痛觉过敏的行为学变化.方法 成年雄性SD大鼠96只,随机分为正常对照组(n=6)、尼古丁戒断组(NT组)、CCI组和NT+CCI组.NT组、CCI组和NT+CCI组大鼠按术后1、3、5、7、14 d分为5个亚组,每个亚组6只.观察各组大鼠上述时间点机械刺激缩足阈值(mechanical withdrawal threshold,MWT)、热刺激缩足潜伏期(thermal withdrawal latency,TWL)的变化.结果 与Control组相比,CCI组大鼠术后1、3、5、7、14d MWT显著降低、TWL明显缩短(P<0.05),至第7d变化最明显(P<0.01);与CCI组比较,NT+CCI组大鼠术后1、3、5、7、14 d MWT和TWL均降低(P<0.05),以术后7d降低最为显著(P<0.01).结论 尼古丁戒断引起CCI大鼠痛觉敏感性增高.%Objective To explore the effect of nicotine withdrawal on postoperative hyperalgesia in chronic constriction injury (CCI) rats.Methods 96 adult male SD rats were randomly divided into control group (n=6),nicotine withdrawal group (NT group),CCI group and NT+CCI group.The rats in NT group,CCI group and NT+CCI group were divided into 5 subgroups according to postoperative 1 d,3 d,5 d,7 d and 14 d,6 rats in each subgroup.The changes of mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were observed at time points above in each group for every rat.Results Compared with control group,MWT and TWL significantly decreased in CCI group at postoperative 1 d,3 d,5 d,7 d and 14 d (P<0.05),to the lowest at the 7th day (P<0.01).Compared with CCI group,MWT and TWL both decreased in NT+CCI group at postoperative 1 d,3 d,5 d,7 d and 14 d (P<0.05),to the lowest at the 7th day (P<0.01).Conclusion Nicotine withdrawal may raise postoperative hyperalgesia in CCI rats.

  17. Effect of Intramuscular Protons, Lactate, and ATP on Muscle Hyperalgesia in Rats.

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    Nicholas S Gregory

    Full Text Available Chronic muscle pain is a significant health problem leading to disability[1]. Muscle fatigue can exacerbate muscle pain. Metabolites, including ATP, lactate, and protons, are released during fatiguing exercise and produce pain in humans. These substances directly activate purinergic (P2X and acid sensing ion channels (ASICs on muscle nociceptors, and when combined, produce a greater increase in neuron firing than when given alone. Whether the enhanced effect of combining protons, lactate, and ATP is the sum of individual effects (additive or more than the sum of individual effects (synergistic is unknown. Using a rat model of muscle nociceptive behavior, we tested each of these compounds individually over a range of physiologic and supra-physiologic concentrations. Further, we combined all three compounds in a series of dilutions and tested their effect on muscle nociceptive behavior. We also tested a non-hydrolyzable form of ATP (α,β-meATP alone and in combination with lactate and acidic pH. Surprisingly, we found no dose-dependent effect on muscle nociceptive behavior for protons, lactate, or ATP when given alone. We similarly found no effect after application of each two-metabolite combination. Only pH 4 saline and α,β-meATP produced hyperalgesia when given alone. When all 3 substances were combined, however, ATP (2.4μm, lactate (10mM, and acidic pH (pH 6.0 produced an enhanced effect greater than the sum of the effects of the individual components, i.e. synergism. α,β me ATP (3nmol, on the other hand, showed no enhanced effects when combined with lactate (10mM or acidic pH (pH 6.0, i.e. additive. These data suggest that combining fatigue metabolites in muscle produces a synergistic effect on muscle nociception.

  18. Erythropoietin reduces neuronal cell death and hyperalgesia induced by peripheral inflammatory pain in neonatal rats

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    Hofmann Cane

    2011-07-01

    Full Text Available Abstract Painful stimuli during neonatal stage may affect brain development and contribute to abnormal behaviors in adulthood. Very few specific therapies are available for this developmental disorder. A better understanding of the mechanisms and consequences of painful stimuli during the neonatal period is essential for the development of effective therapies. In this study, we examined brain reactions in a neonatal rat model of peripheral inflammatory pain. We focused on the inflammatory insult-induced brain responses and delayed changes in behavior and pain sensation. Postnatal day 3 pups received formalin injections into the paws once a day for 3 days. The insult induced dysregulation of several inflammatory factors in the brain and caused selective neuronal cell death in the cortex, hippocampus and hypothalamus. On postnatal day 21, rats that received the inflammatory nociceptive insult exhibited increased local cerebral blood flow in the somatosensory cortex, hyperalgesia, and decreased exploratory behaviors. Based on these observations, we tested recombinant human erythropoietin (rhEPO as a potential treatment to prevent the inflammatory pain-induced changes. rhEPO treatment (5,000 U/kg/day, i.p., coupled to formalin injections, ameliorated neuronal cell death and normalized the inflammatory response. Rats that received formalin plus rhEPO exhibited normal levels of cerebral blood flow, pain sensitivity and exploratory behavior. Treatment with rhEPO also restored normal brain and body weights that were reduced in the formalin group. These data suggest that severe inflammatory pain has adverse effects on brain development and rhEPO may be a possible therapy for the prevention and treatment of this developmental disorder.

  19. Opioid-induced hyperalgesia in community-dwelling adults with chronic pain.

    Science.gov (United States)

    Hooten, W Michael; Lamer, Tim J; Twyner, Channing

    2015-06-01

    The hyperalgesic effects of long-term opioid use in community-dwelling adults with chronic pain have not been widely reported. Therefore, the primary aim of this study was to determine the associations between opioid use and heat pain (HP) perception in a sample of community-dwelling adults with chronic pain. The study cohort involved 187 adults (85 opioid and 102 nonopioid) with chronic pain consecutively admitted to an outpatient interdisciplinary pain treatment program. Heat pain perception was assessed using a validated quantitative sensory test method of levels. An effect of opioid use was observed for nonstandardized (P = 0.004) and standardized (P = 0.005) values of HP 5-0.5 in which values of the opioid group were lower (more hyperalgesic) compared with those of the nonopioid group. HP 5-0.5 is a measure of the slope of the line connecting HP 0.5 (HP threshold) and HP 5 (intermediate measure of HP tolerance). In univariable (P = 0.019) and multiple variable (P = 0.003) linear regression analyses (adjusted for age, sex, body mass index, work status, pain diagnosis, pain severity, depression, and pain catastrophizing), opioid use was associated with lower (more hyperalgesic) nonstandardized values of HP 5-0.5. Similarly, in univariable (P = 0.004) and multiple variable (P = 0.011) linear regression analyses (adjusted for work status, pain diagnosis, pain severity, depression, and pain catastrophizing), opioid use was associated with lower standardized values of HP 5-0.5. In this sample of community-dwelling adults, these observations suggest that long-term opioid use was associated with hyperalgesia independent of other clinical factors known to influence HP perception.

  20. Transcutaneous electrical nerve stimulation reduces pain, fatigue and hyperalgesia while restoring central inhibition in primary fibromyalgia.

    Science.gov (United States)

    Dailey, Dana L; Rakel, Barbara A; Vance, Carol G T; Liebano, Richard E; Amrit, Anand S; Bush, Heather M; Lee, Kyoung S; Lee, Jennifer E; Sluka, Kathleen A

    2013-11-01

    Because transcutaneous electrical nerve stimulation (TENS) works by reducing central excitability and activating central inhibition pathways, we tested the hypothesis that TENS would reduce pain and fatigue and improve function and hyperalgesia in people with fibromyalgia who have enhanced central excitability and reduced inhibition. The current study used a double-blinded randomized, placebo-controlled cross-over design to test the effects of a single treatment of TENS with people with fibromyalgia. Three treatments were assessed in random order: active TENS, placebo TENS and no TENS. The following measures were assessed before and after each TENS treatment: pain and fatigue at rest and in movement; pressure pain thresholds, 6-m walk test, range of motion; 5-time sit-to-stand test, and single-leg stance. Conditioned pain modulation was completed at the end of testing. There was a significant decrease in pain and fatigue with movement for active TENS compared to placebo and no TENS. Pressure pain thresholds increased at the site of TENS (spine) and outside the site of TENS (leg) when compared to placebo TENS or no TENS. During active TENS, conditioned pain modulation was significantly stronger compared to placebo TENS and no TENS. No changes in functional tasks were observed with TENS. Thus, the current study suggests TENS has short-term efficacy in relieving symptoms of fibromyalgia while the stimulator is active. Future clinical trials should examine the effects of repeated daily delivery of TENS, similar to the way in which TENS is used clinically on pain, fatigue, function, and quality of life in individuals with fibromyalgia.

  1. Exercise prevents development of autonomic dysregulation and hyperalgesia in a mouse model of chronic muscle pain.

    Science.gov (United States)

    Sabharwal, Rasna; Rasmussen, Lynn; Sluka, Kathleen A; Chapleau, Mark W

    2016-02-01

    Chronic musculoskeletal pain (CMP) conditions, like fibromyalgia, are associated with widespread pain and alterations in autonomic functions. Regular physical activity prevents the development of CMP and can reduce autonomic dysfunction. We tested if there were alterations in autonomic function of sedentary mice with CMP, and whether exercise reduced the autonomic dysfunction and pain induced by CMP. Chronic musculoskeletal pain was induced by 2 intramuscular injections of pH 5.0 in combination with a single fatiguing exercise task. A running wheel was placed into cages so that the mouse had free access to it for either 5 days or 8 weeks (exercise groups) and these animals were compared to sedentary mice without running wheels. Autonomic function and nociceptive withdrawal thresholds of the paw and muscle were assessed before and after induction of CMP in exercised and sedentary mice. In sedentary mice, we show decreased baroreflex sensitivity, increased blood pressure variability, decreased heart rate variability, and decreased withdrawal thresholds of the paw and muscle 24 hours after induction of CMP. There were no sex differences after induction of the CMP in any outcome measure. We further show that both 5 days and 8 weeks of physical activity prevent the development of autonomic dysfunction and decreases in withdrawal threshold induced by CMP. Thus, this study uniquely shows the development of autonomic dysfunction in animals with chronic muscle hyperalgesia, which can be prevented with as little as 5 days of physical activity, and suggest that physical activity may prevent the development of pain and autonomic dysfunction in people with CMP.

  2. Differential effects of lidocaine on nerve growth factor (NGF)-evoked heat- and mechanical hyperalgesia in humans.

    Science.gov (United States)

    Weinkauf, B; Obreja, O; Schmelz, M; Rukwied, R

    2012-04-01

    We investigated the effects of a non-specific sodium channel blocker (lidocaine) on heat pain thresholds and mechanical impact pain at day 7 and 21 after intradermal injection of 1 μg NGF. Measurements were performed in 12 healthy male subjects prior to and 5 min after intradermal injection of 150 μl lidocaine administered at concentrations of 0.01% (∼0.4 mM) and 0.1% (∼4 mM) to both NGF and control skin sites. NGF caused a maximum reduction of heat pain thresholds at day 7 (NGF 42.6 ± 0.6 vs. 49.4 ± 0.3 °C in control skin). Lidocaine sensitized normal skin for heat pain, but reduced heat hyperalgesia after NGF at day 7 (44.3 ± 0.8 °C, lidocaine 0.1%; p Lidocaine dose-dependently attenuated mechanically-induced pain at both control and NGF-treated sites. Maximum lidocaine effects on mechanical hyperalgesia were recorded at day 21 in NGF skin (pain reduction to VAS 37 ± 4, p lidocaine 0.1%. Lidocaine differentially affects NGF-induced mechanical hyperalgesia (analgesic effect) and heat sensitivity of nociceptors (sensitizing effect). These opposing responses may be attributed to block of sodium channels vs. sensitization of TRPV1. NGF-evoked extreme mechanical impact pain indicates high action potential discharge frequencies, which might be more susceptible to lidocaine block.

  3. Galanin-Mediated Behavioural Hyperalgesia from the Dorsomedial Nucleus of the Hypothalamus Involves Two Independent Descending Pronociceptive Pathways.

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    Diana Amorim

    Full Text Available Activation of the dorsomedial nucleus of the hypothalamus (DMH by galanin (GAL induces behavioural hyperalgesia. Since DMH neurones do not project directly to the spinal cord, we hypothesized that the medullary dorsal reticular nucleus (DRt, a pronociceptive region projecting to the spinal dorsal horn (SDH and/or the serotoninergic raphe-spinal pathway acting on the spinal 5-HT3 receptor (5HT3R could relay descending nociceptive facilitation induced by GAL in the DMH. Heat-evoked paw-withdrawal latency (PWL and activity of SDH neurones were assessed in monoarthritic (ARTH and control (SHAM animals after pharmacological manipulations of the DMH, DRt and spinal cord. The results showed that GAL in the DMH and glutamate in the DRt lead to behavioural hyperalgesia in both SHAM and ARTH animals, which is accompanied particularly by an increase in heat-evoked responses of wide-dynamic range neurons, a group of nociceptive SDH neurones. Facilitation of pain behaviour induced by GAL in the DMH was reversed by lidocaine in the DRt and by ondansetron, a 5HT3R antagonist, in the spinal cord. However, the hyperalgesia induced by glutamate in the DRt was not blocked by spinal ondansetron. In addition, in ARTH but not SHAM animals PWL was increased after lidocaine in the DRt and ondansetron in the spinal cord. Our data demonstrate that GAL in the DMH activates two independent descending facilitatory pathways: (i one relays in the DRt and (ii the other one involves 5-HT neurones acting on spinal 5HT3Rs. In experimental ARTH, the tonic pain-facilitatory action is increased in both of these descending pathways.

  4. Involvement of spinal glutamate transporter-1 in the development of mechanical allodynia and hyperalgesia associated with type 2 diabetes

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    Shi J

    2016-11-01

    Full Text Available Jinshan Shi,1,* Ke Jiang,2,* Zhaoduan Li,3 1Department of Anesthesiology, Guizhou Provincial People’s Hospital, 2Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, 3Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin, People’s Republic of China *These authors contributed equally to this work Abstract: Little is known about the effects of the development of type 2 diabetes on glutamate homeostasis in the spinal cord. Therefore, we quantified the extracellular levels of glutamate in the spinal cord of Zucker diabetic fatty (ZDF rats using in vivo microdialysis. In addition, protein levels of glutamate transporter-1 (GLT-1 in the spinal cord of ZDF rats were measured using Western blot. Finally, the effects of repeated intrathecal injections of ceftriaxone, which was previously shown to enhance GLT-1 expression, on the development of mechanical allodynia and hyperalgesia as well as on basal extracellular level of glutamate and the expression of GLT-1 in the spinal cord of ZDF rats were evaluated. It was found that ZDF rats developed mechanical hyperalgesia and allodynia, which were associated with increased basal extracellular levels of glutamate and attenuated levels of GLT-1 expression in the spinal cord, particularly in the dorsal horn. Furthermore, repeated intrathecal administrations of ceftriaxone dose-dependently prevented the development of mechanical hyperalgesia and allodynia in ZDF rats, which were correlated with enhanced GLT-1 expression without altering the basal glutamate levels in the spinal cord of ZDF rats. Overall, the results suggested that impaired glutamate reuptake in the spinal cord may contribute to the development of neuropathic pains in type 2 diabetes. Keywords: diabetes, peripheral neuropathy, spinal cord, Zucker diabetic fatty rats, glutamate, glutamate transporter-1

  5. Differential effects of systemically administered ketamine and lidocaine on dynamic and static hyperalgesia induced by intradermal capsaicin in humans

    DEFF Research Database (Denmark)

    Gottrup, Hanne; Hansen, Peter Orm; Arendt-Nielsen, Lars;

    2000-01-01

    We have examined the effect of systemic administration of ketamine and lidocaine on brush-evoked (dynamic) pain and punctate-evoked (static) hyperalgesia induced by capsaicin. In a randomized, double-blind, placebo-controlled, crossover study, we studied 12 volunteers in three experiments....... Capsaicin 100 micrograms was injected intradermally on the volar forearm followed by an i.v. infusion of ketamine (bolus 0.1 mg kg-1 over 10 min followed by infusion of 7 micrograms kg-1 min-1), lidocaine 5 mg kg-1 or saline for 50 min. Infusion started 15 min after injection of capsaicin. The following...

  6. Effect of magnesium sulfate on remifentanil-induced hyperalgesia%硫酸镁对瑞芬太尼引起痛觉过敏的影响

    Institute of Scientific and Technical Information of China (English)

    姚维娜; 崔松勤; 吴晓丽; 马正良; 顾小萍

    2011-01-01

    Objective To observe the effect of magnesium sulfate ( MgSO4 ) on remifentanil-induced hyperalgesia in rats model of incision pain. Methods Forty-two male Sprague Dawley(SD) rats were randomly divided into seven groups(n = 6): group C (control), group I (incision pain), group R (remifentanil + incision pain), group Mgl (incision pain+MgSO4 1 000 mg/kg), group MgR1 (remifentanil+incision pain+MgSO4 250 mg/kg), group MgR2 (remifentanil+ incision pain + MgSO4 500 mg/kg), MgR3 group (remifentanil + incision pain+MgSQ4 1 000 mg/kg). MgSO4 contained in 4 ml volume was administered intraperitoneally ten minutes before anesthesia in MgSO4 treatment groups, while saline was administered subcutaneously in group C, group I and group R. All groups except group C received incision pain model. Paw Withdrawal Thermal latency ( PWTL) and Paw Mechanical Withdrawal Threshold (PMW) were detected on the rats' right hind paw at T0(24 h before operation), T1 (6 h after operation), T2 (24 h after operation), and T3 (48 h after operation) in all groups. Results The PWTL and PMW of group R were significantly shorter at T1 ,T2 ,T3, when compared with group I (P<0. 05). The decrement of PMW and PWTL was alleviated by MgSO4 (P <0. 05). The PWTL and PMW of group MgR1, MgR2, and MgR3 were significantly longer when compared with group R (P<0. 05). Conclusion MgSO4 can relieve the incision pain and alleviate remifentanil-induced hyperalgesia in rats.%目的 研究大鼠切口痛模型中硫酸镁对瑞芬太尼诱发的痛觉过敏的影响.方法 42只雄性SD大鼠,随机均分为七组:切口痛组(Ⅰ组)、瑞芬太尼组(R组)、切口痛十硫酸镁组(MgI组)、切口痛十瑞芬太尼十硫酸镁( 250、500、1 000 mg/kg)组(MgR1、MgR2、MgR3组)、对照组(C组).MgI、MgR组均于麻醉前10 min腹腔注射硫酸镁稀释液4ml,余组给予相应生理盐水4ml.除C组外,各组均制作切口痛模型.各组均测定并计算出术前24 h(T0),术后6、24、48 h(T1、T2、T3)大鼠

  7. Evaluation of aqueous and ethanolic extracts of saffron, Crocus sativus L., and its constituents, safranal and crocin in allodynia and hyperalgesia induced by chronic constriction injury model of neuropathic pain in rats.

    Science.gov (United States)

    Amin, Bahareh; Hosseinzadeh, Hossein

    2012-07-01

    The current study was designed to evaluate therapeutic potential of systemically administered ethanolic and aqueous extracts of saffron as well as its bioactive ingredients, safranal and crocin, in chronic constriction injury (CCI)-induced neuropathic pain in rats. The von Frey filaments, acetone drop, and radiant heat test were performed to assess the degree of mechanical allodynia, thermal allodynia and thermal hyperalgesia respectively, at different time intervals, i.e., one day before surgery and 3, 5, 7 and 10 days post surgery. The ambulatory behavior was evaluated using the open field test. A 7-day treatment with the ethanolic and aqueous extracts (50,100 and 200 mg/kg, i.p.) and safranal (0.025, 0.05 and 0.1 mg/kg, i.p.), attenuated the behavioral symptoms of neuropathic pain in a dose dependent manner. Crocin even at the high dose (50 mg/kg) failed to produce any protective role. However, gabapentine (100 mg/kg) as a reference drug significantly alleviated all behavioral manifestations of neuropathic pain compared to control group. In conclusion, the results of this study suggest that ethanolic and aqueous extracts of saffron as well as safranal could be useful in treatment of different kinds of neuropathic pains and as an adjuvant to conventional medicines.

  8. Effect of a high-dose target-controlled naloxone infusion on pain and hyperalgesia in patients following groin hernia repair

    DEFF Research Database (Denmark)

    Pereira, Manuel Pedro; Utke Werner, Mads; Berg Dahl, Joergen

    2015-01-01

    -dose target-controlled naloxone infusion can reinstate pain and hyperalgesia following recovery from open groin hernia repair and thus consistently demonstrate opioid-mediated latent sensitization in humans. METHODS/DESIGN: Patients submitted to unilateral, primary, open groin hernia repair will be included...

  9. Topical glucocorticoid has no antinociceptive or anti-inflammatory effect in thermal injury

    DEFF Research Database (Denmark)

    Pedersen, J L; Møiniche, S; Kehlet, H

    1994-01-01

    injuries were induced with a thermode, which was heated to 49 degrees C for 5 min under standardized pressure. Clobetasol propionate or placebo cream was applied to the skin 1 h before burn injury, immediately after the injury and every 12 h for the next 3 days. Heat pain detection thresholds (HPDT), heat...... pain tolerance (HPT), mechanical pain detection thresholds (MPDT) and the intensity of burn-induced erythema (erythema index, EI) were assessed inside the thermal injury and areas of hyperalgesia to pinprick outside the injury were determined before and regularly for 72 h after the burn injury. Burn...... injury caused a decrease in HPDT, HPT and MPDT, an increase in EI and development of mechanical, secondary hyperalgesia. Clobetasol propionate had no effect on any of the nociceptive or inflammatory variables studied....

  10. Analgesic Effect of Photobiomodulation on Bothrops Moojeni Venom-Induced Hyperalgesia: A Mechanism Dependent on Neuronal Inhibition, Cytokines and Kinin Receptors Modulation

    Science.gov (United States)

    Oliveira, Victoria Regina da Silva; Toniolo, Elaine Flamia; Feliciano, Regiane dos Santos; da Silva Jr., José Antonio; Zamuner, Stella Regina

    2016-01-01

    Background Envenoming induced by Bothrops snakebites is characterized by drastic local tissue damage that involves an intense inflammatory reaction and local hyperalgesia which are not neutralized by conventional antivenom treatment. Herein, the effectiveness of photobiomodulation to reduce inflammatory hyperalgesia induced by Bothrops moojeni venom (Bmv), as well as the mechanisms involved was investigated. Methodology/Principal Findings Bmv (1 μg) was injected through the intraplantar route in the right hind paw of mice. Mechanical hyperalgesia and allodynia were evaluated by von Frey filaments at different time points after venom injection. Low level laser therapy (LLLT) was applied at the site of Bmv injection at wavelength of red 685 nm with energy density of 2.2 J/cm2 at 30 min and 3 h after venom inoculation. Neuronal activation in the dorsal horn spinal cord was determined by immunohistochemistry of Fos protein and the mRNA expression of IL-6, TNF-α, IL-10, B1 and B2 kinin receptors were evaluated by Real time-PCR 6 h after venom injection. Photobiomodulation reversed Bmv-induced mechanical hyperalgesia and allodynia and decreased Fos expression, induced by Bmv as well as the mRNA levels of IL-6, TNF-α and B1 and B2 kinin receptors. Finally, an increase on IL-10, was observed following LLLT. Conclusion/Significance These data demonstrate that LLLT interferes with mechanisms involved in nociception and hyperalgesia and modulates Bmv-induced nociceptive signal. The use of photobiomodulation in reducing local pain induced by Bothropic venoms should be considered as a novel therapeutic tool for the treatment of local symptoms induced after bothropic snakebites. PMID:27749899

  11. Repeated 100 Hz TENS for the Treatment of Chronic Inflammatory Hyperalgesia and Suppression of Spinal Release of Substance P in Monoarthritic Rats

    Directory of Open Access Journals (Sweden)

    Hong-Xiang Liu

    2007-01-01

    Full Text Available Transcutaneous electrical nerve stimulation (TENS has been shown to be an effective measure for pain relief. The aim of the present study was to determine the optimal intensity and interval of repeated 100 Hz TENS for the treatment of chronic inflammatory hyperalgesia in a monoarthritic pain model of the rat, and to assess the changes of the spinal substance P (SP release in response to TENS treatment. A reliable, reproducible chronic monoarthritic pain model was produced by intra-articular injection of complete Freund's adjuvant (CFA at single ankle joint. The efficacy of 100 Hz TENS treatments with different frequencies and intensities was compared. In the acute period (within 3 weeks of monoarthritis, twice-a-week schedule of TENS reduced the swelling of the inflamed ankle significantly. In the stable period (4–9 weeks, however, once-a-week schedule produced a significantly better therapeutic effect on both inflammation and arthritic hyperalgesia than that of twice- or five-times-a-week schedule. Using three levels of intensity of TENS, we found that the weaker (1-1-2 mA stimulation produced significantly better therapeutic effects. Repeated TENS produced a reduction of SP content in spinal perfusate in parallel with the progressive reduction of the arthritic pain scores. Our results suggest that (i consecutive TENS treatments produced cumulative effect for chronic hyperalgesia, (ii for chronic inflammatory hyperalgesia, a weaker intensity and more sparsely arranged treatment schedule may produce better therapeutic effect and (iii a decrease in SP release may serve as one of the possible neurochemical mechanisms underlying the therapeutic effects of multiple TENS treatments on chronic inflammatory hyperalgesia.

  12. Suppression of complete Freund's adjuvant-induced adjuvant arthritis by cobratoxin

    Institute of Scientific and Technical Information of China (English)

    Yan-li LIU; Hai-ming LIN; Rong ZOU; Jun-chao WU; Rong HAN; Laurence N RAYMOND; Paul F REID; Zheng-hong QIN

    2009-01-01

    Aim:Cobratoxin (CTX),the long-chain α-neurotoxin from Thailand cobra venom,has been demonstrated to have analgesic action in rodent pain models.The present study evaluated the anti-inflammatory and anti-nociceptive effects of CTX on adju-vant arthritis (AA) in rats.Methods: Arthritis was induced by injection of complete Freund's adjuvant (CFA) in rats.Paw swelling and hyperalgesia of AA rats were measured at various times after CFA administration.Tumor necrosis factor-a (TNF-α),interleukin-1 (IL-1),interleukin-2 (IL-2) and interleukin-10 (IL-10) levels in serum were determined with ELISA.Histopathological changes in synoviocytes were examined under a microscope.Involvement of the cholinergic system in the effects of CTX was examinedby pretreatment of animals with the α7 nicotinic receptor (α7-nAChR) antagonist methyllycaconitine (MLA).Results: CFA induced marked paw swelling and reduced thresholds of mechanical and cold-induced paw withdrawal.The lev-els of TNF-α,IL-1 and IL-2 in the serum of AA rats were increased,whereas the level of IL-10 was decreased.Histopathologi-cal examination of synoviocytes showed pronounced inflammation and accumulation of collagen.The administration of CTX (17.0 μg/kg,ip) significantly reduced paw swelling and mechanical and thermal hyperalgesia.CTX also reduced the produc-tion ofTNF-α,IL-1,and IL-2 but increased the production of IL-10 and altered pathohistological changes.The analgesic and anti-inflammatory efficacy of CTX was significantly reduced by MLA (3 mg/kg,sc).Conclusion: These results indicate that CTX has a beneficial effect on CFA-induced arthritis by modulating the production of inflammatory cytokines,α7-nAChR appears to mediate the anti-nociceptive and anti-inflammatory actions of CTX.

  13. Histaminergic and non-histaminergic elicited itch is attenuated in capsaicin-evoked areas of allodynia and hyperalgesia

    DEFF Research Database (Denmark)

    Andersen, Hjalte Holm; Elberling, J.; Sharma, Neha

    2017-01-01

    .3 cm(10 min) allodynic skin (p responses to the pruritogens were not significantly altered between the areas of allodynia and normal skin (p > 0.1). An additional experiment showed that pinprick hyperalgesia in the absence of allodynia was sufficient to evoke......BACKGROUND: Chronic pain patients with sensitization may exhibit decreased sensitivity to normally pruritogenic sensory stimuli and moreover occasionally perceive these as painful. This study explored the relationship between itch and pain, by evaluating histaminergic and non-histaminergic itch...... were significantly decreased when provoked in allodynic skin (p skin to 10.3 ± 1.8 cm(10 min) in allodynic skin (p skin to 8.8 ± 2...

  14. Female Adults with Patellofemoral Pain Are Characterized by Widespread Hyperalgesia, Which Is Not Affected Immediately by Patellofemoral Joint Loading

    DEFF Research Database (Denmark)

    Pazzinatto, Marcella Ferraz; de Oliveira Silva, Danilo; Barton, Christian;

    2016-01-01

    with an extra load equivalent 35% of body mass. PPTs and current knee pain (measured on a visual analogue scale) was assessed before and after the loading protocol. PPTs were measured at four sites around the knee and one remote site on the upper contralateral limb. RESULTS: Females with PFP demonstrated......: Participants were recruited via advertisements in fitness centers, public places for physical activity and universities. SUBJECTS: Thirty-eight females with patellofemoral pain, and 33 female pain-free controls. METHODS: All participant performed a novel PFJ loading protocol involving stair negotiation...... symptoms, lowers the PPTs locally at the knee but has no effect on PPT on the upper contralateral limb. This suggests widespread hyperalgesia is not affected by acute symptom aggravation....

  15. Rizatriptan overuse promotes hyperalgesia induced by dural inflammatory stimulation in rats by modulation of the serotonin system.

    Science.gov (United States)

    Su, Min; Ran, Ye; Han, Xun; Liu, Yufei; Zhang, Xu; Tan, Qingche; Li, Ruisheng; Yu, Shengyuan

    2016-08-01

    Clinical and preclinical studies have implicated serotonin (5-HT) and the 5-HT2A receptor (5-HT2AR) in the pathogenesis of medication-overuse headache (MOH). However, with no appropriate animal model to study this phenomenon it is difficult to differentiate the effects of chronic exposure to analgesics from the consequences of frequent headache attacks during the development of MOH. Therefore, this study used a novel animal model of MOH established by a combination of the overuse of rizatriptan (RIZ) and stimulation with dural inflammatory soup (IS) to investigate whether 5-HT and 5-HT2AR are involved in central plasticity and hyperalgesia. Similar to an IS infusion, IS-RIZ treatment induced nociception-related behaviours in Sprague-Dawley rats and increased Fos expression in the cortex and trigeminal pathway, whereas the RIZ injection alone did not. In addition, overuse of RIZ, administration of an IS stimulus, and a combination of these treatments, decreased the periorbital withdrawal threshold, with IS-RIZ treatment having the most significant effects. Both chronic RIZ exposure and recurring nociception decreased 5-HT expression, whereas IS-RIZ treatment led to decreased expression of 5-HT and upregulation of 5-HT2AR, which was positively correlated with Fos activation. These findings suggest that overuse of RIZ does not directly induce pain via the activation of nociceptive pathways but may increase hyperalgesia by influencing the pain modulation system. Furthermore, decreased 5-HT levels and upregulation of 5-HT2AR may play important roles in this system. Taken together, these findings indicate that medication overuse and frequent headache attacks can promote the neural plasticity associated with MOH.

  16. Heat hyperalgesia and mechanical hypersensitivity induced by calcitonin gene-related peptide in a mouse model of neurofibromatosis.

    Directory of Open Access Journals (Sweden)

    Stephanie White

    Full Text Available This study examined whether mice with a deficiency of neurofibromin, a Ras GTPase activating protein, exhibit a nociceptive phenotype and probed a possible contribution by calcitonin gene-related peptide. In the absence of inflammation, Nf1+/- mice (B6.129S6 Nf1/J and wild type littermates responded comparably to heat or mechanical stimuli, except for a subtle enhanced mechanical sensitivity in female Nf1+/- mice. Nociceptive phenotype was also examined after inflammation induced by capsaicin and formalin, which release endogenous calcitonin gene-related peptide. Intraplantar injection of capsaicin evoked comparable heat hyperalgesia and mechanical hypersensitivity in Nf1+/- and wild type mice of both genders. Formalin injection caused a similar duration of licking in male Nf1+/- and wild type mice. Female Nf1+/- mice licked less than wild type mice, but displayed other nociceptive behaviors. In contrast, intraplantar injection of CGRP caused greater heat hyperalgesia in Nf1+/- mice of both genders compared to wild type mice. Male Nf1+/- mice also exhibited greater mechanical hypersensitivity; however, female Nf1+/- mice exhibited less mechanical hypersensitivity than their wild type littermates. Transcripts for calcitonin gene-related peptide were similar in the dorsal root ganglia of both genotypes and genders. Transcripts for receptor activity-modifying protein-1, which is rate-limiting for the calcitonin gene-related peptide receptor, in the spinal cord were comparable for both genotypes and genders. The increased responsiveness to intraplantar calcitonin gene-related peptide suggests that the peripheral actions of calcitonin gene-related peptide are enhanced as a result of the neurofibromin deficit. The analgesic efficacy of calcitonin gene-related peptide receptor antagonists may therefore merit investigation in neurofibromatosis patients.

  17. Local cooling does not prevent hyperalgesia following burn injury in humans

    DEFF Research Database (Denmark)

    Werner, Mads U; Lassen, Birgit Vibeke; Pedersen, Juri L

    2002-01-01

    -inflammatory or anti-hyperalgesic potential of early cooling after thermal injury. Twenty-four healthy volunteers participated in this randomized, single-blinded study. Following baseline measurements, which included inflammatory variables (skin temperature, erythema index) and sensory variables (thermal...... on the burns. One of the thermodes cooled the burn (8 degrees C for 30 min) whereas the other thermode was a non-active dummy on the control burn. Inflammatory and sensory variables were followed for 160 min after end of the cooling procedure. The burn injury induced significant increases in skin temperature...... (Presponses (Presponses (Pskin temperature (P>0...

  18. Antihyperalgesic effect of systemic dexmedetomidine and gabapentin in a rat model of monoarthritis.

    Science.gov (United States)

    Zhang, Wei-Shi; Xu, Hua; Xu, Bo; Sun, Shan; Deng, Xiao-Ming; Zhang, Yu-Qiu

    2009-04-06

    The present study investigated the effects of systemic administration of dexmedetomidine, a selective alpha2 adrenergic receptor (alpha2AR) agonist, and gabapentin either alone or in combination on thermal hyperalgesia evoked by ankle joint inflammation. Monoarthritis of rat ankle joint was induced by an intra-articular injection of Complete Freund's Adjuvant (CFA). The paw withdrawal latency (PWL) from a thermal stimulus was measured in awake rats. Intraperitoneal (i.p.) injection of dexmedetomidine (2.5, 5, 10 and 20 microg/kg) or gabapentin (25, 50, 100 and 200 mg/kg) significantly and dose-dependently increased the PWL of the hindpaw ipsilateral to CFA-injected joint. The PWLs of the non-injected and normal saline (NS)-injected hindpaws were not significantly affected by the two agents at the most doses tested except the highest dose of dexmedetomidine (20 microg/kg). Although low dose of dexmedetomidine (2.5 microg/kg) or gabapentin (25 mg/kg) alone did not affect or lightly increased PWLs of the hindpaw ipsilateral to CFA-injected joint, a combination of dexmedetomidine and gabapentin (2.5 microg/kg+25 mg/kg, or 5 microg/kg+50 mg/kg) significantly reversed CFA-induced thermal hyperalgesia for 60 min without sedation/motor impairment. These results provide the first identification that co-application of dexmedetomidine and gabapentin may synergistically antagonize inflammatory pain, and this might prove to be beneficial in the treatment of arthritic pain.

  19. The α7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat

    DEFF Research Database (Denmark)

    Munro, G; Hansen, Rikke Rie; Erichsen, Hk

    2012-01-01

    ACh receptor agonist compound B with the positive allosteric modulator (PAM) PNU-120596 and the standard non-steroidal anti-inflammatory drug (NSAID), diclofenac, in rats with hind paw inflammation induced by either formalin, carrageenan or complete Freund's adjuvant (CFA). KEY RESULTS: When administered...... before carrageenan, both diclofenac (30 mg·kg(-1) ) and PNU-120596 (30 mg·kg(-1) ) significantly reduced mechanical hyperalgesia and weight-bearing deficits for up to 4 h. Compound B (30 mg·kg(-1) ) also attenuated both measures of pain-like behaviour, albeit less robustly. Whereas compound B and PNU......-120596 attenuated the carrageenan-induced increase in levels of TNF-α and IL-6 within the hind paw oedema, diclofenac only attenuated IL-6 levels. Established mechanical hyperalgesia induced by carrageenan or CFA was also partially reversed by compound B and PNU-120596. However, diclofenac...

  20. Local cooling does not prevent hyperalgesia following burn injury in humans

    DEFF Research Database (Denmark)

    Werner, Mads U; Lassen, Birgit Vibeke; Pedersen, Juri L;

    2002-01-01

    One of the oldest methods of pain relief following a burn injury is local application of ice or cold water. Experimental data indicate that cooling may also reduce the severity of tissue injury and promote wound healing, but there are no controlled studies in humans evaluating the anti-inflammato......One of the oldest methods of pain relief following a burn injury is local application of ice or cold water. Experimental data indicate that cooling may also reduce the severity of tissue injury and promote wound healing, but there are no controlled studies in humans evaluating the anti......-inflammatory or anti-hyperalgesic potential of early cooling after thermal injury. Twenty-four healthy volunteers participated in this randomized, single-blinded study. Following baseline measurements, which included inflammatory variables (skin temperature, erythema index) and sensory variables (thermal...... (Pindex (P0...

  1. Intra-Articular Blockade of P2X7 Receptor Reduces the Articular Hyperalgesia and Inflammation in the Knee Joint Synovitis Especially in Female Rats.

    Science.gov (United States)

    Teixeira, Juliana Maia; Dias, Elayne Vieira; Parada, Carlos Amílcar; Tambeli, Cláudia Herrera

    2017-02-01

    Synovitis is a key factor in joint disease pathophysiology, which affects a greater proportion of women than men. P2X7 receptor activation contributes to arthritis, but whether it plays a role in articular inflammatory pain in a sex-dependent manner is unknown. We investigated whether the P2X7 receptor blockade in the knee joint of male and female rats reduces the articular hyperalgesia and inflammation induced by a carrageenan knee joint synovitis model. Articular hyperalgesia was quantified using the rat knee joint incapacitation test and the knee joint inflammation, characterized by the concentration of cytokines tumor necrosis factor-α, interleukin-1β, interleukin-6, and cytokine-induced neutrophil chemoattractant-1, and by neutrophil migration, was quantified using enzyme-linked immunosorbent assay and by myeloperoxidase enzyme activity measurement, respectively. P2X7 receptor blockade by the articular coadministration of selective P2X7 receptor antagonist A740003 with carrageenan significantly reduced articular hyperalgesia, pro-inflammatory cytokine concentrations, and myeloperoxidase activity induced by carrageenan injection into the knee joint of male and estrus female rats. However, a lower dose of P2X7 receptor antagonist was sufficient to significantly induce the antihyperalgesic and anti-inflammatory effects in estrus female but not in male rats. These results suggest that P2X7 receptor activation by endogenous adenosine 5'-triphosphate is essential to articular hyperalgesia and inflammation development in the knee joint of male and female rats. However, female rats are more responsive than male rats to the antihyperalgesic and anti-inflammatory effects induced by P2X7 receptor blockade.

  2. TRPA1, NMDA receptors and nitric oxide mediate mechanical hyperalgesia induced by local injection of magnesium sulfate into the rat hind paw.

    Science.gov (United States)

    Srebro, Dragana P; Vučković, Sonja M; Savić Vujović, Katarina R; Prostran, Milica Š

    2015-02-01

    Previous studies have shown that while magnesium, an antagonist of the glutamate subtype of N-methyl-D-aspartate receptors, possesses analgesic properties, it can induce writhing in rodents. The aim of this study was to determine the effect and mechanism of action of local (intraplantar) administration of magnesium sulfate (MS) on the paw withdrawal threshold (PWT) to mechanical stimuli. The PWT was evaluated by the electronic von Frey test in male Wistar rats. Tested drugs were either co-administered intraplantarly (i.pl.) with MS or given into the contralateral paw to exclude systemic effects. MS at doses of 0.5, 1.5, 3 and 6.2 mg/paw (i.pl.) induced a statistically significant (as compared to 0.9% NaCl) and dose-dependent mechanical hyperalgesia. Only isotonic MS (250 mmol/l or 6.2% or 6.2 mg/paw) induced mechanical hyperalgesia that lasted at least six hours. Isotonic MS-induced mechanical hyperalgesia was reduced in a dose-dependent manner by co-injection of camphor, a non-selective TRPA1 antagonist (0.3, 1 and 2.5 μg/paw), MK-801, a NMDA receptor antagonist (0.001, 0.025 and 0.1 μg/paw), L-NAME, a non-selective nitric oxide (NO) synthase inhibitor (20, 50 and 100 μg/paw), ARL 17477, a selective neuronal NOS inhibitor (5.7 and 17 μg/paw), SMT, a selective inducible NOS inhibitor (1 and 2.78 μg/paw), and methylene blue, a guanylate cyclase inhibitor (5, 20 and 125 μg/paw). Drugs injected into the contralateral hind paw did not produce significant effects. These results suggest that an i.pl. injection of MS produces local peripheral mechanical hyperalgesia via activation of peripheral TRPA1 and NMDA receptors and peripheral production of NO.

  3. The dorsomedial hypothalamus mediates stress-induced hyperalgesia and is the source of the pronociceptive peptide cholecystokinin in the rostral ventromedial medulla.

    Science.gov (United States)

    Wagner, K M; Roeder, Z; Desrochers, K; Buhler, A V; Heinricher, M M; Cleary, D R

    2013-05-15

    While intense or highly arousing stressors have long been known to suppress pain, relatively mild or chronic stress can enhance pain. The mechanisms underlying stress-induced hyperalgesia (SIH) are only now being defined. The physiological and neuroendocrine effects of mild stress are mediated by the dorsomedial hypothalamus (DMH), which has documented connections with the rostral ventromedial medulla (RVM), a brainstem region capable of facilitating nociception. We hypothesized that stress engages both the DMH and the RVM to produce hyperalgesia. Direct pharmacological activation of the DMH increased sensitivity to mechanical stimulation in awake animals, confirming that the DMH can mediate behavioral hyperalgesia. A behavioral model of mild stress also produced mechanical hyperalgesia, which was blocked by inactivation of either the DMH or the RVM. The neuropeptide cholecystokinin (CCK) acts in the RVM to enhance nociception and is abundant in the DMH. Using a retrograde tracer and immunohistochemical labeling, we determined that CCK-expressing neurons in the DMH are the only significant supraspinal source of CCK in the RVM. However, not all neurons projecting from the DMH to the RVM contained CCK, and microinjection of the CCK2 receptor antagonist YM022 in the RVM did not interfere with SIH, suggesting that transmitters in addition to CCK play a significant role in this connection during acute stress. While the RVM has a well-established role in facilitation of nociception, the DMH, with its well-documented role in stress, may also be engaged in a number of chronic or abnormal pain states. Taken as a whole, these findings establish an anatomical and functional connection between the DMH and RVM by which stress can facilitate pain.

  4. Systemic lidocaine inhibits remifentanil-induced hyperalgesia via the inhibition of cPKCgamma membrane translocation in spinal dorsal horn of rats.

    Science.gov (United States)

    Cui, Weihua; Li, Yanping; Li, Shuren; Yang, Weiwei; Jiang, Jun; Han, Song; Li, Junfa

    2009-10-01

    Remifentanil is being used increasingly as one component of total intravenous anesthesia. Severe postoperative pain has occasionally been reported with discontinuation of remifentanil. This study was designed to determine the involvement of conventional protein kinase Cgamma (cPKCgamma) in the inhibitory action of lidocaine on remifentanil-induced hyperalgesia of rats after propofol-remifentanil-based anesthesia. Male Sprague-Dawley rats were allocated into the following groups randomly: propofol only (P), propofol+remifentanil (R), propofol+remifentanil+lidocaine (RL), and propofol+lidocaine (L). Cumulative pain score and withdrawal response to mechanical stimulation, immunoblotting, and immunofluorescence were applied to observe remifentanil-induced hyperalgesia and cPKCgamma membrane translocation. We found that the cumulative pain score of group R increased significantly at 30, 120, and 300 minutes postanesthesia (Plidocaine. These results suggested that increased cPKCgamma membrane translocation was involved in remifentanil-induced hyperalgesia, which was inhibited by systemic lidocaine and may contribute to reduced postoperative pain in rats after propofol-remifentanil-based anesthesia.

  5. Phosphorylation of the GluN1 subunit in dorsal horn neurons by remifentanil: a mechanism for opioid-induced hyperalgesia.

    Science.gov (United States)

    Zhang, C; Li, S S; Zhao, N; Yu, C

    2015-03-13

    Remifentanil (an ultra-short acting μ-opioid receptor agonist) use has been associated with acute opioid tolerance and hyperalgesia. Previous electrophysiological studies have shown that remifentanil elicits rapid and prolonged upregulation of N-methyl-D-aspartate receptor (NMDAR) currents. However, the effect of remifentanil on the levels of the GluN1 subunit of the NMDAR in dorsal horn neurons (DHNs) has not been reported. We investigated the effect of remifentanil, along with ketamine (NMDAR antagonist) and naloxone (μ-opioid receptor antagonist), on GluN1 mRNA levels and the amount of phosphorylated GluN1 in primary cultures of embryonic rat DHNs. DHNs were isolated from 18-19-day rat embryos and treated with remifentanil or vehicle for 1 h. GluN1 mRNA and protein levels, determined by real time reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively, were significantly and persistently increased by remifentanil exposure compared with the control group (P < 0.05). These results may partially account for the mechanism of remifentanil-induced hyperalgesia. This increase was prevented by ketamine (NMDAR antagonist) and naloxone (μ-opioid receptors antagonist), thus providing a potential therapeutic mechanism for the prevention of opioid-induced hyperalgesia.

  6. Tactile allodynia and formalin hyperalgesia in streptozotocin-diabetic rats: effects of insulin, aldose reductase inhibition and lidocaine.

    Science.gov (United States)

    Calcutt, N A; Jorge, M C; Yaksh, T L; Chaplan, S R

    1996-12-01

    Rats developed tactile allodynia within days of the onset of diabetes and which persisted for up to 8 weeks. Allodynia was prevented by insulin therapy that maintained normoglycemia while established allodynia was reversed by insulin therapy and normoglycemia of days but not hours duration. Tactile allodynia persisted in diabetic rats that received enough insulin to maintain normal body and foot weights but remained hyperglycemic, whereas this therapy was sufficient to correct other nerve disorders in diabetic rats, including deficits of sensory and motor nerve conduction velocity, nerve blood flow and hyperalgesia during the formalin test. Treating diabetic rats with the aldose reductase inhibitor ICI 222155 did not prevent tactile allodynia. Tactile allodynia was of similar magnitude in diabetic rats and nerve injured control rats and diabetes did not alter the magnitude or time course of nerve injury-induced allodynia. Systemic lidocaine treatment alleviated tactile allodynia in nerve injured control rats and both sham-operated and nerve injured diabetic rats. The streptozotocin-diabetic rat develops tactile allodynia that appears to be related to prolonged periods of insulin deficiency or hyperglycemia and which is amenable to treatment with lidocaine. The model may be of use in investigating the efficacy of other potential therapeutic agents for treating painful diabetic neuropathy.

  7. Hyperalgesia by low doses of the local anesthetic lidocaine involves cannabinoid signaling: an fMRI study in mice.

    Science.gov (United States)

    Bosshard, Simone C; Grandjean, Joanes; Schroeter, Aileen; Baltes, Christof; Zeilhofer, Hanns U; Rudin, Markus

    2012-07-01

    Lidocaine is clinically widely used as a local anesthetic inhibiting propagation of action potentials in peripheral nerve fibers. Correspondingly, the functional magnetic resonance imaging (fMRI) response in mouse brain to peripheral noxious input is largely suppressed by local lidocaine administered at doses used in a clinical setting. We observed, however, that local administration of lidocaine at doses 100 × lower than that used clinically led to a significantly increased sensitivity of mice to noxious forepaw stimulation as revealed by fMRI. This hyperalgesic response could be confirmed by behavioral readouts using the von Frey filament test. The increased sensitivity was found to involve a type 1 cannabinoid (CB(1)) receptor-dependent pathway as global CB(1) knockout mice, as well as wild-type mice pretreated systemically with the CB(1) receptor blocker rimonabant, did not display any hyperalgesic effects after low-dose lidocaine. Additional experiments with nociceptor-specific CB(1) receptor knockout mice indicated an involvement of the CB(1) receptors located on the nociceptors. We conclude that low concentrations of lidocaine leads to a sensitization of the nociceptors through a CB(1) receptor-dependent process. This lidocaine-induced sensitization might contribute to postoperative hyperalgesia.

  8. Activation of cannabinoid CB2 receptors reduces hyperalgesia in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis.

    Science.gov (United States)

    Fu, Weisi; Taylor, Bradley K

    2015-05-19

    Clinical trials investigating the analgesic efficacy of cannabinoids in multiple sclerosis have yielded mixed results, possibly due to psychotropic side effects mediated by cannabinoid CB1 receptors. We hypothesized that, a CB2-specific agonist (JWH-133) would decrease hyperalgesia in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Four weeks after induction of experimental autoimmune encephalomyelitis, we found that intrathecal administration of JWH-133 (10-100μg) dose-dependently reduced both mechanical and cold hypersensitivity without producing signs of sedation or ataxia. The anti-hyperalgesic effects of JWH-133 could be dose-dependently prevented by intrathecal co-administration of the CB2 antagonist, AM-630 (1-3μg). Our results suggest that JWH-133 acts at CB2 receptors, most likely within the dorsal horn of the spinal cord, to suppress the hypersensitivity associated with experimental autoimmune encephalomyelitis. These are the first pre-clinical studies to directly promote CB2 as a promising target for the treatment of central pain in an animal model of multiple sclerosis.

  9. Complications of long-term opioid therapy for management of chronic pain: the paradox of opioid-induced hyperalgesia.

    Science.gov (United States)

    Brush, D Eric

    2012-12-01

    While opioids remain a valid and effective analgesic strategy for patients suffering from a wide variety of painful conditions, they are not a panacea. Increasingly, physicians must balance patient expectations of adequate pain control with known limitations of opioid pharmaceuticals including adverse effects, tolerance, addiction, withdrawal, and drug diversion. Further complicating the issue over the last decade is a growing body of evidence suggesting chronic opioid use may unexpectedly worsen the perception of pain in some individuals. This syndrome, termed opioid-induced hyperalgesia (OIH), fundamentally changes our understanding of opioid pharmacodynamics and may influence our approach to management of chronic pain. This manuscript describes the concept OIH and provides an overview of basic science and clinical research to date attempting to characterize this syndrome, as well as ascertain its clinical relevance. The potential existence of OIH in humans is framed within the context of our current understanding of opioids and our prescribing patterns so that physicians may begin to incorporate these ideas into their philosophy of pain management as further information develops. Animal studies reliably validate OIH in controlled models. Rigorous research protocols in humans are lacking, and we cannot yet confidently conclude that OIH manifests in clinically significant ways. However, clinicians should consider the possibility of OIH when evaluating outcomes of patients on chronic opioid therapy.

  10. NF-κB信号通路在鞘内注射血小板活化因子诱发大鼠痛敏中的作用%Role of NF-κB pathway in the development of intrathecal platelet- activating factor- induced hyperalgesia in rats

    Institute of Scientific and Technical Information of China (English)

    杨京利; 刘菊英; 马国平; 熊良志

    2010-01-01

    Objective To investigate the role of NF-κB pathway in the development of intrathecal(IT)platelet-activating factor (PAF)-induced hyperalgesia in rats. Methods Sixty-four male SD rats (200-250 g) in which intrathecal catheters were successfully implanted without complications were randomly divided into 6 groups:group Ⅰ received artificial cerebro-spinal fluid (ACSF) 10 μl IT (n = 16); group Ⅱ received PAF 10 μg in ACSF 10 μl IT; group Ⅲ received 0.1% DMSO 2 ml intraperitoneally (IP) (n = 8); group Ⅳ, Ⅴ, Ⅵ received IP SC-514 (a selective IKK-β inhibitor) 10, 50, 100 mg/kg in 0.1% DMSO 2 ml respectively at 2 h before IT PAF. Paw withdrawal threshold to mechanical stimulation (PWMT) and paw withdrawal latency to thermal stimuli (PWTL) were measured before (baseline) and at 5, 15, 30, 45, 60 min and then every 30 min for another 4 h after IT administration. The animals were killed after the last pain threshold measurement at 5 h after IT PAF. The lumbar segment (L4-6) of the spinal cord was removed for determination of TNF-α and IL-lβ content (by ELISA).Results lntrathecal PAF induced tactile allodynia and thermal hyperalgesia rapidly, increased the expression of TNF-α and IL-lβ in lumbar spinal cord. Pretreatment with SC-514 attenuated PAF-induced hyperalgesia and inhibited the increase in TNF-α and IL-1β expression in the spinal cord. Conclusion NF-κB is involved in intrathecal PAF-induced hyperalgesia.%目的 评价NF-κB信号通路在鞘内注射血小板活化因子(PAF)诱发大鼠痛敏中的作用.方法 鞘内置管成功的雄性SD大鼠64只,体重200~250 g,随机分为6组:人工脑脊液(ACSF)对照组(AC组,n=16)鞘内注射ACSF 10μl;PAF诱发大鼠痛敏组(PAF组,n=16)鞘内注射PAF 10μg(溶于10μl ACSF);二甲基亚砜(DMSO)对照组(DC组,n=8)和低、中和高剂量SC-514组(S1-3组,n=8)分别于鞘内注射PAF前2 h腹腔注射0.1%DMSO溶液2 ml、SC-514(溶于2 ml 0.1%DMSO溶液)10、50、100 mg/kg.分别

  11. Pharmacogenomic study of the role of the nociceptin/orphanin FQ receptor and opioid receptors in diabetic hyperalgesia.

    Science.gov (United States)

    Rutten, Kris; Tzschentke, Thomas M; Koch, Thomas; Schiene, Klaus; Christoph, Thomas

    2014-10-15

    Targeting functionally independent receptors may provide synergistic analgesic effects in neuropathic pain. To examine the interdependency between different opioid receptors (µ-opioid peptide [MOP], δ-opioid peptide [DOP] and κ-opioid peptide [KOP]) and the nociceptin/orphanin FQ peptide (NOP) receptor in streptozotocin (STZ)-induced diabetic polyneuropathy, nocifensive activity was measured using a hot plate test in wild-type and NOP, MOP, DOP and KOP receptor knockout mice in response to the selective receptor agonists Ro65-6570, morphine, SNC-80 and U50488H, or vehicle. Nocifensive activity was similar in non-diabetic wild-type and knockout mice at baseline, before agonist or vehicle administration. STZ-induced diabetes significantly increased heat sensitivity in all mouse strains, but MOP, DOP and KOP receptor knockouts showed a smaller degree of hyperalgesia than wild-type mice and NOP receptor knockouts. For each agonist, a significant antihyperalgesic effect was observed in wild-type diabetic mice (all Preceptor compared with wild-type diabetic mice. Morphine was the only agonist that demonstrated near-full antihyperalgesic efficacy across all non-cognate receptor knockouts. Partial or near-complete reductions in efficacy were observed with Ro65-6570 in DOP and KOP receptor knockouts, with SNC-80 in NOP, MOP and KOP receptor knockouts, and with U50488H in NOP and DOP receptor knockouts. There was no evidence of NOP and MOP receptor interdependency in response to selective agonists for these receptors. These findings suggest that concurrent activation of NOP and MOP receptors, which showed functional independence, may yield an effective and favorable therapeutic analgesic profile.

  12. Laparoscopic Cholecystectomy for Gallbladder Calculosis in Fibromyalgia Patients: Impact on Musculoskeletal Pain, Somatic Hyperalgesia and Central Sensitization.

    Science.gov (United States)

    Costantini, Raffaele; Affaitati, Giannapia; Massimini, Francesca; Tana, Claudio; Innocenti, Paolo; Giamberardino, Maria Adele

    2016-01-01

    Fibromyalgia, a chronic syndrome of diffuse musculoskeletal pain and somatic hyperalgesia from central sensitization, is very often comorbid with visceral pain conditions. In fibromyalgia patients with gallbladder calculosis, this study assessed the short and long-term impact of laparoscopic cholecystectomy on fibromyalgia pain symptoms. Fibromyalgia pain (VAS scale) and pain thresholds in tender points and control areas (skin, subcutis and muscle) were evaluated 1week before (basis) and 1week, 1,3,6 and 12months after laparoscopic cholecystectomy in fibromyalgia patients with symptomatic calculosis (n = 31) vs calculosis patients without fibromyalgia (n. 26) and at comparable time points in fibromyalgia patients not undergoing cholecystectomy, with symptomatic (n = 27) and asymptomatic (n = 28) calculosis, and no calculosis (n = 30). At basis, fibromyalgia+symptomatic calculosis patients presented a significant linear correlation between the number of previously experienced biliary colics and fibromyalgia pain (direct) and muscle thresholds (inverse)(pfibromyalgia pain significantly increased and all thresholds significantly decreased at 1week and 1month (1-way ANOVA, pFibromyalgia pain and thresholds returned to preoperative values at 3months, then pain significantly decreased and thresholds significantly increased at 6 and 12months (pfibromyalgia patients undergoing cholecystectomy thresholds did not change; in all other fibromyalgia groups not undergoing cholecystectomy fibromyalgia pain and thresholds remained stable, except in fibromyalgia+symptomatic calculosis at 12months when pain significantly increased and muscle thresholds significantly decreased (pfibromyalgia symptoms and that laparoscopic cholecystectomy produces only a transitory worsening of these symptoms, largely compensated by the long-term improvement/desensitization due to gallbladder removal. This study provides new insights into the role of visceral pain comorbidities and the effects of

  13. One night of total sleep deprivation promotes a state of generalized hyperalgesia: a surrogate pain model to study the relationship of insomnia and pain.

    Science.gov (United States)

    Schuh-Hofer, Sigrid; Wodarski, Rachel; Pfau, Doreen B; Caspani, Ombretta; Magerl, Walter; Kennedy, Jeffrey D; Treede, Rolf-Detlef

    2013-09-01

    Sleep disturbances are highly prevalent in chronic pain patients. Understanding their relationship has become an important research topic since poor sleep and pain are assumed to closely interact. To date, human experimental studies exploring the impact of sleep disruption/deprivation on pain perception have yielded conflicting results. This inconsistency may be due to the large heterogeneity of study populations and study protocols previously used. In addition, none of the previous studies investigated the entire spectrum of nociceptive modalities. To address these shortcomings, a standardized comprehensive quantitative sensory protocol was used in order to compare the somatosensory profile of 14 healthy subjects (6 female, 8 male, 23.5 ± 4.1 year; mean ± SD) after a night of total sleep deprivation (TSD) and a night of habitual sleep in a cross-over design. One night of TSD significantly increased the level of sleepiness (P<0.001) and resulted in higher scores of the State Anxiety Inventory (P<0.01). In addition to previously reported hyperalgesia to heat (P<0.05) and blunt pressure (P<0.05), study participants developed hyperalgesia to cold (P<0.01) and increased mechanical pain sensitivity to pinprick stimuli (P<0.05) but no changes in temporal summation. Paradoxical heat sensations or dynamic mechanical allodynia were absent. TSD selectively modulated nociception, since detection thresholds of non-nociceptive modalities remained unchanged. Our findings show that a single night of TSD is able to induce generalized hyperalgesia and to increase State Anxiety scores. In the future, TSD may serve as a translational pain model to elucidate the pathomechanisms underlying the hyperalgesic effect of sleep disturbances.

  14. 大鼠切口痛模型中鞘内注射不同剂量KN93对瑞芬太尼诱发的痛觉过敏的影响%Effects of different dose of KN93 on remifentanil-induced hyperalgesia

    Institute of Scientific and Technical Information of China (English)

    程崇学; 赵鑫; 张兢; 顾小萍; 马正良

    2013-01-01

    Objective To observe effects of different dose of (calcium/calmodulin-dependent protein kinase Ⅱ,CaMK Ⅱ)inhibitor KN93 on the hyperalgesia induced by remifentanil in rat model of incisional pain.Methods Thirty six Sprague Dawley rats were divided randomly into 6 groups with 6 rats each.Control; Incisional pain group; Remifentanil group; KN93 group (25 μg);KN93 group (50 μg); KN93 group (100 μg).The model of incisional pain was performed in all groups except the control.In remifentanil group and KN93 (25,50,100 μg) groups,remifentanil (40 μg/kg) was given subcutaneously 30 min after the beginning of surgery.The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) at the times of 24 h before and 2,6,24,48 h after surgery were underwent.Results Compared with the incisional pain group,the rats in the remifentanil group { the PWMT (20.86±2.55,19.57±1.81,21.87±2.01,22.26± 1.91) and the PWTL [(8.47±1.52) s,(8.58±1.51) s,(8.45±2.05) s,(9.06±1.47) s]} showed sensory hyperalgesia (P<0.05).25 μg KN93 had no effect on the hyperalgesia induced by remifentanil,while 50 μg and 100 μg KN93 can relieve the hyperalgesia induced by remifentanil (P<0.05).Conclusions Remifentanil can induce sensory hyperalgesia; Intrathecal injection KN93 may relieve the hyperalgesia dose-dependently.%目的 观察不同剂量KN93对瑞芬太尼痛觉过敏大鼠痛行为的影响. 方法 采用完全随机分组方法,将36只雄性SD大鼠分为6组(每组6只):①空白对照组;②切口组;③瑞芬太尼组;④KN93 25 μg组;⑤KN93 50 μg组;⑥KN93 100 μg组.除空白对照组外,其余各组均制作切口痛模型、瑞芬太尼组及KN93 3个剂量组,手术过程中皮下输注瑞芬太尼(40 μg/kg,1 mg溶于40 ml生理盐水中)30 min.各组大鼠分别于术前24h、术后2、6、24、48 h测定术侧机械缩足阈值(paw withdrawal mechanical threshold,PWMT)和热缩足潜伏期(paw withdrawal thermal latency,PWTL).

  15. Effect of ketamine on remifentanil induced hyperalgesia in incision pain rats%氯胺酮对瑞芬太尼诱发切口痛大鼠痛觉敏化的干预效应

    Institute of Scientific and Technical Information of China (English)

    郭文俊; 薛庆生; 于布为

    2012-01-01

    目的 探讨瑞芬太尼对大鼠切口痛的痛觉敏化作用及氯胺酮的干预效应.方法 选用健康雄性SD大鼠32只,随机分为四组:对照组(C组)静脉注射生理盐水10 ml,90 min后做切口痛模型;瑞芬太尼组(R组)持续泵注瑞芬太尼0.8 μg·kg-1 ·min-1,90 min后做切口痛模型;氯胺酮预处理组(K组)静脉推注氯胺酮8 mg/kg,90 min后做切口痛模型;联合处理组(KR组)静脉推注氯胺酮8mg/kg,30 min后泵注瑞芬太尼0.8μg·kg-1·min-1,60 min后做切口痛模型.采用热痛仪和von Frey纤毛测定各组大鼠的热痛阈和机械痛阈值.结果 术后2h各组热痛阈值和机械痛阈值显著降低(P<0.05),R组明显低于其他组(P<0.05);术后120 h,各组热痛阈值较术前降低(P<0.05),C组与K组机械痛阈明显下降(P<0.05).结论 瑞芬太尼静脉输注可引起大鼠切口痛痛觉敏化.小剂量氯胺酮预处理无术后镇痛作用,但氯胺酮预处理可拮抗瑞芬太尼诱发的大鼠切口痛痛觉敏化作用.%Objective To observe the effect of ketamine on remifentanil induced hyperalgesia in incision pain rats. Methods Thirty-two healthy male SD rats were randomly divided to four groups (n=8): control group (group C), 90 min after saline intravenous injection, incision pain nxidel was established; remifentanil group (group R), after continuous infusion of remifentanil at a rate of 0. 8 μg·kg-1·min-1 for 90 min, incision pain model was established; ketamine group (group K), 90 min after ketamine 8 mg/kg intravenous injection, incision pain model was established; ketamine and remifentanil group (group KR), ketamine 8 mg/kg L v. 30min before remifentanil continuous infusion for 60 min, incision pain model was established Thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) were evaluated. Results TWL and MWT decreased significantly at 2 h after operation in all groups, and TWL and MWT in group R were lower than the other 3 groups

  16. Advance in studies of hyperalgesia induced by remifentanil%瑞芬太尼诱发痛觉过敏的研究进展

    Institute of Scientific and Technical Information of China (English)

    王哲银; 杨亚利; 任永功

    2010-01-01

    Remifentanil has gained increasing popularity as an opioid for intravenous anaesthesia due to its fast and predictable onset and offset independenting of the infusion time.However,more and more attention has been paid to the hyperalgesia induced by remifentanil.Research of the mechanisms and preventions of hyperalgesia induced by remifentanil not only provides clinical guidement of medicine usage,but also contributes to the development of new drug.%瑞芬太尼因其起效迅速和消除不依赖输注时间而广泛用于静脉麻醉,但其所诱发的痛觉过敏现象却越来越受到重视.对瑞芬太尼诱发痛觉过敏的机制及其预防措施进行研究,不仅为临床正确用药提供指导,还有助于新药的研发.

  17. Research development on opioid-induced hyperalgesia%阿片类药物诱导痛觉过敏的研究进展

    Institute of Scientific and Technical Information of China (English)

    王小慧; 王俊

    2011-01-01

    阿片类药物能促使中枢敏化及诱导痛觉过敏,称为阿片类药物诱导的痛觉过敏(Opioid-induced hyperalgesia,OIH),此现象已经被大量临床观察和基础研究所证实.近年来,关于OIH产生机制的研究正在成为麻醉和疼痛治疗领域的热点.目前,关于OIH产生机制的研究主要集中在中枢谷氨酰能系统活性增强、内源性神经肽的作用、脊髓下行易化作用等方面.本文就OIH的发生机制、评估与治疗等方面的进展进行综述.%Opioid-induced hyperalgesia ( OIH ) is most broadly defined as a state of nociceptive sensitization caused by exposure to opioids, which has been confirmed by large amounts of clinical and basic science evidences. The study of its mechanism in anesthesia and pain management area is becoming a hot spot. At the present time, studies on the mechanism of OIH focus on the central glutaminergic system, endogenous neuropeptide and descending facilitation. The article summarized the mechanisms of OIH, as well as its assessment and management.

  18. Nociceptor-expressed ephrin-B2 regulates inflammatory and neuropathic pain

    Directory of Open Access Journals (Sweden)

    Kullander Klas

    2010-11-01

    Full Text Available Abstract Background EphB receptors and their ephrin-B ligands play an important role in nervous system development, as well as synapse formation and plasticity in the adult brain. Recent studies show that intrathecal treatment with EphB-receptor activator ephrinB2-Fc induced thermal hyperalgesia and mechanical allodynia in rat, indicating that ephrin-B2 in small dorsal root ganglia (DRG neurons and EphB receptors in the spinal cord modulate pain processing. To examine the role of ephrin-B2 in peripheral pain pathways, we deleted ephrin-B2 in Nav1.8+ nociceptive sensory neurons with the Cre-loxP system. Sensory neuron numbers and terminals were examined using neuronal makers. Pain behavior in acute, inflammatory and neuropathic pain models was assessed in the ephrin-B2 conditional knockout (CKO mice. We also investigated the c-Fos expression and NMDA receptor NR2B phosphorylation in ephrin-B2 CKO mice and littermate controls. Results The ephrin-B2 CKO mice were healthy with no sensory neuron loss. However, pain-related behavior was substantially altered. Although acute pain behavior and motor co-ordination were normal, inflammatory pain was attenuated in ephrin-B2 mutant mice. Complete Freund's adjuvant (CFA-induced mechanical hyperalgesia was halved. Formalin-induced pain behavior was attenuated in the second phase, and this correlated with diminished tyrosine phosphorylation of N-methyl-D-aspartic acid (NMDA receptor subunit NR2B in the dorsal horn. Thermal hyperalgesia and mechanical allodynia were significantly reduced in the Seltzer model of neuropathic pain. Conclusions Presynaptic ephrin-B2 expression thus plays an important role in regulating inflammatory pain through the regulation of synaptic plasticity in the dorsal horn and is also involved in the pathogenesis of some types of neuropathic pain.

  19. Glutamate receptor ligands attenuate allodynia and hyperalgesia and potentiate morphine effects in a mouse model of neuropathic pain.

    Science.gov (United States)

    Osikowicz, Maria; Mika, Joanna; Makuch, Wioletta; Przewlocka, Barbara

    2008-09-30

    Recent studies have indicated that metabotropic glutamate receptors mGluR5, mGluR2/3 and mGluR7 are present in the regions of central nervous system important for nociceptive transmission, but their involvement in neuropathic pain has not been well established. We demonstrated that acute and chronic administration of MPEP (mGluR5 antagonist), LY379268 (mGluR2/3 agonist), and AMN082 (mGluR7 agonist) attenuated allodynia (von Frey test) and hyperalgesia (cold plate test) as measured in Swiss albino mice on day seven after chronic constriction injury (CCI) to the sciatic nerve. Moreover, single administration of MPEP (30 mg/kg; i.p.) or LY379268 (10mg/kg; i.p.) injected 30 min before morphine potentiated morphine's effects (20mg/kg; i.p.) in the mouse CCI model, as measured by both the tests mentioned above. However, a single administration of AMN082 (3mg/kg; i.p.) potentiated the effects of a single morphine injection (20mg/kg; i.p.) in the von Frey test only. Chronic administration (7 days) of low doses of MPEP, LY379268 or AMN082 (all drugs at 3mg/kg; i.p.) potentiated the effects of single doses of morphine (3, 10, and 20mg/kg; i.p.) administered on day seven; however, AMN082 only potentiated the effect in the cold plate test. Additionally, the same doses of MPEP and LY379268 (but not AMN082) chronically co-administered with morphine (40 mg/kg; i.p.) attenuated the development of morphine tolerance in CCI-exposed mice. Our data suggest that mGluR5, mGluR2/3, and mGluR7 are involved in injury-induced plastic changes in nociceptive pathways and that the mGluR5 and mGluR2/3 ligands enhanced morphine's effectiveness in neuropathy, which could have therapeutic implications.

  20. Role of extracellular signal-regulated kinase in central amygdala on fentanyl-induced hyperalgesia in rats%中央杏仁核细胞外信号调节激酶在芬太尼诱发大鼠痛觉过敏中的作用

    Institute of Scientific and Technical Information of China (English)

    尹平平; 葛胜辉; 罗放

    2015-01-01

    .5 nmol was injected via the catheter.In group U2, hyperalgesia was induced, and 6.5 h later ERK1/2 inhibitor U0126 1.5 nmol was injected via the catheter.Mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal threshold (TWT) were measured before fentanyl injection, at 6.5 h after injection, and at 30 min after DMSO or U0124/U0126 administration via the catheter (T0-2).After the last measurement of pain threshold, the rats were sacrificed, and the amygdala tissues were sampled for detection of the expression of phosphorylated ERK1/2 (p-ERK1/2) by Western blot in groups C and H.Results Compared with group C, the MWT and TWT were significantly decreased at T1,2in H and U1 groups, and at T1in group U2 (P<0.05) , the expression of p-ERK2 was up-regulated (P<0.05) , and no significant change was found in the expression of p-ERK1 in group H (P>0.05).Compared with group H,the MWT and TWT were significantly increased at T2 in group U2 (P<0.05) , and no significant change was found in MWT, TWT in group U1 (P>0.05).Conclusion ERK2 activation in the central amygdala is involved in the development of fentanyl-induced hyperalgesia in rats.

  1. Relationships between Irritable Bowel Syndrome Pain, Skin Temperature Indices of Autonomic Dysregulation, and Sensitivity to Thermal Cutaneous Stimulation

    Directory of Open Access Journals (Sweden)

    Fong Wong

    2010-01-01

    Full Text Available This study evaluated relationships between irritable bowel syndrome (IBS pain, sympathetic dysregulation, and thermal pain sensitivity. Eight female patients with diarrhea-predominant IBS and ten healthy female controls were tested for sensitivity to thermal stimulation of the left palm. A new method of response-dependent thermal stimulation was used to maintain pain intensity at a predetermined level (35% by adjusting thermal stimulus intensity as a function of pain ratings. Clinical pain levels were assessed prior to each testing session. Skin temperatures were recorded before and after pain sensitivity testing. The temperature of palmar skin dropped (1.5∘C when the corresponding location on the opposite hand of control subjects was subjected to prolonged thermal stimulation, but this response was absent for IBS pain patients. The patients also required significantly lower stimulus temperatures than controls to maintain a 35% pain rating. Baseline skin temperatures of patients were significantly correlated with thermode temperatures required to maintain 35% pain ratings. IBS pain intensity was not significantly correlated with skin temperature or pain sensitivity. The method of response-dependent stimulation revealed thermal hyperalgesia and increased sympathetic tone for chronic pain patients, relative to controls. Similarly, a significant correlation between resting skin temperatures and thermal pain sensitivity for IBS but not control subjects indicates that tonic sympathetic activation and a thermal hyperalgesia were generated by the chronic presence of visceral pain. However, lack of a significant relationship between sympathetic tone and ratings of IBS pain casts doubt on propositions that the magnitude of IBS pain is determined by psychological stress.

  2. Endothelin-1 Induces Thermal Hyperalgesia in Mice%内皮素-1引起热痛觉过敏的研究

    Institute of Scientific and Technical Information of China (English)

    梁杰贤; 季文进; 洪迅; 郭中敏; 刘培庆

    2006-01-01

    目的研究内皮素-1(ET-1)在局部引起热痛觉过敏的表现及机制.方法小鼠分为生理盐水对照组(NS组)、ET-1组(ET组)、ETA受体拮抗剂BQ123加ET-1组(BE组),每组6例.NS足底注射生理盐水,ET组足底注射10 pmol ET-1,BE组注射3 nmol BQ123 20 min后再注射ET-1.测量注药前后15 min、30 min、45 min及60 min热痛阈值.结果 NS组热痛阈值无明显变化,ET组热痛阈值降低,60 min时热痛阈值基本恢复,BE组热痛阈值无明显变化.结论 ET-1可在局部通过与ETA受体结合引起动物的热痛觉过敏.

  3. Persistent at-level thermal hyperalgesia and tactile allodynia accompany chronic neuronal and astrocyte activation in superficial dorsal horn following mouse cervical contusion spinal cord injury.

    Science.gov (United States)

    Watson, Jaime L; Hala, Tamara J; Putatunda, Rajarshi; Sannie, Daniel; Lepore, Angelo C

    2014-01-01

    In humans, sensory abnormalities, including neuropathic pain, often result from traumatic spinal cord injury (SCI). SCI can induce cellular changes in the CNS, termed central sensitization, that alter excitability of spinal cord neurons, including those in the dorsal horn involved in pain transmission. Persistently elevated levels of neuronal activity, glial activation, and glutamatergic transmission are thought to contribute to the hyperexcitability of these dorsal horn neurons, which can lead to maladaptive circuitry, aberrant pain processing and, ultimately, chronic neuropathic pain. Here we present a mouse model of SCI-induced neuropathic pain that exhibits a persistent pain phenotype accompanied by chronic neuronal hyperexcitability and glial activation in the spinal cord dorsal horn. We generated a unilateral cervical contusion injury at the C5 or C6 level of the adult mouse spinal cord. Following injury, an increase in the number of neurons expressing ΔFosB (a marker of chronic neuronal activation), persistent astrocyte activation and proliferation (as measured by GFAP and Ki67 expression), and a decrease in the expression of the astrocyte glutamate transporter GLT1 are observed in the ipsilateral superficial dorsal horn of cervical spinal cord. These changes have previously been associated with neuronal hyperexcitability and may contribute to altered pain transmission and chronic neuropathic pain. In our model, they are accompanied by robust at-level hyperaglesia in the ipsilateral forepaw and allodynia in both forepaws that are evident within two weeks following injury and persist for at least six weeks. Furthermore, the pain phenotype occurs in the absence of alterations in forelimb grip strength, suggesting that it represents sensory and not motor abnormalities. Given the importance of transgenic mouse technology, this clinically-relevant model provides a resource that can be used to study the molecular mechanisms contributing to neuropathic pain following SCI and to identify potential therapeutic targets for the treatment of chronic pathological pain.

  4. Avaliação da hiperalgesia e alterações histológicas do gânglio da raiz dorsal induzidas pelo núcleo pulposo Evaluation of hyperalgesia and histological changes of dorsal root ganglion induced by nucleus pulposus

    Directory of Open Access Journals (Sweden)

    André Luiz de Souza Grava

    2010-01-01

    estruturas do gânglio da raiz dorsal e apresentaram aumento da intensidade nos períodos mais longos de observação.OBJECTIVE: To evaluate hyperalgesia and histological changes of dorsal root ganglia induced by nucleus pulposus (NP contact. METHODS: Twenty Wistar rats were used, divided into two experimental groups. In one of the groups, a fragment of the autologous NP was removed from the sacroccocigeal region and deposited on the L5 dorsal root ganglia. In the control group, the NP was removed from the sacrococcygeal region, L5 dorsal root ganglia were exposed and covered by a piece of adipous fat tissue. Hyperalgesia was evaluated by the von Frey electronic test and Hargreaves test, and histological changes of the dorsal root ganglia by HE staining and immunohistochemistry using iNOS. The evaluation of hyperalgesia and histological changes of the dorsal root ganglia were performed on the third postoperative day and after 1, 3, 5, and 7 weeks. RESULTS: NP induced higher intensity mechanical and thermal hyperalgesia. Dorsal root ganglia in contact with nucleus pulposus presented histological changes and the intensity of these changes were proportional to the length of time in contact. The expression of iNOS was higher in the glial cells in contact with the nucleus pulposus. CONCLUSION: The contact of nucleus pulposus with dorsal root ganglia induced histological changes and mechanical and thermal hyperalgesia. These changes were more intense after longer period of evaluation.

  5. Disturbance of response to acute thermal pain in naturally occurring cholecystokinin-a receptor gene knockout Otsuka Long-Evans Tokushima Fatty (OLETF) rats.

    Science.gov (United States)

    Miyasaka, Kyoko; Nomoto, Shigeki; Ohta, Minoru; Kanai, Setsuko; Kaneko, Takao; Tahara, Shoichi; Funakoshi, Akihiro

    2006-08-01

    Otsuka Long-Evans Tokushima Fatty (OLETF) rats lack cholecystokinin-A receptor (CCK-AR) because of a genetic abnormality. We observed that body temperature homeostasis in response to changes in ambient temperature was deteriorated in OLETF rats, while the functions of the signal outputs from the hypothalamus to effectors were not impaired. Deteriorated homeostasis was also seen in CCK-AR deficient (-/-) mice. In the present study, we examined whether the sensory pathway involved in transmitting signals about temperature from the skin to the brain was impaired in OLETF rats. To elucidate the involvement of CCK-AR function, we conducted the same experiment in CCK-AR(-/-) mice. Responses to thermal pain were assessed using the Hargreaves' plantar test apparatus. Shortening of withdrawal latency was observed in OLETF rats compared to control rats, indicating thermal hyperalgesia. Behavioral responses following paw withdrawal were disturbed in OLETF rats. The 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid contents in the hippocampus and frontal cortex of OLETF rats were significantly higher than in those of the controls. CCK-AR(-/-) mice did not show any differences from wild-type mice. In conclusion, OLETF rats showed thermal hyperalgesia and disturbed responses to thermal pain, and an alteration of 5-HT function might have a role in this disturbance.

  6. Effects of naringenin on allodynia and hyperalgesia in rats with chronic constriction injury-induced neuropathic pain%柚苷配基对慢性压迫性损伤引起的大鼠触摸痛及痛觉过敏的影响

    Institute of Scientific and Technical Information of China (English)

    Shyam Kaulaskar; Pravinkumar Bhutada; Anand Rahigude; Dilpesh Jain; Uday Harle

    2012-01-01

    OBJECTIVE:To study the analgesic effects of naringenin on chronic constriction injury (CCI)model of neuropathic pain.METHODS:After inducing of neuropathic pain by CCI,treatment with 25 and 50 mg/kg of naringenin and 10 mg/kg of pregabalin was given.Rats were evaluated for behavioral tests using Hargreaves apparatus for thermal hyperalgesia,pin prick test for tactile mechanical hyperalgesia and cold water-induced allodynia on days 0,3,5,7,14 and 21.At the end of study,oxidative stress parameters were measured.RESULTS:Naringenin showed ameliorating action against CCI-induced neuropathic pain in all the tested models.Also,naringenin attenuated the elevated levels of lipid peroxidation and nitric oxide,and restored the level of reduced glutathione.CONCLUSION:The results of the present investigation suggest that naringenin exhibits analgesic effect in sciatic nerve injury model.%目的:研究柚苷配基对慢性压迫性神经损伤模型的镇痛效果.方法:经慢性压迫性损伤建立神经性疼痛大鼠模型后,分别给予模型大鼠25和50 mg/kg的柚苷配基以及10 mg/kg的普加巴林.在第0、3、5、7、14和21天采用Hargreaves方法评估大鼠的行为变化,针刺实验测试触觉性机械痛觉过敏和经冷水诱发的异常性疼痛,最后测定氧化应激反应参数.结果:柚苷配基能缓解经慢性压迫性损伤诱发的神经性疼痛,减轻脂质过氧化反应,降低一氧化氮水平,恢复还原型谷胱甘肽含量.结论:柚苷配基能缓解坐骨神经损伤引起的疼痛.

  7. 鸡矢藤注射液和野木瓜注射液对大鼠足底皮下化学组织损伤诱致自发痛、痛敏和炎症的作用%Effects of intravenous Injections Paederiae and Stauntonia on spontaneous pain, hyperalgesia and inflammation induced by cutaneous chemical tissue injury in the rat

    Institute of Scientific and Technical Information of China (English)

    彭小莉; 高喜玲; 陈军; 黄熙; 陈会生

    2003-01-01

    -induced persistent spontaneous pain-related responses ( PSPR), primary thermal/mechanical hyperalgesia and inflammation in conscious rats. Injection of bee venom ( BV, 0.1 mg, 50 μl) into the plantar surface of one hind paw resulted in not only a 1-h monophasic PSPR such as flinching reflex in the injected paw and a subsequent period of 3 -4 days primary heat and mechanical hyperalgesia, but also a marked sign of inflammation, including redness and swelling of the plantar surface in the injected paw. Intraplantar injection of formalin produced two phases of PSPR as reported previously. Systemic pre-treatment with three doses of IP (0. 32, 1.6 and 9.0ml/kg, 500% ) or IS (0.32, 1.6 and 9.0 ml/kg, 250% ) produced a dose-dependent suppression of the BV- or formalin-induced flinching reflex of 1 h time course as compared with the saline control group. Post-treatment with IP or IS 5 min after BV injection also produced a significant suppression of the flinching reflex in both BV test and formalin test respectively, as compared with the control group. However, neither pre- nor post-treatment with IP or IS produced any significantly suppressive effect on the BV-induced primary heat and mechanical hyperalgesia and inflammation. The analgesia produced by IP or IS was not mediated by the endogenous opioid receptors since naloxone, a non-selective opioid receptor antagonist, had no reversal effect on the IP and IS-produced analgesia in the BV-induced PSPR. Our present results suggest that IP or IS might prevent and relieve clinical persistent spontaneous pain, but without any anti-nociceptive and anti-inflammatory effects on the primary heat hyperalgesia, mechanical hyperalgesia, as well as inflammatory responses. The BV test might be a useful model of pain to evaluate and screen anti-nociceptive and anti-inflammatory effects of certain compounds of the Chinese medicinal herbs on the pathological origins of pain.

  8. 大鼠鞘内注射JWH015对瑞芬太尼诱发痛觉过敏的影响%Effect of intrathecal injection JWH015 on the remifentani-induced hyperalgesia in rats

    Institute of Scientific and Technical Information of China (English)

    张威; 刘晓杰; 蒋明; 刘成龙; 张娟; 马正良; 顾小萍

    2012-01-01

    目的 在大鼠切口痛模型基础上探讨大麻素受体2(cannabinoid receptor 2,CB2R)激动剂JWH015对瑞芬太尼诱发的痛觉过敏的影响.方法 30只雄性Sprague-Dawley(SD)大鼠采用随机数字表法分成5组(每组6只):对照组(C组)、切口痛组(I组)、瑞芬太尼组(R组)、切口痛+JWH015组(JI组)、切口痛+瑞芬太尼+JWH015组(JR组).JI组与JR组在造模前30 min鞘内注射10 μg JWH015,而C组、Ⅰ组、R组均给予20%的二甲基亚砜(dimethyl sulfoxide,DMSO)溶液,容积均为10μl.除C组外,其余各组均制作切口痛模型,R组和JR组在造模的同时皮下泵注瑞芬太尼0.04 mg/kg,其余组皮下泵注生理盐水,容积均为0.4 ml,30 min泵完.测定术前24h及术后2、6、24和48 h大鼠切口手术同侧后爪的机械缩足反射阈值(paw withdrawal mechanical threshold,PWMT)和热缩足反射潜伏期(paw withdrawal thermal latency,PWTL). 结果 与C组和基础值比较,Ⅰ 组术后各时间点PWMT和PWTL均降低(P<0.05);与Ⅰ组比较,R组术后各时间点PWMT(6.3±0.8)、(6.3±0.8)、(6.3±1.0)、(6.8±0.9)g和PWTL (12.8±1.2)、(12.2±0.9)、(13.4±1.1)、(13.5±1.3)s均明显降低(P<0.05);与R组相比,JR组术后6、24和48 h的PWMT(7.9±1.0)、(9.9±1.1)、(8.4±1.1)g和PWTL(17.3±1.9)、(19.9±1.3)、(17.7±1.2)s明显升高(P<0.05).结论 鞘内注射JWH-015可以有效缓解由瑞芬太尼诱发的切口周围组织痛觉过敏.%Objective To investigate the effect of cannabinoid receptor 2 (CB2R) agonist JWH015 on the hyperalgesia induced by remifentanil in a rat model of incision pain. Methods Thirty Sprague-Dawley (SD) rats were randomly divided into 5 groups (n=6):control group(group C),incisional pain group(group I),incisional pain plus JWH015 group (group JI),remifentanil group (group R),and JWH015 plus remifentanil group (group JR).10 μg JWH015 diluted by 10 μl 20% dimethyl sulfoxide (DMSO)solution was intrathecally injected in each rat of group JI and JR 30 min

  9. Akt抑制剂Ⅳ对瑞芬太尼痛觉过敏的预防和治疗作用%Effects of Akt inhibitor Ⅳ on prevention and treatment the hyperalgesia induced by remifentanil

    Institute of Scientific and Technical Information of China (English)

    隽立芹; 马正良; 顾小萍

    2013-01-01

    目的观察造模前后鞘内注射Akt抑制剂Ⅳ对切口痛瑞芬太尼痛觉过敏小鼠痛行为学的影响。方法 C57BL/6小鼠40只,随机分为5组:切口痛+DMSO组(I组,n=8)、瑞芬太尼+DMSO组(R 组,n=8)造模前给予 Akt 抑制剂Ⅳ0.08μg/10μl 组(A1组,n=8)、造模后6 h 给予 Akt 抑制剂Ⅳ0.08μg/10μl组(A2组,n=8)、造模后1 d给予Akt抑制剂Ⅳ0.08μg/10μl组(A3组,n=8)。所有分组均在右侧足做切口痛,R组和各A组同时皮下泵注瑞芬太尼(0.04 mg/kg)30 min。R组和各A组分别在术前30 min、术后6 h、1 d鞘内给予10%二甲基亚砜(DMSO)和Akt抑制剂Ⅳ10μl。于术前1 d及术后6 h、1、2、3、5、7 d检测各组小鼠右侧后足热缩足潜伏期(paw withdrawal thermal latency,PWTL)及机械缩足阈值(paw mechanical withdrawal threshold,PMWT)。结果与I组和基础值比较,R组术后各时间除术后7 d外PWMT和PWTL均降低(P<0.05);与R组相比,A1、A2组术后6 h、1 d、2 d及A3组术后1 d、2 d的PWMT和PWTL明显升高(P<0.05);A1、A2、A3组的各时间点的PWMT和PWTL有统计学差异(P<0.05)。结论 Akt参与瑞芬太尼诱导的痛觉过敏,预先和造模后鞘内注射Akt抑制剂Ⅳ都能够有效缓解瑞芬太尼诱发的痛觉过敏。%Objective To investigate the effects of intrathecal injection of Akt inhibitor Ⅳ on the hyperalgesia induced by remifentanil in a incision pain model. Methods Forty C57BL/6 male mice were randomly divided into 5 groups (n=8): incision pain+DMSO group (group I), incision pain+remifentanil+DMSO group (group R), before modeling Akt inhibitor Ⅳ 0.08μg/10μl group (group A1), 6h after modeling Akt inhibitor Ⅳ 0.08μg/10μl group (group A2), 1d after modeling Akt inhibitor IV 0.08μg/10μl group (group A3). All groups were made model of incisional pain in the right paw, in group R and group A1, A2, A3, remifentanil (0.04 mg/kg) were

  10. Spinal microglia contributes to postoperative hyperalgesia in incisional rats with nicotine abstinence%小胶质细胞参与尼古丁戒断切口痛大鼠术后痛觉过敏的研究

    Institute of Scientific and Technical Information of China (English)

    刘献文; 刘忠; 张宗旺

    2014-01-01

    目的 探讨脊髓小胶质细胞在尼古丁戒断切口痛大鼠术后痛觉过敏中的作用. 方法 SD大鼠42只采用随机数字表法随机分为3组.单纯切口痛组(IP组,18只):依处死时间再分为3亚组(每组6只),均做切口痛模型;尼古丁戒断切口痛组(N+IP组,18只):依处死时间再分为3亚组(每组6只),皮下注射尼古丁连续7d后做切口痛模型;米诺环素组(M组,6只):同N+IP组,做切口痛模型前1h腹腔内注射米诺环素100 mg/kg.所有大鼠分别于术后第1、2、3、5、7天对大鼠术侧行机械刺激缩足阈值(mechanical withdrawal threshold,MWT)和热刺激缩足潜伏期(thermal withdrawal latency,TWL)测定.IP组和N+IP组大鼠在术后第1、3、7天痛行为学测试后处死.取脊髓L4~ 6段,免疫组织化学法测定Ca2+接头蛋白(ionized calcium binding adapter molecule-1,IBA-1)阳性细胞的表达. 结果 与IP组比较,N+IP组大鼠在术后1 d~7 d MWT和TWL均显著降低(P<0.01);与N+IP组比较,M组大鼠在术后第1天MWT[(28.1±1.7)g vs (22.3±2.4)g]和TWL[(7.5±1.3)s vs(5.2±1.2)s]明显升高(P<0.01),而第2天~第7天无变化(P>0.05).组内比较,IP组大鼠脊髓背角IBA-1阳性细胞术后第3天比术后第1天和第7天明显增多(P<0.01).与IP组比较,在术后第1、3、7天N+IP组大鼠IBA-1阳性细胞明显增多(P<0.01). 结论 尼古丁暴露引起大鼠脊髓背角小胶质细胞活化,小胶质细胞活化参与了尼古丁戒断切口痛大鼠术后痛觉过敏.%Objective To explore whether spinal microglia contributes to postoperative hyperalgesia in incisional rats with nicotine abstinence.Methods Forty-two SD rats were randomized into one of the 3 groups of rats.IP Group (n=18) which was divided into 3 sub-groups according to the executed time,six rats in each group.The rats underwent incisional pain model.N+IP group (n=18) which was divided into 3 sub-groups according to the executed time,six rats in each group.The rats underwent

  11. Effects of ketamine pretreatment on preventing remifentanil-induced hyperalgesia%氯胺酮预防瑞芬太尼痛觉过敏的实验研究

    Institute of Scientific and Technical Information of China (English)

    吴晓丽; 马正良; 顾小萍; 崔松勤

    2010-01-01

    Objective To investigate the effects of ketamine on preventing remifentanil- induced hyperalgesia in postoperative pain rat models. Methods Sixty SD rats were randomly divided into 5 groups (n=1 2): control group (C); incisional pain group (Ⅰ); ketamine group (K); remifentanil group (R); ketamine+ remifentanil group (K+R). A right hind paw plantar incision was performed in groups I, K, Rand K+R. Ketamine ( 10 mg/kg 0.1 ml ) was injected subcutaneously 30 min before plantar incision in groups K and K+R.In groups R and K+R, remifentanil (0.04 mg/kg 0.4 ml) were infused subcutaneously with a pump within 30 min at the moment of surgical incision. All rats were anesthetized with sevoflurane. The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were used to evaluate the behavioral changes and measured 24 h before incision and 2, 6, 24, 48 after incision. Results Compared with group C and baseline, the decrease of PWMT and PWTL were observed at 2, 6, 24, 48 h after incision in groupI; Compared with group I, the significant decrease of PWMT (6.48±1.23) g and PWTL ( 11.13±1.95 ) s were observed at 2 h after incision in group R, and this level continued until 48 h after incision; Compared with group R, the significant increase of PWMT (9.36±1.76,9.41±1.50, 10.18±1.42, 10.15±1.48) g and PWTL( 15.66±2.42, 16.24±2.55, 15.13±3.07, 15.66±2.44) s were observed at 2,6,24,48 h after incision in group K+R. Conclusion ketamine pretreatment prevents the development remifentanil-induced hyperalgesia in postoperative pain a rat model.%目的 观察预先皮下注射氯胺酮对瑞芬太尼诱发切口痛模型大鼠痛觉过敏的影响.方法 雄性SD大鼠60只,将大鼠随机分为5组:对照组(C组)、切口痛组(Ⅰ组)、氯胺酮(K组)、瑞芬太尼组(R组)、氯胺酮+瑞芬太尼组(K+R组).Ⅰ组,K组,R组和K+R组行右后足跖肌切口;K组和K+R组术前单次皮下注射氯胺酮0.1 ml(10mg/kg);R组和K+R组切皮开始

  12. Analgesic effects of methanolic extracts of the leaf or root of Moringa oleifera on complete Freund's adjuvant-induced arthritis in rats%辣木叶或根的甲醇提取物对弗氏佐剂致关节炎大鼠模型的止痛作用

    Institute of Scientific and Technical Information of China (English)

    Homa Manaheji; Soheila Jafari; Jalal Zaringhalam; Shamsah Rezazadeh; Reza Taghizadfarid

    2011-01-01

    Objective: Moringa oleifera (family Moringaceae) has been widely used in African folk medicine,and researchers have recently revealed its anti-inflammatory effects in human.This study aimed to evaluate the analgesic properties of methanolic extracts of M.oleifera in complete Freund's adjuvant (CFA)-induced arthritis in rats.Methods: Adult male Wistar rats, weighing 200 to 220 g, were used in this study.Adjuvant arthritis was induced on day 0 by a single subcutaneous injection of CFA.The prepared extracts from both the root and leaf (200, 300 and 400 mg/kg) of M.oleifera were administered intraperitonealy to rats in the treatment groups 0, 3 and 6 d after CFA injection and indomethacin (5 mg/kg) was used as a positive control drug.Thermal hyperalgesia and mechanical allodynia were evaluated for the analgesic effect 0, 3 and 6 d after CFA injection.Combined methanolic root and leaf extracts of M.oleifera (200 mg/kg) were also tested for the analgesic effect.Results: The potency of the root or leaf extracts of M.oleifera (300 and 400 mg/kg) was similar to that of indomethacin, resulted in significant reductions in both thermal hyperalgesia and mechanical allodynia in rats with CFA-induced arthritis compared with the control group after 3 and 6 d,respectively (P<0.01 or P<0.05).Combined root and leaf extracts (200 mg/kg) of M.oleifera resulted in a significant reduction in thermal hyperalgesia compared with the control group after 3 and 6 d, respectively (P<0.01).Prophylactic injections of combined root and leaf extracts of M.oleifera (200 mg/kg) resulted in a significant reduction in thermal hyperalgesia compared with the control group, the root extracts group, and the leaf extracts group after 3 and 6 d, respectively (P<0.01).Conclusion: The methanolic extracts of the root or leaf of M.oleifera are effective in the reduction of pain induced by CFA in rats.A comparison of single and combination therapies of root and leaf extracts also showed a synergistic

  13. Pharmacokinetics of eugenol and its effects on thermal hypersensitivity in rats.

    Science.gov (United States)

    Guénette, Sarah Annie; Ross, Andréanne; Marier, Jean-Francois; Beaudry, Francis; Vachon, Pascal

    2007-05-07

    Neuropathic pain is a type of chronic pain following central or peripheral nervous system lesions that cause allodynia (pain initiated by a non-painful stimulus) and hyperalgesia (increased pain sensation following a painful stimulus). The first objective of the study was to evaluate the pharmacokinetics of eugenol, the principle chemical constituent of clove oil, following a gavage administration (40 mg/kg) in male Sprague-Dawley rats. The second objective was to evaluate the effect of repeated oral administrations of eugenol on hyperalgesia and allodynia using an experimental model of neuropathic pain in rats. Thermal and mechanical sensitivity (Hargreave's test and von Frey filaments) were determined in sciatic nerve cuff-implanted rats. Sensitivities were assessed following repeated oral administrations of 40 mg/kg of eugenol or saline for 5 days (n=6 per group). Pharmacokinetic parameters were calculated using noncompartmental methods. Serial blood samples were collected over 24 h. Concentrations of eugenol in blood and plasma peaked rapidly following oral administration. Mean T(1/2) values of eugenol in plasma and blood were long (14.0 and 18.3 h, respectively), suggesting a potential accumulation of the drug following repeated administrations. Reaction time to thermal stimuli appeared to increase constantly following repeated administrations of eugenol. On the last day of treatment, eugenol treatments resulted in a statistically significant prolongation of the reaction time to thermal stimuli in rats compared to the saline group (Mean+/-S.E.M.: 11.4+/-1.23 vs. 6.1+/-0.53 s, P<0.01). These results support the hypothesis that eugenol may alleviate neuropathic pain and that the cumulative effect of the drug may be in part responsible for this effect following repeated daily administrations.

  14. 蛋白激酶Cα相互作用蛋白在瑞芬太尼痛觉过敏中的作用%Role of protein interacting with Cα kinase in remifentanil induced hyperalgesia

    Institute of Scientific and Technical Information of China (English)

    元元; 王超; 王国林

    2013-01-01

    背景 瑞芬太尼痛觉过敏是指应用瑞芬太尼所导致的机体对伤害性刺激的反应增强,其发生机制与N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)受体-蛋白激酶C (protein kmase C,PKC)通路介导的脊髓中枢敏化相关.蛋白激酶Cα相互作用蛋白(protein interacting withCαkinase,PICK1)是PKCα的靶蛋白之一,也是在PKCα和突触后膜受体蛋白间起重要作用的衔接蛋白. 目的 探讨PICK1在瑞芬太尼痛觉过敏发生及维持中的作用. 内容 对PICK1的结构、功能及其在瑞芬太尼痛觉过敏中的研究进行综述. 趋向 通过PICK1在瑞芬太尼痛觉过敏中的研究,为瑞芬太尼痛觉过敏的预防及治疗提供新的靶点.%Background Remifentanil therapy aiming at alleviating pain may render patients more sensitive to pain,which is defined as remifentanil induced hyperalgesia.N-methyl-D-aspartic acid (NMDA) receptor-protein kinase C (PKC) mediated spinal central sensitization is involved in the mechanisms of remifentanil induced hyperalgesia.Protein interacting with Cα kinase (PICK1) is one of the target proteins of protein kinase Cα.PICK1 is an important adapter protein between PKCα and postsynaptic receptors.PICK1 contains a PDZ domain and a BAR domain.PICK1 plays important roles in synaptic plasticity,neural conduction,peripheral nerve sensation,cell growth and cytoadherence.Objective This review focus on the role of PICK1 in remifentanil induced hyperalgesia.Content This review provides a comprehensive summary of structure and function of PICK1 as well as its progressions in remifentanil induced hyperalgesia.Trend PICK1 may provide a new way for the treatment of remifentanil induced hyperalgesia.

  15. Identification of transient receptor potential vanilloid 4 downstream signaling molecule and its effect in behavioural hyperalgesia following chronic compression of the dorsal root ganglion in rats%瞬时感受器电位离子通道香草素受体4下游信号分子的确定及其对大鼠背根神经节慢性压迫后痛觉过敏的作用

    Institute of Scientific and Technical Information of China (English)

    丁欣利; 张杨; 王永慧; 宁丽萍; 岳寿伟

    2011-01-01

    目的:探讨大鼠背根神经节慢性压迫CCD后瞬时感受器电位离子通道香草素受体4(TRPV4)下游信号分子及其在痛觉过敏中的机制.方法:鞘内分别注射TRPV4拮抗剂钉红(RR)、TRPV4反义寡脱氧核苷酸(AS ODN)和一氧化氮合成酶(NOS)抑制剂L-NAME,检测CCD大鼠背根神经节DRG内一氧化氮(NO)代谢产物亚硝酸盐(nitrite)含量变化,并观测热刺激缩爪反应潜伏期(PWL)的变化.结果:鞘内分别注射RR、TRPV4 AS ODN和L-NAME后,均能够显著降低CCD大鼠DRG内亚硝酸盐含量(P<0.05).CCD大鼠的热痛敏行为也能够显著改善(P<0.05).结论:TRPV4及其下游信号分子NO参与介导CCD大鼠的热痛觉过敏,%Objective: To investigate transient receptor potential vanilloid 4 (TRPV4) downstream signaling molecule and its effect in behavioural hyperalgesia following chronic compression of dorsal root ganglion (DRG) (CCD) in rats.Method: Intrathecal administration of ruthenium red (RR,TRPV4 antagonist), TRPV4 antisense oligodeoxynucleotide (ODN)(TRPV4 AS ODN) or L-NAME (inhibitor of NO synthase) were adopted to study the thermal stimuli paw withdrawl latency (PWL) and the nitrite (an index of nitric oxide formation) production in the DRG of CCD rats.Result: Intrathecal administration of RR TRPV4 AS ODN or L-NAME induced significant increase of PWL(P<0.05)and significant decrease of nitrite in DRG(P<0.05), compared with control rats, respectively.Conclusion: TRPV4-NO pathway is involved in thermal hyperalgesia in CCD rats.

  16. Relationship between toll-like receptor 3 of spinal astrocytes and development of hyperalgesia in rats%脊髓星形胶质细胞TLR3与大鼠痛觉过敏形成的关系

    Institute of Scientific and Technical Information of China (English)

    章沿锋; 姚尚龙; 张小洺; 张德仁

    2009-01-01

    目的 评价脊髓星形胶质细胞Toll样受体3(TLR3)与大鼠痛觉过敏形成的关系.方法 雄性SD大鼠,体重180-250 g,取鞘内置管成功的大鼠126只,随机分为3组(n=42),正常对照组(C组);生理盐水组(NS组)鞘内注射生理盐水0.5 ml/kg,1次,d.连续7 d;痛觉过敏组(H组)腹腔注射米诺环素40me/kg+鞘内注射Poly(I:C)0.5 mg/kg,1次,d,连续7 d.各组于鞘内给药前1d和鞘内给药后1、3、5、7、10、14、21、28 d时测定机械痛阈和热痛阈;各组于鞘内给药后7 d时处死6只大鼠,取L4,5脊髓节段,采用免疫组化法测定脊髓背角胶质纤维酸性蛋白(GFAP)表达;各组于鞘内给药前1d和鞘内给药后1、7,14、21、28 d时各处死6只大鼠,取L4,5脊髓节段,采用RT-PCR法测定TLR3 mRNA表达.结果 与C组和Ns组比较,H组机械痛阈降低,脊髓背角GFAP和TLR3 mRNA表达上调(P<0.05).结论 TLR3与其特异性配体结合后,激活脊髓背角星形胶质细胞,诱发大鼠痛觉过敏.%Objective To evaluate the relationship between toll-like receptor 3(TLR3)of spinal astrocytes and development of hyperalgesia induced by intrathecal Poly(I:C)in rats.Methods Male SD-rats weighing 180-250 g were anesthetized with intraperitoneal(IT)10%chloral hydrate 3-3.5 ml/mg.Intrathecnl catheter was placed at L6-S1 interspace with the tip positioned at lumbar enlargement.One hundred and twenty.six SD rats in which IT catheters were successfully placed were randomly divided into 3 groups(n=42 each):group Ⅰ normal control(C);group Ⅱ received normal saline 0.5ml/kg IT, once a day for 7 consecutive days(NS); group Ⅲ received minocycline 40 mg/kg IP+Poly(1:C)0.5 mg/kg IT once a day for 7 consecutive days(H).Paw withdrawal threshold to von Frey filament stimulation(PWT)and paw withdrawal latency to neciceptive thermal stimulation(PWL)were measured at 1 d before operation and 1,3,5,7.10,14.21,28 day after IT injection.Six animals were kiUed at 1d before operation and 1,7,14,21,28 d after

  17. Opioid-induced redistribution of 6TM and 7TM μ opioid receptors: A hypothesized mechanistic facilitator model of opioid-induced hyperalgesia.

    Science.gov (United States)

    Wang, Wei; Wang, Yan; Zhang, Wei; Jin, Xiaoju; Liu, Yusheng; Xu, Shiqin; Lei, Liming; Shen, Xiaofeng; Guo, Xirong; Xia, Xiaoqiong; Wang, Fuzhou

    2016-08-01

    Opioids are still the most popular form of pain treatment, but many unavoidable side effects make opioids a big challenge in effective pain management. Opioid-induced hyperalgesia (OIH), a paradoxical phenomenon, portrays an increased sensitivity to harmful stimuli caused by opioid exposure. Changes in the neural modulation are considered a major contributor to the development of OIH. Activation of opioid receptors (ORs) and corresponding downstream molecules are the vital composition of functional performance of opioids. Increasing interests were proposed of the interaction between ORs and other neural transmitter systems such as glutamatergic, GABAergic and adrenergic ones to the genesis of OIH. G protein coupled μ-opioid receptor (MOR) was studied comprehensively on its role in the development of OIH. In addition to the relationship between MOR and other neurotransmitter receptors, a new intracellular MOR that has six transmembrane (6TM) domains was identified, and found to perform a pro-nociceptive task in contrast to the counterpart 7TM isoform. A mechanistic model of OIH in which both 6TM and 7TM MORs undergoing membrane redistribution upon opioid exposure is proposed which eventually facilitates the neurons more sensitive to nociceptive stimulation than that of the preceding opioid exposure.

  18. Electroacupuncture attenuates visceral hyperalgesia and inhibits the enhanced excitability of colon specific sensory neurons in a rat model of irritable bowel syndrome.

    Science.gov (United States)

    Xu, G-Y; Winston, J H; Chen, J D Z

    2009-12-01

    The causes of irritable bowel syndrome remain elusive and there are few effective treatments for pain in this syndrome. Electroacupunture (EA) is used extensively for treatment of various painful conditions including chronic visceral hyperalgesia (CVH). However, mechanism of its analgesic effect remains unknown. This study was designed to investigate effect of EA on colon specific dorsal root ganglion (DRG) neurons in rats with CVH. CVH was induced by intracolonic injection of acetic acid (AA) in 10-day-old rats. Electromyography and patch clamp recordings were performed at age of 8-10 weeks. Colon DRG neurons were labelled by injection of DiI into the colon wall. EA was given at ST36 in both hindlimbs. As adults, neonatal AA-injected rats displayed an increased sensitivity to colorectal distension (CRD) and an enhanced excitability of colon DRG neurons. EA treatment for 40 min significantly attenuated the nociceptive responses to CRD in these rats; this attenuation was reversed by pretreatment with naloxone. EA treatment for 40 min per day for 5 days produced a prolonged analgesic effect and normalized the enhanced excitability of colon DRG neurons. Furthermore, in vitro application of [D-Ala(2), N-MePhe(4), Gly(5)-Ol] enkephalin (DAMGO) suppressed the enhanced excitability of colon neurons from rats with CVH. These findings suggest that EA produced-visceral analgesia, which might be mediated in a large part by endogenous opioids pathways, is associated with reversal of the enhanced excitability of colon DRG neurons in rats with CVH.

  19. JCM-16021, a Chinese Herbal Formula, Attenuated Visceral Hyperalgesia in TNBS-Induced Postinflammatory Irritable Bowel Syndrome through Reducing Colonic EC Cell Hyperplasia and Serotonin Availability in Rats.

    Science.gov (United States)

    Qin, Hong-Yan; Xiao, Hai-Tao; Leung, Fung-Ping; Yang, Zhi-Jun; Wu, Justin C Y; Sung, Joseph J Y; Xu, Hong-Xi; Tong, Xu-Dong; Bian, Zhao-Xiang

    2012-01-01

    The present study aimed to investigate the analgesic effect of JCM-16021, a revised traditional Chinese herbal formula, on postinflammatory irritable bowel syndrome (PI-IBS) in rats. The trinitrobenzene sulfonic (TNBS) acid-induced PI-IBS model rats were orally administrated with different doses of JCM-16021 (1.2, 2.4, and 4.8 g/kg/d) for 14 consecutive days. The results showed that JCM-16021 treatment dose-dependently attenuated visceral hyperalgesia in PI-IBS rats. Further, the colonic enterochromaffin (EC) cell number, serotonin (5-HT) content, tryptophan hydroxylase expression, and mechanical-stimuli-induced 5-HT release were significantly ameliorated. Moreover, the decreased levels of mucosal cytokines in PI-IBS, especially the helper T-cell type 1- (T(h)1-) related cytokine TNF-α, were also elevated after JCM-16021 treatment. These data demonstrate that the analgesic effect of JCM-16021 on TNBS-induced PI-IBS rats may be medicated via reducing colonic EC cell hyperplasia and 5-HT availability.

  20. JCM-16021, a Chinese Herbal Formula, Attenuated Visceral Hyperalgesia in TNBS-Induced Postinflammatory Irritable Bowel Syndrome through Reducing Colonic EC Cell Hyperplasia and Serotonin Availability in Rats

    Directory of Open Access Journals (Sweden)

    Hong-Yan Qin

    2012-01-01

    Full Text Available The present study aimed to investigate the analgesic effect of JCM-16021, a revised traditional Chinese herbal formula, on postinflammatory irritable bowel syndrome (PI-IBS in rats. The trinitrobenzene sulfonic (TNBS acid-induced PI-IBS model rats were orally administrated with different doses of JCM-16021 (1.2, 2.4, and 4.8 g/kg/d for 14 consecutive days. The results showed that JCM-16021 treatment dose-dependently attenuated visceral hyperalgesia in PI-IBS rats. Further, the colonic enterochromaffin (EC cell number, serotonin (5-HT content, tryptophan hydroxylase expression, and mechanical-stimuli-induced 5-HT release were significantly ameliorated. Moreover, the decreased levels of mucosal cytokines in PI-IBS, especially the helper T-cell type 1- (Th1- related cytokine TNF-α, were also elevated after JCM-16021 treatment. These data demonstrate that the analgesic effect of JCM-16021 on TNBS-induced PI-IBS rats may be medicated via reducing colonic EC cell hyperplasia and 5-HT availability.

  1. Thermal comfort

    DEFF Research Database (Denmark)

    d’Ambrosio Alfano, Francesca Romana; Olesen, Bjarne W.; Palella, Boris Igor;

    2014-01-01

    Thermal comfort is one of the most important aspects of the indoor environmental quality due to its effects on well-being, people's performance and building energy requirements. Its attainment is not an easy task requiring advanced design and operation of building and HVAC systems, taking...... into account all parameters involved. Even though thermal comfort fundamentals are consolidated topics for more than forty years, often designers seem to ignore or apply them in a wrong way. Design input values from standards are often considered as universal values rather than recommended values to be used...... under specific conditions. At operation level, only few variables are taken into account with unpredictable effects on the assessment of comfort indices. In this paper, the main criteria for the design and assessment of thermal comfort are discussed in order to help building and HVAC systems designers...

  2. Matrix Thermalization

    CERN Document Server

    Craps, Ben; Nguyen, Kévin

    2016-01-01

    Matrix quantum mechanics offers an attractive environment for discussing gravitational holography, in which both sides of the holographic duality are well-defined. Similarly to higher-dimensional implementations of holography, collapsing shell solutions in the gravitational bulk correspond in this setting to thermalization processes in the dual quantum mechanical theory. We construct an explicit, fully nonlinear supergravity solution describing a generic collapsing dilaton shell, specify the holographic renormalization prescriptions necessary for computing the relevant boundary observables, and apply them to evaluating thermalizing two-point correlation functions in the dual matrix theory.

  3. Oridonin Alleviates Visceral Hyperalgesia in a Rat Model of Postinflammatory Irritable Bowel Syndrome: Role of Colonic Enterochromaffin Cell and Serotonin Availability.

    Science.gov (United States)

    Zang, Kai-Hong; Shao, Yun-Yun; Zuo, Xiao; Rao, Zhi; Qin, Hong-Yan

    2016-06-01

    The aim of this present study was to investigate the effect of oridonin on visceral hyperalgesia and colonic serotonin availability in a rat model of trinitrobenzenesulfonic acid-induced postinflammatory irritable bowel syndrome (PI-IBS). Rats were randomly divided into five groups: normal control, PI-IBS model, PI-IBS+low-dose oridonin (5 mg/kg), PI-IBS+median-dose oridonin (10 mg/kg), and PI-IBS+high-dose oridonin (20 mg/kg). Rats in control and model groups were orally administered with water by gavage, whereas rats in oridonin-treated groups were orally administered with different dosages of oridonin, and drugs were given for 14 consecutive days. Compared with the control group, the pain threshold pressure was significantly reduced in PI-IBS rats. The colonic enterochromaffin (EC) cell number, serotonin content, and the protein expression of tryptophan hydroxylase (TPH) were markedly increased and the protein expression of serotonin reuptake transporter was significantly decreased in PI-IBS rats. The spleen index in PI-IBS rats was decreased, and the levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-4, and IL-13 in the colon of PI-IBS rats were also markedly decreased. Oridonin treatment dose dependently increased pain threshold pressure, and markedly decreased colon EC cell numbers, TPH expression, and serotonin content in PI-IBS rats. Oridonin treatment also significantly increased the spleen index as well as the levels of TNF-α, IFN-γ, IL-4, and IL-13 in the colon of PI-IBS rats. Results of this study demonstrate that the analgesic effect of oridonin in PI-IBS rats is associated with reduced colonic EC cell hyperplasia and 5-HT availability, the regulatory effect of oridonin on colonic cytokine production may be correlated with its effect on colonic EC cell number.

  4. Research Progress on Opioid-induced Hyperalgesia in Cancer Pain Control%癌痛治疗中痛觉过敏的研究进展

    Institute of Scientific and Technical Information of China (English)

    郭东勇

    2012-01-01

    癌痛影响着每一位晚期癌症患者的正常生活.阿片类药物是目前治疗癌痛的主力军,但是随着治疗和研究的深入,阿片类药物诱发的痛觉过敏(OIH)等并发症也逐渐凸显并越发受到重视,相关机制的研究正成为癌痛治疗领域的热点.本文从中枢谷氨酰能系统、信号传导通路、阿片受体及外周受体、细胞内机制、遗传因素及相关临床研究等方面对OIH的研究进展进行综述,旨在为临床上OIH的诊断及治疗提供相关依据.%All patients with advanced cancer suffer from cancer pain. Currently, opioids are the first line drugs in the management of cancer pain. Consequently, the incidence of opioid-induced hyperalgesia ( OIH ) is increasing and more attention has been focused on it. Research on the related mechanisms of OIH has recently becomes a hot topic in cancer pain control. The research progress on OIH from the central glutaminergic system, signal transduction pathways, opioid and peripheral receptors, the intracellular mechanism, genetic factors, and relevant clinical observations are discussed to provide information for clinical diagnosis and treatment of OIH.

  5. Thermal Hardware for the Thermal Analyst

    Science.gov (United States)

    Steinfeld, David

    2015-01-01

    The presentation will be given at the 26th Annual Thermal Fluids Analysis Workshop (TFAWS 2015) hosted by the Goddard Space Flight Center (GSFC) Thermal Engineering Branch (Code 545). NCTS 21070-1. Most Thermal analysts do not have a good background into the hardware which thermally controls the spacecraft they design. SINDA and Thermal Desktop models are nice, but knowing how this applies to the actual thermal hardware (heaters, thermostats, thermistors, MLI blanketing, optical coatings, etc...) is just as important. The course will delve into the thermal hardware and their application techniques on actual spacecraft. Knowledge of how thermal hardware is used and applied will make a thermal analyst a better engineer.

  6. Effects of cyclin dependent kinase 5 inhibitor Roscovitine on remifentanil-induced hyperalgesia%细胞周期素依赖蛋白激酶-5抑制剂Roscovitine对瑞芬太尼痛觉过敏大鼠痛行为的影响

    Institute of Scientific and Technical Information of China (English)

    刘晓杰; 顾小萍; 张威; 张兢; 马正良

    2011-01-01

    目的 探讨预先鞘内注射细胞周期素依赖蛋白激酶-5(Cdk5)抑制剂Roscovitine对瑞芬太尼痛觉过敏大鼠痛行为的影响.方法 SD雄性大鼠45只,随机数字表法分成5组(n=9):对照组(C)、切口痛组(Ⅰ)、瑞芬太尼组(R)、Roscovitine组(ROS)、Roscovitine+瑞芬太尼组(ROS+ R).ROS,ROS+R组术前30 min鞘内给予Roscovitine10μl(50μg),余组给予20% DMSO10μl.除C组外均制作切口痛模型;R和ROS+R组切皮同时皮下泵注瑞芬太尼0.4ml (0.04mg/kg) 30 min.于术前24h、术后2h、6h、24h、48h检测大鼠术侧足底机械缩足阈值(paw withdrawal mechanical threshold,PWMT)和热缩足潜伏期(paw withdrawal thermal latency,PWTL).结果 与C组相比,Ⅰ组术后PWMT、PWTL明显降低(P<0.01).与Ⅰ组相比,R组术后PWMT,PWTL明显降低(P<0.01);而ROS组术后PWTL明显升高[2h:(20.26±1.33)s,(17.97±0.47) s;48h:(22.15±0.60)s,(19.89±1.27)s] (P<0.05).ROS+R与R组相比,术后2h PWTL[ (19.13±1.72)s,(14.41±2.30)s]及PWMT[(10.4±1.95)g,(6.38±0.91)g]开始升高,分别持续至48h[(19.24±2.80)s,(14.87±1.95)s]和24h[ (8.88±1.41)g,(6.83 ±0.80)g] (P<0.05).结论 Roscovitine能减轻大鼠切口引起的热痛敏,并能缓解瑞芬太尼诱发的切口痛大鼠痛觉过敏.%Objective To study the effects of intrathecal injection of cyclin dependent kinase 5 inhibitor Roscovitine on the hyperalgesia induced by remifentanil in a rat model of incisional pain.Methods Forty-five SD rats were randomly divided into 5 groups ( n =9 in each group):control group ( C ),incisional pain group ( Ⅰ ),Roscovitine group(ROS),remifentanil group(R) and Roscovitine + remifentanil group ( ROS + R).Roscovitine (50μg/10μl) was injected intrathecally at 30 min before plantar incision in groups ROS and ROS + R,other groups were injected with 20% DMSO(10μl).All groups except for C group needed to be made the model of incisional pain.In group R and ROS + R,remifentanil(0.04 mg/kg) was infused subcutaneously

  7. Analgesic tolerance without demonstrable opioid-induced hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain.

    Science.gov (United States)

    Chu, Larry F; D'Arcy, Nicole; Brady, Caitlin; Zamora, Abigail Kathleen; Young, Chelsea Anne; Kim, Julie Eunwoo; Clemenson, Anna Marie; Angst, Martin S; Clark, J David

    2012-08-01

    Although often successful in acute settings, long-term use of opioid pain medications may be accompanied by waning levels of analgesic response not readily attributable to advancing underlying disease, necessitating dose escalation to attain pain relief. Analgesic tolerance, and more recently opioid-induced hyperalgesia, have been invoked to explain such declines in opioid effectiveness over time. Because both phenomena result in inadequate analgesia, they are difficult to distinguish in a clinical setting. Patients with otherwise uncomplicated low-back pain were titrated to comfort or dose-limiting side effects in a prospective, randomized, double-blind, placebo-controlled clinical trial using sustained-release morphine or weight-matched placebo capsules for 1 month. A total of 103 patients completed the study, with an average end titration dose of 78 mg morphine/d. After 1 month, the morphine-treated patients developed tolerance to the analgesic effects of remifentanil, but did not develop opioid-induced hyperalgesia. On average, these patients experienced a 42% reduction in analgesic potency. The morphine-treated patients experienced clinically relevant improvements in pain relief, as shown by a 44% reduction in average visual analogue scale pain levels and a 31% improvement in functional ability. The differences in visual analogue scale pain levels (P = .003) and self-reported disability (P = .03) between both treatment groups were statistically significant. After 1 month of oral morphine therapy, patients with chronic low-back pain developed tolerance but not opioid-induced hyperalgesia. Improvements in pain and functional ability were observed.

  8. Electroacupuncture activates corticotrophin-releasing hormone-containing neurons in the paraventricular nucleus of the hypothalammus to alleviate edema in a rat model of inflammation

    Directory of Open Access Journals (Sweden)

    Berman Brian M

    2008-05-01

    Full Text Available Abstract Background Studies show that electroacupuncture (EA has beneficial effects in patients with inflammatory diseases. This study investigated the mechanisms of EA anti-inflammation, using a rat model of complete Freund's adjuvant (CFA-induced hind paw inflammation and hyperalgesia. Design Four experiments were conducted on male Sprague-Dawley rats (n = 6–7/per group. Inflammation was induced by injecting CFA into the plantar surface of one hind paw. Experiment 1 examined whether EA increases plasma adrenocorticotropic hormone (ACTH levels. Experiments 2 and 3 studied the effects of the ACTH and corticotropin-releasing hormone (CRH receptor antagonists, ACTH(11–24 and astressin, on the EA anti-edema. Experiment 4 determined whether EA activates CRH neurons in the paraventricular nucleus of the hypothalammus. EA treatment, 10 Hz at 3 mA and 0.1 ms pulse width, was given twice for 20 min each, once immediately post and again 2 hr post-CFA. Plasma ACTH levels, paw thickness, and paw withdrawal latency to a noxious thermal stimulus were measured 2 h and 5 h after the CFA. Results EA significantly increased ACTH levels 5 h (2 folds after CFA compared to sham EA control, but EA alone in naive rats and CFA alone did not induce significant increases in ACTH. ACTH(11–24 and astressin blocked EA anti-edema but not EA anti-hyperalgesia. EA induced phosphorylation of NR1, an essential subunit of the N-methyl-D-aspartic acid (NMDA receptor, in CRH-containing neurons of the paraventricular nucleus. Conclusion The data demonstrate that EA activates CRH neurons to significantly increase plasma ACTH levels and suppress edema through CRH and ACTH receptors in a rat model of inflammation.

  9. Thermal Clothing

    Science.gov (United States)

    1997-01-01

    Gateway Technologies, Inc. is marketing and developing textile insulation technology originally developed by Triangle Research and Development Corporation. The enhanced thermal insulation stems from Small Business Innovation Research contracts from NASA's Johnson Space Center and the U.S. Air Force. The effectiveness of the insulation comes from the microencapsulated phase-change materials originally made to keep astronauts gloved hands warm. The applications for the product range from outer wear, housing insulation, and blankets to protective firefighting gear and scuba diving suits. Gateway has developed and begun marketing thermal regulating products under the trademark, OUTLAST. Products made from OUTLAST are already on the market, including boot and shoe liners, winter headgear, hats and caps for hunting and other outdoor sports, and a variety of men's and women's ski gloves.

  10. Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity

    Directory of Open Access Journals (Sweden)

    Pauza Mary E

    2008-03-01

    Full Text Available Abstract A common complication associated with diabetes is painful or painless diabetic peripheral neuropathy (DPN. The mechanisms and determinants responsible for these peripheral neuropathies are poorly understood. Using both streptozotocin (STZ-induced and transgene-mediated murine models of type 1 diabetes (T1D, we demonstrate that Transient Receptor Potential Vanilloid 1 (TRPV1 expression varies with the neuropathic phenotype. We have found that both STZ- and transgene-mediated T1D are associated with two distinct phases of thermal pain sensitivity that parallel changes in TRPV1 as determined by paw withdrawal latency (PWL. An early phase of hyperalgesia and a late phase of hypoalgesia are evident. TRPV1-mediated whole cell currents are larger and smaller in dorsal root ganglion (DRG neurons collected from hyperalgesic and hypoalgesic mice. Resiniferatoxin (RTX binding, a measure of TRPV1 expression is increased and decreased in DRG and paw skin of hyperalgesic and hypoalgesic mice, respectively. Immunohistochemical labeling of spinal cord lamina I and II, dorsal root ganglion (DRG, and paw skin from hyperalgesic and hypoalgesic mice reveal increased and decreased TRPV1 expression, respectively. A role for TRPV1 in thermal DPN is further suggested by the failure of STZ treatment to influence thermal nociception in TRPV1 deficient mice. These findings demonstrate that altered TRPV1 expression and function contribute to diabetes-induced changes in thermal perception.

  11. 切口周围组织中白细胞介素-1β参与尼古丁戒断大鼠术后切口痛痛觉过敏的研究%Interleukin-1β in the surrounding incision tissues is involved in postoperative hyperalgesia in rats with nicotine withdrawal

    Institute of Scientific and Technical Information of China (English)

    逯素芬; 于爱兰; 刘献文; 张宗旺

    2014-01-01

    目的 探讨切口周围组织中白细胞介素(interleukin,IL)-1β在尼古丁戒断大鼠术后切口痛痛觉过敏中的作用.方法 SD大鼠96只,按随机数字表法分为4组:正常对照组(Naive组,6只)、尼古丁戒断组(NT组,30只)、切口痛组(IP组,30只)和尼古丁戒断切口痛组(NT+IP组,30只).NT组、IP组和NT+IP组大鼠按术前2h和术后2、24、48、72 h分为5个亚组,每个亚组6只.观察各组大鼠上述时间点机械刺激缩足阈值(paw mechanical withdrawal threshold,MWT)、热刺激缩足潜伏期(paw thermal withdrawal latency,TWL)和后爪水肿的变化;取大鼠术侧后爪切口周围皮肤组织,应用酶联免疫分析法检测IL-1β含量.结果 与IP组比较,NT+IP组大鼠术后2、24、48、72 h MwT和TWL均降低(P<0.05),且术侧后爪水肿明显,其中以术后24 h水肿最为显著(P<0.01).与IP组各时间点比较,NT+IP组大鼠相应时间点切口周围组织中IL-1β水平明显增高(P<0.01).与术前2 h(19.7±1.9) ng/L比较,NT+IP组大鼠切口周围组织中IL-1β水平术后各时间点均明显升高(P<0.01);术后2h(62.2±3.7) ng/L开始升高,至术后48 h(129.5±6.3) ng/L达高峰,术后72 h开始回降.结论 尼古丁戒断引起大鼠术后痛觉敏感性增高,局部水肿明显;IL-1β参与了尼古丁戒断大鼠术后切口痛痛觉过敏.%Objective To explore the contribution of interleukin (IL)-1β in surrounding incision tissues to postoperative hyperalgesia in rats with nicotine withdrawal.Methods Ninety-six SD rats were randomly divided into Naive group (n=6),NT group (n=30),IP group (n=30) and NT+IP group (n=30).The rats in NT group,IP group and NT+IP group were divided into 5 subgroups by preoperative 2 h,postoperative 2,24,48 h and 72 h,six in each subgroup.Both paw mechanical withdrawal threshold (MWT) and paw thermal withdrawal latency (TWL) were determined at above time points for every rats.The hind paw edema was also observed.The level of IL-1β in the

  12. Fentanyl induced hyperalgesia and upregulation of pro-inflammatory cytokines in dorsal root ganglions in ;rats%芬太尼可诱导大鼠痛觉过敏与背根神经节促炎因子过表达

    Institute of Scientific and Technical Information of China (English)

    常路; 叶芳; 舒海华; 杨琳; 黄文起

    2016-01-01

    目的:探索大剂量芬太尼诱导的痛觉过敏模型中,大鼠背根神经节促炎因子的表达。方法:64只雄性SD大鼠分为2组(n =32),皮下注射芬太尼60μg/kg或生理盐水共4次,每次注射间隔15 min。注射前1 d和注射后1、2、3、4 h及1~7 d对大鼠进行压尾机械伤害阈值(TFT)和足底热伤害潜时(PWL)测试。注射前1 d和注射后4 h及1、3、5、7 d每组选取4只大鼠处死,取腰段背根神经节(DRG),以酶联免疫吸附法测定前列腺素E2、白介素1-β、白介素6和肿瘤坏死因子α的表达。结果:对照组大鼠的行为学及DRG中促炎因子水平在各个时间点无统计学差异。实验组大鼠注射后1~4 h TFT及PWL值升高,1~3 d降低;DRG促炎因子在注射后1、3、5、7 d表达升高。结论:大剂量芬太尼可引起大鼠痛觉过敏及DRG促炎因子升高。促炎因子表达峰值延迟于痛觉过敏的表现,且持续更长时间,和痛觉过敏无直接相关。%Objective To investigate the expression of pro-inflammatory cytokines in lumbar dorsal root ganglions (DRG) of rats model of high-dose fentanyl induced hyperalgesia. Methods 64 male SD rats were divided into 2 groups (n = 32), fentanyl group and normal saline (NS) group. The rats were injected with fentanyl (60 μg/kg) or NS 4 times in total subcutaneously with a 15-minute interval. Mechanical and thermal nociception were measured via the tail pressure test (tail flick thresholds, TFT) and paw withdrawal test (paw withdrawal latency, PWL) at 1 day before, at 1, 2, 3 and 4 hour and on 1 ~ 7 day after administration. 4 rats were sacrificed and the lumbar DRG were harvested to analyze the expression of PGE2 , IL-1β, IL-6 and TNF-αvia ELISA. Results There were no significant changes of TFT, PWL and the expression of pro-inflammatory cytokines in DRG compared to baseline of rats in NS group. The value of TFT , PWL in fentanyl group were above the baseline

  13. Thermal insulator

    Energy Technology Data Exchange (ETDEWEB)

    Yamamoto, R.; Asada, Y.; Matsuo, Y.; Mikoda, M.

    1985-07-16

    A thermal insulator comprises an expanded resin body having embedded therein an evacuated powder insulation portion which consists of fine powder and a container of film-like plastics or a film-like composite of plastics and metal for enclosing the powder. The resin body has been expanded by a Freon gas as a blowing agent. Since a Freon gas has a larger molecular diameter than the constituent gases of air, it is less likely to permeate through the container than air. Thus present invention provides a novel composite insulator which fully utilizes the benefits of vacuum insulation without necessitating a strong and costly material for a vacuum container.

  14. Thermal Relativity

    Institute of Scientific and Technical Information of China (English)

    赵柳

    2011-01-01

    The group G of general coordinate transformations on the thermodynamic configuration space ε spanned by all the extensive variables keeps the first law of thermodynamics invariant. One can introduce a metric with Lorentzian signature on the space ε, with the corresponding line element also being invariant under the action of G. This line element is identi6ed as the square of the proper entropy. Thus the second law of thermodynamics is also formulated invariantly and this lays down the foundation for the principle of thermal relativity.

  15. Gabapentin reduces CX3CL1 signaling and blocks spinal microglial activation in monoarthritic rats

    Directory of Open Access Journals (Sweden)

    Yang Jia-Le

    2012-05-01

    Full Text Available Abstract Background Spinal glia, particularly microglia and astrocytes, are of the utmost importance in the development and maintenance of chronic pain. A recent study from our laboratory revealed that gabapentin, a recommended first-line treatment for multiple neuropathic conditions, could also efficiently antagonize thermal hyperalgesia evoked by complete Freund's adjuvant (CFA-induced monoarthritis (MA. In the present study, we investigated whether the spinal glia are involved in the anti-hyperalgesic effect of gabapentin and how this event occurs. Results Unilateral intra-articular injection of CFA produced a robust activation of microglia and astrocytes. These cells exhibited large cell bodies, thick processes and increases in the ionized calcium binding adapter molecule 1 (Iba-1, a microglial marker or the glia fibrillary acidic protein (GFAP, an astrocytic marker. These cells also displayed immunoreactive signals, and an upregulation of the voltage-gated calcium channels (VGCCs α2/δ-1 subunit, CX3CL1 and CX3CR1 expression levels in the spinal cord. These changes were associated with the development of thermal hyperalgesia. Immunofluorescence staining showed that VGCC α2/δ-1 subunit, a proposed gabapentin target of action, was widely distributed in primary afferent fibers terminals and dorsal horn neurons. CX3CL1, a potential trigger to activate microglia, colocalized with VGCC α2/δ-1 subunits in the spinal dorsal horn. However, its receptor CX3CR1 was mainly expressed in the spinal microglia. Multiple intraperitoneal (i.p. gabapentin injections (100 mg/kg, once daily for 4 days with the first injection 60 min before intra-articular CFA suppressed the activation of spinal microglia, downregulated spinal VGCC α2/δ-1 subunits decreased CX3CL1 levels and blocked the development of thermal hyperalgesia in MA rats. Conclusions Here we provide the first evidence that gabapentin diminishes CX3CL1 signaling and spinal microglia

  16. Analgesic effect of intra-amygdala infusion of U0126 on fentanyl-induced hyperalgesia in rats%杏仁核注射 U0126对芬太尼诱发大鼠痛觉过敏的镇痛效应

    Institute of Scientific and Technical Information of China (English)

    罗放; 尹平平; 李珍

    2016-01-01

    Objective To explore the role of extracellular signal-regulated kinase (ERK)in central nucleus of amygdala (CeA)in the mechanism of fentanyl-induced hyperalgesia (OIH)in rats. Methods Step 1:12 healthy male Sprague-Dawley rats,weighing 60-100 g,were randomly divided into OIH and Control group.The mechanical paw withdrawal threshold (PWT)and the thermal paw withdrawal latency (PWL)were tested at pre-and post-OIH induction.Then the level of p-ERK in the CeA was analyzed by Western blotting.Step 2:After successful induction of OIH and catheterization in CeA,another 30 SD male rats were randomly divided into 5 groups (n = 6 each):Group OIH;Group OIH+U0124;Group OIH+U0126(0.1 5 nmol);Group OIH+U0126(0.45 nmol)and Group OIH+U0126 (1.5 nmol),then 0.3 μl of DMSO,U0124 (1.5 nmol),U0126 (0.1 5 nmol,0.45 nmol,1.5 nmol)was given through the catheter separately.PWT and PWL were tested before cathe-terization,at pre-OIH induction,post-OIH induction and 0.5 h after CeA drug administration.After the last test of pain threshold,the rats were sacrificed and CeA tissues were sampled for analyzing the expression of p-ERK by western blot.Results In step 1 compared with control group,PWT and PWL of OIH group were sharply decreased post-OIH induction (P <0.05),concomitant increase of the expression of p-ERK in CeA in OIH group was also observed.In step 2,both PWT and PWL were sharply decreased post-OIH induction (P <0.05).Intra-CeA U0126 injection,but not U0124, reversed both behavioral hyperalgesia and molecular activation of ERK in CeA in a dose-dependent manner (P <0.05).Conclusion ERK plays a pivotal role in the maintenance of fentanyl-induced hy-peralgesia.Targeting inhibition of ERK activation in CeA can alleviate fentanyl-induced hyperalgesia.%目的:探讨杏仁核中央核(CeA)细胞外信号调节蛋白激酶(ERK)在芬太尼诱发痛觉过敏(OIH)发病机制中的作用。方法实验一:雄性 SD 大鼠12只,随机分为实验组(OIH 模型组)和对照组,OIH

  17. Role of p38MAPK signal transduction pathway in cerebral fractalkine-induced hyperalgesia in mice%p38MAPK信号转导通路在脑组织fractalkine诱发小鼠痛觉过敏中的作用

    Institute of Scientific and Technical Information of China (English)

    王爱桃; 武庆平; 姚尚龙; 徐建军; 袁世荧; 崔永武; 温树正; 邱颐

    2012-01-01

    .Anti-CX3CR1 1 μg and SB203580 1 μg were injected i.c.v.at 1 h before fractalkine injection in groups CF and SF respectively.Paw withdrawal latency to a thermal nociceptive stimulus (PWL) was measured at 30 min before the drugs were injected into cerebral lateral ventricle and 30,60,120 and 240 min after fractalkine injection.Five animals were sacrificed after PWL measurement at each time point and their brains were removed for determination of phosphorylated p38MAPK protein expression (by Western blot analysis).Five animals were sacrificed at 30 min before the drugs were injected into cerebral lateral ventricle and 6,12 and 24 h after fractalkine injection for determination of IL-1β and TNF-α contents in the brain (by ELISA) in all the 4 groups.In group F 5 animals were sacrificed at 4 h after fractalkine injection for determination of action of fractalkine on microglia or astrocyte (by immunofluorescence).Results Fractalkine i.c.v.injection significantly reduced PWL and increased phosphorylated 38MAPK,IL-1β and TNF-α levels in group F as compared with group C.Pretreatment with anti-CX3CR1 or SB203580 significantly decreased fractalkine-induced hyperalgesia and phosphorylated-p38MAPK,IL-1β and TNF-α levels in groups CF and SF as compared with group F.Fractalkine was localized at microglia.Conclusion p38MAPK signal transduction pathway is involved in cerebral fractalkine-induced hyperalgesia in mice.

  18. 大鼠切口痛模型中氯化锂对瑞芬太尼诱发痛觉过敏的影响%Effects of lithium chloride on remifentanil-induced hyperalgesia in rat model of incisional pain

    Institute of Scientific and Technical Information of China (English)

    王琛; 姚维娜; 马正良; 顾小萍

    2011-01-01

    RL1~3 groups were 36,9,18,36 mg/kg respectively,accordingly saline were administered intraperitoneally to group C,I and R. R greup and RL1~3 groups were pumped subcutaneously with remifentanil (40 μg/kg)at the speed of 0.8 ml/h at fifteen minutes after anesthesia with sevoflurane,while group C,I and IL were pumped subcutaneously with saline accordingly. All groups except C were made the model of incisional pain. At T0(24 hours before operation)and T1 (6 hours after operation), T2 (24 hours after operation ), T3 (48 h after operation)respectively, paw withdrawal thermal latency (PWTL) and paw mechanical withdrawal threshold(PMW) were detected on the rats' right hindpaw in all groups. Results:At T1,T2,T3,the PMW and PWTL were significantly lower in group R and significantly higher in group IL then those in group I(P < 0.05). Comparing with group R,the PMW and PWTL in RL groups were significantly higher (P < 0.05). Conclusion:In rat model of incisional pain,remifentanil could induce hyperalgesia on the area of adjacent to the incision;lithium chloride could increase the pain threshold of incision and prevent the remifentanil-induced hyperalgesia.

  19. Effects of dexmedetomidine on remifentanil-induced hyperalgesia in a rat model of incisional pain%大鼠切口痛模型中右美托咪定对瑞芬太尼诱发的痛觉过敏的影响

    Institute of Scientific and Technical Information of China (English)

    崔松勤; 吴晓丽; 姚维娜; 马正良; 顾小萍

    2010-01-01

    Objective To observe the effects of pretreatment of dexmedetomidine(DEX)on remifentanilinduced hyperalgesia in a rat model of incisional pain.Methods Sixty male SD rats were randomly divided into five groups:C group(control),I group(incisional pain),R group(remifentanil+incisional pain),ID group(incisional pain+DEX),RD group(remifentanil+incisional pain+DEX).ID and RD group were administered subcutaneously DEX 50μg/kg at ten minutes before anesthesia with sevoflurane.All groups except C group needed to be made the model of incisional pain.A 1 cm long incision was made through skin and fascia of the plantar aspect of the foot.The skin was apposed with 2 mattress sutures.At 24 hours before operation(T0),6 hours(T1),24 hours(T2)and 48 hours(T3)after operation respectively.Paw Withdrawal Thermal latency(PWTL)and Paw Mechanical Withdrawal Threshold(PMW)were detected on the rats' right hind paw in all groups.Results At T1,T2,T3,compared with I group((7.70±0.67)g,(10.79±1.83)g,(10.97±1.87)g),the PMW of R group ((3.72±0.71)g,(6.54±1.27)g,(7.27±1.53)g)were significantly longer(P<0.05);compared with I group((20.74±2.72)s,(16.56±1.38)s,(22.55±2.01)s),the PWTL of R group((11.81±2.52)s,(11.27 ±2.30)s,(12.30±2.21)s)were significantly longer(P<0.05).Compared with I group,the PMW of ID group were only significantly longer(P<0.05)at T1((11.57±2.48)g).Compared with R group,the PMW of RD group were significantly longer at T1((14.03±1.01)g),T2((14.27±1.33)g),T3((14.26±1.58)g)(P<0.05)and the PWTL of RD group were significantly longer at T1((23.56±1.53)s),T2((16.54±3.24)s)(P<0.05).Conclusion In a rat model of incisional pain,remifentanil could induce hyperalgesia,and dexmedetomidine could prevent the remifentanil-induced hyperalgesia.%目的 研究大鼠切口痛模型中右美托咪定(DEX)对瑞芬太尼诱发的痛觉过敏的影响.方法 60只雄性SD大鼠随机均分成5组:对照组(C),切口痛组(I),切口痛+瑞芬太尼组(R),切口痛+DEX组(ID

  20. Thermal conductivity of thermal-battery insulations

    Energy Technology Data Exchange (ETDEWEB)

    Guidotti, R.A.; Moss, M.

    1995-08-01

    The thermal conductivities of a variety of insulating materials used in thermal batteries were measured in atmospheres of argon and helium using several techniques. (Helium was used to simulate the hydrogen atmosphere that results when a Li(Si)/FeS{sub 2} thermal battery ages.) The guarded-hot-plate method was used with the Min-K insulation because of its extremely low thermal conductivity. For comparison purposes, the thermal conductivity of the Min-K insulating board was also measured using the hot-probe method. The thermal-comparator method was used for the rigid Fiberfrax board and Fiberfrax paper. The thermal conductivity of the paper was measured under several levels of compression to simulate the conditions of the insulating wrap used on the stack in a thermal battery. The results of preliminary thermal-characterization tests with several silica aerogel materials are also presented.

  1. CEQATR Thermal Test Overview

    Science.gov (United States)

    Balusek, Alan R.

    2009-01-01

    A thermal test overview of the Constellation Environmental Qualification and Acceptance Test Requirement (CEQATR) is presented. The contents include: 1) CEQATR Thermal Test Overview; 2) CxP Environments; 3) CEQATR Table 1.2-1; 4) Levels of Assembly; 5) Definitions for Levels of Assembly; 6) Hardware Applicability; 7) CEQATR Thermal-Related Definitions; 8) Requirements for unit-level thermal testing; 9) Requirements for major assembly level thermal testing; 10) General thermal testing requirements; 11) General thermal cycle, thermal vacuum profiles; 12) Test tolerances; 13) Vacuum vs Ambient; 14) Thermal Gradient; 15) Sequence of Testing; 16) Alternative Strategies; 17) Protoflight; 18) Halt/Hass; 19) Humidity; and 20) Tailoring.

  2. Seasonal thermal energy storage

    Energy Technology Data Exchange (ETDEWEB)

    Allen, R.D.; Kannberg, L.D.; Raymond, J.R.

    1984-05-01

    This report describes the following: (1) the US Department of Energy Seasonal Thermal Energy Storage Program, (2) aquifer thermal energy storage technology, (3) alternative STES technology, (4) foreign studies in seasonal thermal energy storage, and (5) economic assessment.

  3. Interference of age and repetition of the same noxious stimulus on hyperalgesia Interferência da idade e repetição do mesmo estímulo doloroso na hiperalgesia

    Directory of Open Access Journals (Sweden)

    Jose F. Ibañez

    2010-09-01

    Full Text Available Pain in animals has been recognized for less than one century. Several authors confirm that animals are capable to process, register and modulate nociceptive stimuli in a very similar way to human kind and there are several evidences registering the impact of pain sensation over vital systems interfering on disease outcome. Nevertheless, despite some evidences that animals, as human beings, can store information from past painful experiences less is known about how this so called pain memory works. The aims of this study were: to evaluate if the response to a painful stimuli differs during different stages of life and if repetition of a same acute stimuli in the same animal interferes with expression of hyperalgesia. Thus, 60 rats were selected and arranged in 3 equal groups: 3 months, 6 months, and 9 months of age. All animals were injected 5% formalin solution in the plantar face of hind paw under volatile general anesthesia. Von Frey filaments were applied at 1h, 24h and 48h after sensitization. Injection was repeated twice with a 30-day interval, each time in a different hind paw. Results showed that younger rats express lower hyperalgesia thresholds in the first stimulation compared to elder animals and that repetition of same stimulus diminishes hyperalgesia thresholds when it begins during infant period and augments hyperalgesia thresholds when it begins during elder ages.A dor nos animais tem sido reconhecida há pouco manos de um século. Vários autores reconhecem que os animais são capazes de processar, registrar e modular estímulos nociceptivos de modo muito similar aos seres humanos e há várias evidências registrando o impacto da sensação dolorosa sobre os sistemas vitais e curso da doença. Entretanto, a despeito das evidências de que os animais, como os seres humanos, podem armazenar informações passadas de experiências dolorosas pouco se sabe sobre como a chamada memoria de dor funciona. Os objetivos deste estudo foram

  4. The role of peroxynitrite in opioid tolerance or opioid induced hyperalgesia%过氧亚硝酸阴离子引起阿片耐受或痛觉过敏的研究进展

    Institute of Scientific and Technical Information of China (English)

    王春艳; 王国林

    2014-01-01

    背景 吗啡等阿片类药物是临床疼痛治疗的代表性药物,主要用于急、慢性疼痛和癌痛的治疗,但长期应用可产生诸多副作用,如吗啡耐受和痛觉过敏等,从而大大限制了阿片类药物在临床上的使用. 目的 通过对近年过氧亚硝基阴离子在吗啡耐受和痛觉过敏中所起作用的研究进行总结,帮助读者了解国外相关研究的最新趋势和进展. 内容 就过氧亚硝基阴离子的生成途径、消除方式和过氧亚硝基阴离子在阿片耐受或痛觉过敏中的作用方式进行综述.得出如下结论,过氧亚硝基阴离子主要通过硝基化体内蛋白质酪氨酸残基、激活神经炎症和促进细胞凋亡3个方面,引起阿片耐受或痛觉过敏. 趋向 随着越来越多的学者对过氧亚硝基阴离子在吗啡耐受和痛觉过敏中发挥的重要作用达成共识,过氧亚硝基阴离子有望成为临床疼痛治疗的新靶点.%Background Opioids are the most powerful analgesics for the treatment of acute pain,chronic pain and cancer pain.Although opioids have analgesic effect,long term opioids exposure can induce many side effects including morphine tolerance and hyperalgesia.The use of opioids,therefore,is largely limited in clinical settings.Objective The relevant literatures in recent years involved in the role of peroxynitrite in morphine tolerance and hyperalgesia were summarized,which helps readership to update the latest information about this topic.Content The generation of peroxynitrite,eliminating methods and the role of peroxynitrite in opioids tolerance or hyperalgesia were reviewed in this article.Those researches suggest that peroxynitrite plays an important role in morphine tolerance and hyperalgesia mainly through nitrating protein tyrosine residues,activating the neuroinflammation and promoting neuron apoptosis.Trend Since the effect of peroxynitrite is widely acknowledged,peroxynitrite may become a new target to relieve pain in

  5. 己酮可可碱对大鼠趾部切口术后痛觉过敏镇痛效应的实验观察%Effects of pentoxifylline of prior intraperitoneal administration on the plantar incision -induced hyperalgesia in rats

    Institute of Scientific and Technical Information of China (English)

    徐旭; 石翊飒; 汪静; 王红; 刘志龙; 李雅楠; 张荣智

    2012-01-01

    ) injection of prior intraperitoneal administration applied on the plantar incision-induced postoperative hyperalgesia in rats. Methods The postoperative pain rats model with plantar incision were used for this experiment.All sixty adult male Sprague-Dawley rats weighting 180 g-250 g were randomly divided into two groups:single-dose group (group Ⅰ ) and the continuous treatment group (group Ⅱ ).The group Ⅰ was divided into 5 subgroups (n=6):control group (group C) was given normal saline (NS),PTX treatment groups (group PTX1-4) were given 12.5,25,50,100 mg/kg PTX by single time intraperitoneal administration.Group Ⅱ was divided into 5 subgroups (n=6):control group (group C) was given NS,pentoxifylline treatment groups (group PTX1-4) were administered PTX (12.5,25,50,100 mg/kg intraperitoneally) systemically daily.In the preoperative 30 min,all subgroups of the group Ⅰ were given different doses of PTX intraperitoneally and the corresponding volume of NS,and measured at each time point of the mechanical withdrawal threshold (MWT),thermal withdrawal latency and withdrawal duration at pre-incision (T0),then 1,3,5 h after surgery (T1-3).From 30 min before the operation to day1-7 post-operation,all subgroups of the group Ⅱ were systemically daily intraperitoneally administrated different doses of PTX and the corresponding volume of NS,and measured at each time point of the mechanical withdrawal threshold (MWT),thermal withdrawal latency and withdrawal duration at pre-incision (T0),then 1,2,3,5,7 d after surgery (T1-6).Results ① Comparison in the groups:in group Ⅰ,MWT was higher at T1 than at T2 in group PTX3,4 (P<0.05 or P<0.01 ).Compared with them in group PTX3,4 at T3,MWT was increased at T1-2,and thermal withdrawal latency threshold was increased too,following thermal withdrawal duration reduced at T1(P<0.05 or P<0.01 ).② Comparison between groups:in group Ⅰ,compared with group C,MWT was significantly raised at T1-2 in group PTX3,4.Furthermore,thermal

  6. Dexmedetomidine blocks hyperalgesia and dorsal root ganglia ERK signal activation in a rat model of neuropathic pain%右美托咪定缓解神经病理性疼痛大鼠的痛觉过敏并抑制背根神经节内p-ERK信号通路的激活

    Institute of Scientific and Technical Information of China (English)

    曹铭辉; 何惠燕; 纪风涛; 刘玲; 刘付宁; 刘安民; 李方成

    2011-01-01

    目的 观察重复腹腔注射右美托咪定(DEX)对神经病理性疼痛大鼠的痛觉过敏和背根神经节(DRG)中ERK信号通路激活的影响.方法 给坐骨神经部分结扎(PSNL)神经病理性疼痛大鼠重复腹腔注射不同剂量的DEX.观察各组大鼠的机械、热痛觉过敏阈值.行为学测试完成后用免疫荧光和Western blot方法检测大鼠手术侧L5 DRG中p-ERK的表达.结果 (1)腹腔注射DEX 40 μg/kg 7、14 d均明显减轻PSNL诱导的机械、热痛觉过敏(P<0.05).而腹腔注射DEX20μg/kg对PSNL大鼠疼痛行为学无明显影响.(2)重复腹腔注射40μg/kg DEX 7、14 d p-ERK的平均荧光强度比同一时间点的PSNL组明显减弱(P<0.05),但仍明显高于对照组(P<0.05).重复腹腔注射20μg/kg对PSNL大鼠p-ERK的平均荧光强度无明显影响(P>0.05).(3)Westem blot 结果显示重复腹腔注射40μg/kg DEX 7、14 d明显抑制PSNL诱导的p-ERK的蛋白表达增多(P<0.05).重复腹腔注射20μg/kg对PSNL大鼠p-ERK的蛋白表达无明显影响(P>0.05).结论 重复腹腔注射DEX能够减轻神经损伤引起的痛觉过敏,抑制外周初级感觉神经系统中ERK信号通路的激活可能是其缓解的疼痛症状的机制之一.%Objective To investigate the effect of systemic administration of dexmedetomidine, a selective alpha 2 adrenergic receptor agonist, on mechanical and thermal hyperalgesia and dorsal root ganglia ERK activation induced by neuropathic pain. Methods Intraperitoneal injection of dexmedetomidine was repeatedly given once daily for 7 days or 14 days with the first injection one day before partial sciatic nerve ligation ( PSNL) surgery. Mechanical and thermal nociceptive thresholds were assessed in all animals. Then, animals were killed at corresponding time points, and the L5 DRG was removed for L5 DRG ERK activation status analysis by using immunoflurecence and Western blotting. Results (1) Partial sciatic never ligation produced a robust mechanical and

  7. 脊髓背角神经元上调Nav1.8通道参与缺血再灌注损伤后痛觉过敏的机制%Mechanisms of ischemia-reperfusion induced hyperalgesia via up-regulation of neu-ronal Nav1. 8 channel in spinal dorsal horn

    Institute of Scientific and Technical Information of China (English)

    李晓倩; 张再莉; 马虹

    2016-01-01

    Objective To observe the effects of intrathecal injection (IT) of Nav1. 8 channel inhibitor 619C89 on hyperalgesia and spinal cord levels of neuronal Nav1. 8 expressions in rat model of spinal cord ischemia-reperfusion injury ( SCIRI) . Methods Male Sprague-Dawley rats were randomly divided into three groups:group S, group H (SCIRI+IT NS) and Nav1. 8 channel inhibitor group (group I,SCIRI+IT 5 μg/30 μL 619C89). The lumbar intrath-ecal catheters were implanted in L5-6 of rats and SCIRI models were established by aortic arch occlusion for 14 min. The thermal and mechanical nociceptive thresholds were assessed by paw withdrawal latency ( PWL ) to radiant heat and von Frey filaments. The 619C89 was administered intrathecally for 3 days before surgery. The spinal mRNA expression of Nav1. 8 was assessed by Real time-PCR and double immunofluorescence staining was performed for examination of the distribution of neurons and Nav1. 8 and also quantification of NeuN/Nav1. 8 positive cells of dorsal horn at 1,3,5, 7 and 14 days after surgery. Results Compared with group S,animals in group H had significantly lower mechanical and thermal pain thresholds,but higher spinal mRNA expression of Nav1. 8 ( P<0. 05 ) . Rats in group I had signifi-cantly higher mechanical and thermal pain thresholds and significantly lower mRNA expression of Nav1. 8 compared with those in group H (at any observed time points after IR,but most significantly at 7 days,P<0. 05). Double fluo-rescent staining showed the distribution of increased fluorescence intensity of Nav1. 8 was similar to that of fluorescent staining of NeuN ( neuronal marker) . The number of NeuN/Nav1. 8 positive cells was greatly increased in group H, whereas the number was obviously decreased in group I ( P<0. 05 ) . Conclusion Up-regulation of neuronal Nav1. 8 channel in spinal dorsal horn plays a role in IR-induced hyperalgesia.%目的:观察鞘内注射钠通道抑制剂619C89对脊髓缺血再灌注损伤引起的痛觉过

  8. Role of calcium/calmodulin-dependent kinase Ⅱ alpha in central nucleus of amygdale in fentanyl-induced hyperalgesia in rats: the relationship with mEPSCs%中央杏仁核钙/钙调素依赖性蛋白激酶Ⅱα在芬太尼诱发大鼠痛觉过敏中的作用:与mEPSCs的关系

    Institute of Scientific and Technical Information of China (English)

    李珍; 王忠三; 罗放

    2016-01-01

    Objective To evaluate the role of calcium/calmodulin-dependent kinase Ⅱ alpha (CaMK Ⅱα) in the central nucleus of the amygdale (CeA) in fentanyl-induced hyperalgesia in rats and the relationship with miniature excitatory postsynaptic currents (mEPSCs).Methods Thirty-two male Sprague-Dawley rats,weighing 50-80 g,in which the CeA was successfully cannulated,were randomly divided into 4 groups (n=8 each) using a random number table:control 1 group (group C1),fentanylinduced hyperalgesia 1 group (group FIH1),KN92 group,and KN93 group.Normal saline was injected subcutaneously,and dimethyl sulfoxide (DMSO) was given into the amygdale in group C1.In group FIH1,fentanyl was injected subcutaneously (60 μg/kg per time,4 times in total,15-min interval,cumulative dose of 240 μg/kg) to establish the model of hyperalgesia.In KN92 and KN93 groups,KN92 and KN93 10 nmol were given into the CeA after establishing the model.The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal threshold (TWT) were measured at 6 and 7 h after fentanyl or normal saline injection.Another 12 Sprague-Dawley rats were selected and randomly divided into either control 2 group (group C2) or fentanyl-induced hyperalgesia 2 group (group FIH2) using a random number table with 6 rats in each group.The brains were removed and sliced 12 h later,and the frequency and amplitude of mEPSCs were recorded.KN93 10 nmol was then added to the artificial cerebral spinal fluid,and the frequency and amplitude of mEPSCs were recorded by whole cell patch-clamp technique.Results Compared with group C 1,the MWT and TWT were significantly decreased at 6 h after fentanyl or normal saline injection in FIH1,KN92 and KN93 groups,and at 7 h after fentanyl or normal saline injection in FIH and KN92 groups (P<0.05).Compared with group FIH1,the MWT and TWT were significantly increased at 7 h after fentanyl or normal saline injection in group KN93 (P<0.05),and no significant change was found in group KN92 (P

  9. Battery Thermal Characterization

    Energy Technology Data Exchange (ETDEWEB)

    Keyser, Matthew; Saxon, Aron; Powell, Mitchell; Shi, Ying

    2016-06-07

    This poster shows the progress in battery thermal characterization over the previous year. NREL collaborated with U.S. DRIVE and USABC battery developers to obtain thermal properties of their batteries, obtained heat capacity and heat generation of cells under various power profiles, obtained thermal images of the cells under various drive cycles, and used the measured results to validate thermal models. Thermal properties are used for the thermal analysis and design of improved battery thermal management systems to support achieve life and performance targets.

  10. Effects of intrathecal injection of different dose of protein kinase B inhibitor Ⅳ on hyperalgesia induced by remifentanil%鞘内注射不同浓度蛋白激酶B抑制剂Ⅳ对瑞芬太尼痛觉过敏的影响

    Institute of Scientific and Technical Information of China (English)

    隽立芹; 马正良; 顾小萍

    2014-01-01

    Objective To investigate the role and mechanism of protein kinase B (Akt) in opioid-induced hyperalgesia (OIH) with an incisional pain model.Methods Sixty C57BL/6 male mice were randomly divided into 5 groups (n=12):incision pain+ dimethyl sulfoxide(DMSO) group(group Ⅰ),incision pain+remifentanil+DMSO group(group R),Akt inhibitor Ⅳ 0.08 μg/10 μl group(group A1),Akt inhibitor Ⅳ 0.16 μg/10 μl group(group A2) and Akt inhibitor Ⅳ 0.32 μg/10 μl group(group A3).DMSO was the solvent of Akt inhibitor Ⅳ.Incisional pain model was made in the right paw of all the mice.In group R and group A1,A2,A3,subcutaneous remifentanil(0.04 mg/kg) was infused for 30 min while the surgery was being performed and intrathecal 10 μl DMSO(10%) with corresponding concentration of the Akt inhibitor Ⅳ 10 μl was injected respectively.The paw mechanical withdrawal threshold (PMWT) and the paw withdrawal thermal latency(PWTL) was tested at 1 d(T0) before and 6 h(T1),1(T2),2(T3),3(T4),5(T5),7 d(T6) after surgery.Results Compared with group Ⅰ and the baseline value,PMWT and PWTL were significantly decreased after surgery except 7 d in group R and all group A(P<0.05).Compared with group R,PMWT[(5.03±0.62),(6.10±0.86),(5.92±0.88),(6.01±1.02) g.(4.07±0.79),(4.73±0.48),(4.77±0.59),(4.86±0.56) g.(5.05±0.75),(5.99±0.63),(5.99±0.71),(6.00±0.81) g] and PWTL[(0.48±0.06),(0.60±0.08),(0.61±0.07),(0.58±0.04) s.(0.38±0.07),(0.50±0.08),(0.48±0.06),(0.45±0.08) s.(0.37±0.09),(0.52±0.09),(0.49±0.12),(0.58±0.21) s] were significantly increased after surgery except 7 d in groups A1,A2,A3 (P<0.05).While there was no significant difference among group A1,A2 and A3 (P>0.05).Conclusions Intrathecal injection of different doses of Akt inhibitor Ⅳ effectively alleviates hyperalgesia induced by remifentanil in non-dose-dependent way.%目的 通过观察鞘内注射不同浓度的蛋白激酶B(protein kinase B,Akt)抑制剂Ⅳ对切口痛瑞芬太尼痛觉过敏小鼠痛

  11. Introduction to thermal transport

    Directory of Open Access Journals (Sweden)

    Simon R. Phillpot

    2005-06-01

    Full Text Available The relentless increase in the thermal loads imposed on devices and materials structures is driving renewed interest among materials scientists and engineers in the area of thermal transport. Applications include thermal barrier coatings on turbine blades, thermoelectric coolers, high-performance thermal transfer liquids, and heat dissipation in microelectronics. These, and other applications, demand not only ever more efficient thermal management, but also a better fundamental understanding of the underlying physical mechanisms.

  12. Dynamic thermal environment and thermal comfort.

    Science.gov (United States)

    Zhu, Y; Ouyang, Q; Cao, B; Zhou, X; Yu, J

    2016-02-01

    Research has shown that a stable thermal environment with tight temperature control cannot bring occupants more thermal comfort. Instead, such an environment will incur higher energy costs and produce greater CO2 emissions. Furthermore, this may lead to the degeneration of occupants' inherent ability to combat thermal stress, thereby weakening thermal adaptability. Measured data from many field investigations have shown that the human body has a higher acceptance to the thermal environment in free-running buildings than to that in air-conditioned buildings with similar average parameters. In naturally ventilated environments, occupants have reported superior thermal comfort votes and much greater thermal comfort temperature ranges compared to air-conditioned environments. This phenomenon is an integral part of the adaptive thermal comfort model. In addition, climate chamber experiments have proven that people prefer natural wind to mechanical wind in warm conditions; in other words, dynamic airflow can provide a superior cooling effect. However, these findings also indicate that significant questions related to thermal comfort remain unanswered. For example, what is the cause of these phenomena? How we can build a comfortable and healthy indoor environment for human beings? This article summarizes a series of research achievements in recent decades, tries to address some of these unanswered questions, and attempts to summarize certain problems for future research.

  13. 鞘内注射巴氯酚对神经病理性痛大鼠的镇痛作用及其对脊髓GABA转运体-1的影响%Effects of intrathecal injection of GABAB receptor agonist baclofen on hyperalgesia and spinal GAT-1 of neuropathic rats

    Institute of Scientific and Technical Information of China (English)

    朱珊珊; 谭珊珊; 曾因明

    2011-01-01

    目的 研究鞘内注射GABAB受体激动剂巴氯酚(baclofen,Bac)对神经病理性痛大鼠的镇痛作用及其对脊髓GABA转运体-1的影响.方法 建立坐骨神经结扎致神经病理性痛大鼠模型.在行为学实验部分,将32只大鼠随机分为NS组、Bac1组、Bac2组、Bac3组(n=8),分别鞘内注射生理盐水、0.1、0.3、1.0 μg巴氯酚10 μl,并分别于给药前、给药后0.5、1、2、4、8、12、24 h测定大鼠机械缩足反射阈值(mechanical withdrawl threshold,MWT)和热缩足反射潜伏期(thermal withdrawl latency,TWL)以及运动功能.在第2部分,将大鼠分为 NS组与Bac组,鞘内分别给予0.3 μg巴氯酚或生理盐水,分别于给药前、给药后1、4、8 h取大鼠脊髓腰段,免疫组织化学检测脊髓节段GAT-1免疫阳性神经元(n=6);分别于给药前、给药后30 min、1、2、4、8、12和24 h取大鼠脊髓腰段,用Western blot方法测定脊髓节段GAT-1蛋白含量(n=4).结果 鞘内注射巴氯酚后0.5~2 h,Bac1组、Bac2组与Bac3组大鼠MWT和TWL均较NS组明显升高(P0.05).结论 鞘内注射GABAB受体激动剂巴氯酚可减轻坐骨神经结扎致神经病理性痛大鼠的痛觉过敏,其镇痛作用可能与抑制脊髓水平GAT-1的表达有关.%Aim To explore the effects of intrathecal injection of GABAB receptor agonist baclofen on hyperalgesia and spinal GAT-I of neuropathic rats induced by chronic constriction of sciatic nerve. Methods The left common sciatic nerve of anesthetized rats was tied loosely to establish the chronic constriction injury CCI ) model. For the behavioral experiments, 32 rats exhibiting neuropathic pain after nerve ligation were divided into 4 groups ( n =8 ): NS group, Bacl group,Bac2 group and Bac3 group, which were intrathecally injected with normal saline, 0. 1 . 0. 3 and 1. 0 μg baclofen respectively. MWT ( mechanical withdrawl threshold )and TWL( thermal withdrawl latency ) were recorded before drug administration, 0. 5 . 1, 2. 4, 8,12 h

  14. Effects of CaMK Ⅱ inhibitor KN93 on remifentanil-induced hyperalgesia%鞘内注射钙调蛋白依赖性蛋白激酶Ⅱ抑制剂KN93对瑞芬太尼痛觉过敏大鼠痛行为的影响

    Institute of Scientific and Technical Information of China (English)

    程崇学; 张兢; 马正良; 顾小萍

    2012-01-01

    目的 观察鞘内注射钙调蛋白依赖性蛋白激酶Ⅱ( CaMKⅡ)抑制剂KN93对瑞芬太尼痛觉过敏大鼠痛行为的影响.方法 SD雄性大鼠60只按随机数字表法分为5组:空白对照组(C组,n=12)、切口痛(Ⅰ组,n=12)、瑞芬组(R组,n=12)、二甲基亚砜组(DMSO组,n=12)以及KN93组(n=12).除空白对照组外均做切口痛模型,瑞芬组、DMSO组及KN93组切皮同时经皮下泵注瑞芬太尼(0.04 mg/kg,1 mg溶于40 ml生理盐水)30 min.DMSO组及KN93组术前30 min分别鞘内给予10% DMS0 20μl和KN9320μl(50 μg溶于20 μl 10% DMSO中).各组分别在术前24h及术后2h、6h、24h、48h检测术侧热缩足潜伏期(Paw withdrawal thermal latency,PWTL)及机械缩足阈值(Paw mechanical withdrawal threshold,PMWT).结果 与C组相比,Ⅰ组术后各时间点PWTL[( 11.24 ±0.69)s,(10.36±0.29)s,(11.29±1.12)s,(12.21±0.75)s]及PMWT[ (25.5±1.20)s,(24.92±1.98)s,( 25.47±1.54)s,(27.14±1.04)s]明显降低(P<0.05);与Ⅰ组相比,R组术后PWTL[(8.48±0.72)s,(8.58±0.45)s,(8.46±0.92)s,(9.07±0.79)s]及PMWT[ (21.2±2.42)s,(19.58±1.12)s,(21.87±1.56)s,(22.26±1.64)s]明显降低(P<0.05);与R组相比,KN93组术后各点PWTL[( 13.32±0.73)s,(11.79±0.32)s,(11.86±0.98)s,(12.76±0.82)s]及PMWT[ (29.75±1.38)s,(28.27±1.16)s,(26.5±1.02)s,(27.79±1.22)s]明显升高(P<0.05).结论 鞘内注射KN93能够缓解瑞芬太尼诱发的痛觉过敏.%Objective To study the effects of intrathecal injection of CaMK Ⅱ inhibitor KN93 on the hyperalgesia induced by remifentanil in a incision pain model.Methods Sixty SD rats were divided randomly into 5 groups ( n =12):C group (control) ; (I) group ( incision pain ) ; R group ( incision pain + remifentanil ) ; DMSO group ( incision pain + remifentanil + DMSO) and KN93 group ( incision pain + remifentanil).In group R,DMSO and KN93,remifentanil (0.04 mg/kg,1 mg remifentanil was dissolved in 40 ml NS ) needed to be infused subcutaneously 30 min at the moment of surgery

  15. The effect of remifentanil-induced hyperalgesia by different dose of μ-receptor antagonist CTOP%不同剂量μ受体拮抗剂CTOP对瑞芬太尼诱发痛觉过敏的影响

    Institute of Scientific and Technical Information of China (English)

    师瑾; 薛朝霞; 胡古月; 吕晓敏; 张鹏

    2013-01-01

    目的 观察不同剂量的CTOP对瑞芬太尼引起的切口痛大鼠痛觉过敏的影响.方法 采用完全随机法将30只SD雄性大鼠随机为5组(每组6只):正常组(A组);切口痛组(B组);切口痛+瑞芬太尼组(C组);切口痛+瑞芬太尼+CTOP低剂量组(D组);切口痛+瑞芬太尼+CTOP高剂量组(E组).测定各组大鼠基础状态下(T0)的热缩足反射潜伏期(pawwithdrawal thermal latency,PWTL)后,以5%水合氯醛350 mg/kg大鼠腹腔麻醉,A、B、C组尾静脉注射生理盐水0.4 ml,D、E组分别注射CTOP 0.5 μg/kg、0.5 mg/kg,溶于0.4 ml生理盐水内.给药结束10 min后,除A组外全部于右后爪做切口,同时由尾静脉以0.8 ml/h的速度40 μg/kg的剂量分别给A、B组泵生理盐水,C、D、E组泵瑞芬太尼,各30 min.术后2(T1)、24 h(T2)测定PWTL,处死大鼠取脊髓,用酶联免疫法(ELISA)测定强啡肽表达. 结果 T1、T2时间点C组PWTL结果[(10.2±3.0)、(6.2±2.6)s]与A组[(13.3±2.4)、(13.4±2.2)s]、B组[(13.5±2.7)、(11.5±4.1)s]比较,差异有统计学意义(P<0.05),PWTL时间缩短;且C组强啡肽结果(172±17) ng/L与A、B组(78±9)、(120±10) ng/L比较,差异有统计学意义(P<0.05),强啡肽表达增多;D、E两组T2的PWTL值和强啡肽结果与C组比较,差异均有统计学意义,PWTL时间延长,强啡肽表达减少;D、E两组强啡肽表达比较,差异有统计学意义(P<0.05). 结论 在大鼠切口痛模型中,瑞芬太尼导致了切口周围组织痛觉过敏;应用μ受体拮抗剂可以缓解痛觉过敏,低剂量的效果更加显著.%Objective To investigate the effect of different dose of μ-receptor antagonist CTOP on remifentanil-induced hyperalgesia in incisional pain rat model by observing rats' paw withdrawal thermal latency (PWTL)and the dynorphin expression in spinal cord.Methods Thirty male SD rats were randomly divided into 5 groups (n=6):control group (A),incisional pain group (B),incisional pain +remifentanil group (C),incisional pain

  16. Thermal diffusivity effect in opto-thermal skin measurements

    Energy Technology Data Exchange (ETDEWEB)

    Xiao, P; Imhof, R E [Faculty of ESBE, London South Bank University, 103 Borough Road, London SE1 0AA (United Kingdom); Cui, Y [Sunrise Systems Limited, Flint Bridge Business Centre, Ely Road, Waterbeach, Cambridge CB5 9QZ (United Kingdom); Ciortea, L I; Berg, E P, E-mail: xiaop@lsbu.ac.u [Biox Systems Ltd, 103 Borough Road, London SE1 0AA (United Kingdom)

    2010-03-01

    We present our latest study on the thermal diffusivity effect in opto-thermal skin measurements. We discuss how thermal diffusivity affects the shape of opto-thermal signal, and how to measure thermal diffusivity in opto-thermal measurements of arbitrary sample surfaces. We also present a mathematical model for a thermally gradient material, and its corresponding opto-thermal signal. Finally, we show some of our latest experimental results of this thermal diffusivity effect study.

  17. 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...

  18. Effect and mechanism of the co-regulation of HCN2-GLT-1 on the spinal cord level of the visceral nociception and hyperalgesia following exposure to posttraumatic stress disorder-like stress in rats

    Directory of Open Access Journals (Sweden)

    Lei JI

    2014-10-01

    Full Text Available Objective To explore the potential role of HCN2-GLT-1 [hyperpolarization-activated cyclic nucleotide-gated (HCN-2 channel and astrocytic glutamate transporter 1 (GLT-1] in co-mediating visceral hyperalgesia at the spinal cord level following exposure to PTSD (posttraumatic stress disorder-like stress in rats. Methods Adult female SD rats were randomly divided into normal control group (n=14, PTSD group (n=15 and PTSD+CTX group [pretreated with ceftriaxone (CTX, n=15]. The animal model of PTSD was reproduced by using single-prolonged stress (SPS combined with electric shock. The alteration of visceral sensitivity was evaluated by measuring the viscero-motor response (VMR to graded colorectal distension (CRD 7 days after PTSD. The transcription of the gene encoding the GLT-1 was selectively induced by CTX to up-regulate the GLT-1 expression. The expression of spinal HCN2 and the effect of CTX on it were evaluated by immunofluorescence. Results HCN2 expression increased significantly in the spinal cord within 7 days after the exposure to PTSD as compared with that of control group (78.05±6.49 vs 121.12±4.85, P<0.001. The expression of HCN2 significantly decreased when being treated with CTX (121.12±4.85 vs 98.24±5.86, P=0.012. HCN2 expression significantly increased in PTSD+CTX group compared with that of the control group (78.05±6.49 vs 98.24±5.86, P=0.024. The value of AUCVMR in PTSD group (0.2913±0.0229 was obviously higher than that in PTSD+CTX group (0.2175±0.0090 when the pressure of CRD was 20 mmHg (P=0.005. When the pressure was changed into 40 mmHg and 60 mmHg, the values of AUCVMR in PTSD group (0.6200±0.0278, 0.7663±0.0262 respectively were significantly higher than those in normal control group (0.3786±0.0155, 0.5271±0.0212, respectively, P<0.001 and PTSD+CTX group (0.5038±0.0336, 0.6400±0.0245, respectively, P=0.006, or P=0.001. Conclusions CTX may exert an effect by directly up-regulating the expression of GLT-1

  19. 曲马多抑制瑞芬太尼致术后痛觉过敏的量效关系%Dose-response relationship of tramadol for inhibiting postoperative hyperalgesia after remifentanil-based anesthesia

    Institute of Scientific and Technical Information of China (English)

    张黄丽; 刘保江; 薛朝霞

    2011-01-01

    Objective To investigate the dose-response relationship of tramadol for inhibiting the postoperative hyperalgesia after remifentanil-based anesthesia. Methods Sixty ASA Ⅰ or Ⅱ , 20 - 60 year-old patients receiving laparoscopic cholecystectomy were randomly allocated into six tramadol dose groups( 3.1,2.5,2.0,1.6,1.3,1.0 mg/kg ). All patients received tramadol before the beginning of the surgery. Propofol and remifentanil were used for the general anaesthesia. Remifentanil was infused at 0.25 μg/( kg · min ).Pain was assessed with VAS at 15 min after tracheal extubation( VAS <4 was defined as effective ). A Probit analysis was performed to calculate the efficient doses of tramadol for inhibiting hyperalgesia in 50% and 95% of patients ( ED50 and ED95 ). Results The ED50 of tramadol was 1.66 mg/kg ( 95 % CI 1.41 - 1.94 mg/kg ) and ED95 was 3.10 mg/kg ( 95 % CI 2.47 - 5.59 mg/kg ). Conclusion The ED50 and ED95 of tramadol for inhibiting the postoperative hyperalgesia after remifentanil-based anesthesia with 0.25 μg/( kg · min ) of remifentanil in patients following laparoscopic cholecystectomy are 1.66 mg/kg and 3.10 mg/kg, respectively.%目的 确定曲马多抑制瑞芬太尼致术后痛觉过敏的量效关系.方法 选择60例ASAⅠ或Ⅱ级,20-60岁择期全麻腹腔镜下行胆囊切除术的成年患者,按所用曲马多的剂量(3.1,2.5,2.0,1.6,1.3,1.0 mg/kg)随机分为6组.于手术开始前给予规定剂量的曲马多.以丙泊酚和瑞芬太尼行全静脉麻醉,瑞芬太尼维持剂量为0.25 μg/(kg · min),记录清醒拔管后15 minVAS评分(VAS4分为抑制痛觉过敏有效),用Probit回归分析数据,得出曲马多抑制瑞芬太尼致术后痛觉过敏的ED 50 和ED 95.结果 曲马多抑制瑞芬太尼致术后痛觉过敏的ED 50 为1.66 mg/kg(95%可信区间:1.41-1.94 mg/kg),ED 95 为 3.10 mg/kg(95%可信区间:2.47-5.59 mg/kg).结论 曲马多抑制瑞芬太尼致术后痛觉过敏的ED 50 和ED 95 分别为1.66 mg

  20. δ-阿片受体抑制阿片诱发痛觉过敏的研究进展%The role of δ- opioid receptor in the inhibition of opioid induced hyperalgesia

    Institute of Scientific and Technical Information of China (English)

    李依泽; 王海云; 王国林

    2012-01-01

    Background Opioids are the most powerful analgesics for the treatment of moderate to severe pain.Although opioids have analgesic effect,they have many side effects at the same time.Long term opioids exposure can induce hyperalgesia and tolerance.Moreover,increasing the dose of opioids,paradoxically,aggravates the hyperalgesia and tolerance,causing a vicious cycle.The use of opioids,therefore,is largely limited in the clinical setting. Objective The relevant literatures involved in the role of δ-opioid receptors in the attenuation of opioid induced hyperalgesia (OIH) in recent years were summarized,which helps readership to update the latest information about this topic. Content The structure,distribution,physiological function and the progress of antihyperalgesic effect of δ-opioid receptors were reviewed in this article.Those researches suggest that OIH and tolerance can be attenuated by the inhibition of δ-opioid receptor phosphorylation,knocking out δ-opioid receptor coding genes and the application of δ-opioid receptor antagonists. Trend Since the antihyperalgesia effect of δ-opioid receptor is widely acknowledged,δ- opioid receptor may become a new target to relieve pain in the clinical setting.%背景 阿片类药物是治疗中、重度疼痛的主要药物,长时间应用可出现阿片诱发的痛觉过敏和耐受,而增加药物剂量可造成更严重的痛觉过敏和耐受,从而形成恶性循环,很大程度上限制了阿片类药物在临床工作中的应用.目的 通过对近年δ-阿片受体在痛觉过敏中所起作用的研究进行总结,帮助读者了解国外相关研究的最新趋势和进展.内容 就δ-阿片受体的结构、分布、生理功能和δ-阿片受体的抗痛觉过敏作用的研究进展进行综述.得出如下结论,通过抑制δ-阿片受体磷酸化、敲除δ-阿片受体编码基因和应用δ-阿片受体拮抗剂等方法,可抑制痛觉过敏和耐受的形成.趋向 随着越来越多的学者对

  1. Electroacupuncture Reduces Carrageenan- and CFA-Induced Inflammatory Pain Accompanied by Changing the Expression of Nav1.7 and Nav1.8, rather than Nav1.9, in Mice Dorsal Root Ganglia

    OpenAIRE

    Chun-Ping Huang; Hsiang-Ni Chen; Hong-Lin Su; Ching-Liang Hsieh; Wei-Hsin Chen; Zhen-Rung Lai; Yi-Wen Lin

    2013-01-01

    Several voltage-gated sodium channels (Navs) from nociceptive nerve fibers have been identified as important effectors in pain signaling. The objective of this study is to investigate the electroacupuncture (EA) analgesia mechanism by changing the expression of Navs in mice dorsal root ganglia (DRG). We injected carrageenan and complete Freund's adjuvant (CFA) into the mice plantar surface of the hind paw to induce inflammation and examined the antinociception effect of EA at the Zusanli (ST3...

  2. 辣椒素受体在内皮素-1引起热痛觉过敏中的作用%Role of vanilloid receptors in thermal hyperalgesia induced by intraplantar endothelin-1 administration

    Institute of Scientific and Technical Information of China (English)

    季文进; 梁杰贤; 赵国栋

    2007-01-01

    目的 研究辣椒素受体对内皮素-1(ET-1)引起热痛觉过敏的影响.方法 选用辣椒素受体基因敲除小鼠(KO小鼠)及其野生型C57BL/6J小鼠(WT小鼠),分为KO组与WT组,两组分别按3、10、30、100 pmol剂量足底注射ET-1(溶于10 μl磷酸盐缓冲液,n=6).测量注药前和注药后15、30、45及60min时逃避时间(PWT).结果 ET-1引起两组动物PWT降低,在WT组降低幅度更明显,WT组PWT随着ET-1剂量的增加而降低,而KO组PWT在剂量为30 pmol时降低最为明显.结论 ET-1引起的热痛觉过敏部分通过辣椒素受体起作用.

  3. Effect of intrathecally administered oxytocin on thermal hyperalgesia in neuropathic pain rat%鞘内注射催产素对大鼠神经痛反应的影响

    Institute of Scientific and Technical Information of China (English)

    马飞; 苗旺; 王蕾

    2002-01-01

    目的:观察不同剂量催产素对神经痛大鼠热痛敏的影响.方法:在脊神经结扎致坐骨神经损伤大鼠模型上采用辐射热缩腿反射的方法,以抬脚潜伏期作为观察指标.结果:蛛网膜下腔注射催产素(1ng,2.5ng,5ng)对神经痛大鼠有镇痛作用,呈剂量相关关系.结论:鞘内注射催产素对神经痛大鼠有镇痛作用.

  4. 蛋白激酶C在ET-1引起热痛觉过敏中的作用%The Role of Protein Kinase C in Thermal Hyperalgesia Induced by Endothelin-1

    Institute of Scientific and Technical Information of China (English)

    梁杰贤; 郭中敏; 季文进; 刘培庆

    2006-01-01

    目的 研究蛋白激酶C(PKC)途径在内皮素-1(ET-1)引起热痛觉过敏中的作用.方法 小鼠分为PKC抑制剂Bisindolylmaleimide Ⅰ(BIM)组(BIM组)、ET-1组(ET组)、BIM加ET-1组(BE组),每组6只.BIM组足底注射BIM 5 nmol 15 min后再注射PBS,ET-1组注射PBS 15 min后再注射10 pmol ET-1,BE组注射5 nmol BIM 15 min后再注射10 pmol ET-1.测量注药前及注药后15、30、45及60 min对热逃避反应时间.结果 BIM组与BE组热痛觉阈值无明显变化,ET组热痛觉阈值降低.结论 局部注射ET-1通过激活PKC途径从而引起热痛觉过敏.

  5. Solar Thermal Rocket Propulsion

    Science.gov (United States)

    Sercel, J. C.

    1986-01-01

    Paper analyzes potential of solar thermal rockets as means of propulsion for planetary spacecraft. Solar thermal rocket uses concentrated Sunlight to heat working fluid expelled through nozzle to produce thrust.

  6. Ouellette Thermal Test Facility

    Data.gov (United States)

    Federal Laboratory Consortium — The Thermal Test Facility is a joint Army/Navy state-of-the-art facility (8,100 ft2) that was designed to:Evaluate and characterize the effect of flame and thermal...

  7. Ouellette Thermal Test Facility

    Data.gov (United States)

    Federal Laboratory Consortium — The Thermal Test Facility is a joint Army/Navy state-of-the-art facility (8,100 ft2) that was designed to: Evaluate and characterize the effect of flame and thermal...

  8. Thermal Performance Benchmarking (Presentation)

    Energy Technology Data Exchange (ETDEWEB)

    Moreno, G.

    2014-11-01

    This project will benchmark the thermal characteristics of automotive power electronics and electric motor thermal management systems. Recent vehicle systems will be benchmarked to establish baseline metrics, evaluate advantages and disadvantages of different thermal management systems, and identify areas of improvement to advance the state-of-the-art.

  9. Nanoscale Thermal Transport

    Science.gov (United States)

    2003-01-15

    171.64.49.29. Redistribution subject toneed high thermal conductivity. In others, such as thermal barriers or thermoelectric materials used for solid-state re... thermal barriers . Significant decreases in conductivity have been observed recently in nanocrystalline ZrO2 :Y2O3 ~Ref. 118! and attributed to the

  10. Thermally favourable gauge mediation

    Energy Technology Data Exchange (ETDEWEB)

    Dalianis, Ioannis, E-mail: Ioannis.Dalianis@fuw.edu.p [Institute of Theoretical Physics, Faculty of Physics, University of Warsaw, ul. Hoza 69, Warsaw (Poland); Lalak, Zygmunt, E-mail: Zygmunt.Lalak@fuw.edu.p [Institute of Theoretical Physics, Faculty of Physics, University of Warsaw, ul. Hoza 69, Warsaw (Poland)

    2011-03-14

    We discuss the thermal evolution of the spurion and messenger fields of ordinary gauge mediation models taking into account the Standard Model degrees of freedom. It is shown that for thermalized messengers the metastable susy breaking vacuum becomes thermally selected provided that the susy breaking sector is sufficiently weakly coupled to messengers or to any other observable field.

  11. TNF-alpha neutralizing antibody blocks thermal sensitivity induced by compound 48/80-provoked mast cell degranulation [v1; ref status: indexed, http://f1000r.es/1mq

    Directory of Open Access Journals (Sweden)

    Devavani Chatterjea

    2013-08-01

    Full Text Available Background:  Neuro-inflammatory circuits in the tissue regulate the complex pathophysiology of pain.  Protective nociceptive pain serves as an early warning system against noxious environmental stimuli.  Tissue-resident mast cells orchestrate the increased thermal sensitivity following injection of basic secretagogue compound 48/80 in the hind paw tissues of ND4 mice.  Here we investigated the effects of pre-treatment with TNF-α neutralizing antibody on compound 48/80-provoked thermal hyperalgesia.  Methods:  We treated ND4 Swiss male mice with intravenous anti-TNF-α antibody or vehicle 30 minutes prior to bilateral, intra-plantar compound 48/80 administration and measured changes in the timing of hind paw withdrawal observed subsequent to mice being placed on a 51oC hotplate.  We also assessed changes in tissue swelling, TNF-α gene expression and protein abundance, mast cell degranulation, and neutrophil influx in the hind paw tissue.  Findings:  We found that TNF-α neutralization significantly blocked thermal hyperalgesia, and reduced early tissue swelling. TNF-α neutralization had no significant effect on mast cell degranulation or neutrophil influx into the tissue, however.  Moreover, no changes in TNF-α protein or mRNA levels were detected within 3 hours of administration of compound 48/80.  Interpretation:  The neutralizing antibodies likely target pre-formed TNF-α including that stored in the granules of tissue-resident mast cells. Pre-formed TNF-α, released upon degranulation, has immediate effects on nociceptive signaling prior to the induction of neutrophil influx.  These direct effects on nociceptors are abrogated by TNF-α blockade resulting in compromised nociceptive withdrawal responses to acute, harmful environmental stimuli.

  12. PAR2-PKC 通路调控 TRPV1介导内脏高敏感性参与肠易激综合征%PAR2-PKC pathway regulated TRPV1 mediates visceral hyperalgesia to participate in the irritable bowel syndrome

    Institute of Scientific and Technical Information of China (English)

    黄斌; 黄适; 张涛; 陈远能

    2015-01-01

    Visceral hyperalgesia is one of characteristic pathophysiological mechanisms of irritable bowel syndrome ( IBS) .The mechanism of visceral hyperalgesia is unclear and thought to involve a variety of enteric nervous secreted neurotransmitters , cytokines and receptors .The exact mechanism of visceral hyperalgesia at present has not yet fully un-derstood , but TRPV1 upregulation and phosphorylation mediated pain sensitization was considered to be one of the key events.Excessive activation of PAR-PKC pathway phosphorylate the TRPV 1 and lower its threshold , eventually leading to the occurring of visceral hyperalgesia .This article reviewed the recent advance about the visceral hyperalgesia led by the upregulation and phosphorylation of TRPV 1 which was regulated by PAR-PKC pathway .%内脏高敏感性是肠易激综合征( irritable bowel syndrome ,IBS)特征性病理生理机制之一,其发生涉及多种肠神经分泌的递质、细胞因子和受体,内脏高敏感性的发生机制目前尚未明确,但是辣椒素受体(transient receptor potential vanilloid 1,TRPV1)上调及磷酸化介导痛觉敏化被认为是内脏高敏感性发生的关键性事件之一。 PAR2-PKC通路过度活化,可介导TRPV1磷酸化,TRPV1开放阈值下降,内脏疼痛感知异常,最终导致内脏高敏感性的发生。本文就近年来关于PAR2-PKC通路调控TRPV1磷酸化及上调介导IBS内脏高敏感性的相关研究作一概述。

  13. Necessity of Eigenstate Thermalization

    Science.gov (United States)

    De Palma, Giacomo; Serafini, Alessio; Giovannetti, Vittorio; Cramer, Marcus

    2015-11-01

    Under the eigenstate thermalization hypothesis (ETH), quantum-quenched systems equilibrate towards canonical, thermal ensembles. While at first glance the ETH might seem a very strong hypothesis, we show that it is indeed not only sufficient but also necessary for thermalization. More specifically, we consider systems coupled to baths with well-defined macroscopic temperature and show that whenever all product states thermalize then the ETH must hold. Our result definitively settles the question of determining whether a quantum system has a thermal behavior, reducing it to checking whether its Hamiltonian satisfies the ETH.

  14. Thermal Management and Thermal Protection Systems

    Science.gov (United States)

    Hasnain, Aqib

    2016-01-01

    During my internship in the Thermal Design Branch (ES3), I contributed to two main projects: i) novel passive thermal management system for future human exploration, ii) AVCOAT undercut thermal analysis. i) As NASA prepares to further expand human and robotic presence in space, it is well known that spacecraft architectures will be challenged with unprecedented thermal environments. Future exploration activities will have the need of thermal management systems that can provide higher reliability, mass and power reduction and increased performance. In an effort to start addressing the current technical gaps the NASA Johnson Space Center Passive Thermal Discipline has engaged in technology development activities. One of these activities was done through an in-house Passive Thermal Management System (PTMS) design for a lunar lander. The proposed PTMS, functional in both microgravity and gravity environments, consists of three main components: a heat spreader, a novel hybrid wick Variable Conductance Heat Pipe (VCHP), and a radiator. The aim of this PTMS is to keep electronics on a vehicle within their temperature limits (0 and 50 C for the current design) during all mission phases including multiple lunar day/night cycles. The VCHP was tested to verify its thermal performance. I created a thermal math model using Thermal Desktop (TD) and analyzed it to predict the PTMS performance. After testing, the test data provided a means to correlate the thermal math model. This correlation took into account conduction and convection heat transfer, representing the actual benchtop test. Since this PTMS is proposed for space missions, a vacuum test will be taking place to provide confidence that the system is functional in space environments. Therefore, the model was modified to include a vacuum chamber with a liquid nitrogen shroud while taking into account conduction and radiation heat transfer. Infrared Lamps were modelled and introduced into the model to simulate the sun

  15. Changes in CCL3 and CCR5 expression in spinal cord during hyperalgesia induced by remifentanil in rats with incisional pain%瑞芬太尼诱发切口痛大鼠痛觉过敏时脊髓CCL3和CCR5表达水平的变化

    Institute of Scientific and Technical Information of China (English)

    李楠; 张麟临; 舒瑞辰; 王志芬; 丁玲; 敖吉莹; 王国林

    2015-01-01

    Objective To evaluate the changes in the expression of CC-chemokine ligand 3 (CCL3) and CC-chemokine receptor 5 (CCR5) in the spinal cord during hyperalgesia induced by remifentanil in rats with incisional pain.Methods Thirty-two male Sprague-Dawley rats,aged 2-3 months,weighing 240-260 g,were randomly divided into 4 groups (n=8 each) using a random number table:control group (group C),incisional pain group (group Ⅰ),remifentanil group (group R) and remifentanil+incisional pain group (group R+I).A 1-cm longitudinal incision was made in the plantar surface of the left hindpaw in anesthetized rats.While the model of incisional pain was established,remifentanil was infused for 60 min at 1 μg · kg-1 · min-1.At 24 h before infusion of remifentanil (baseline) and 2,6,24 and 48 h after the end of infusion,the mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured.The rats were sacrificed after the last measurement of pain threshold,the lumbar segment (L4-6) of the spinal cord was removed for determination of CL3 and CCR5 mRNA expression (by real-time PCR) and CL3 and CCR5 expression (by Western blot).Results Compared with group C,the MWT was significantly decreased,the TWL was shortened,and the expression of CCL3 and CCR5 mRNA and protein was up-regulated in I,R and R+ I groups.Compared with I and R groups,the MWT was significantly dccreascd,the TWL was shortened,and the expression of CCL3 and CCR5 mRNA and protein was up-regulated in group R+I.Conclusion The mechanism by which remifentanil induces hyperalgesia is related to up-regulated expression of CCL3 and CCR5 in the spinal cord of rats with incisional pain.%目的 评价瑞芬太尼诱发切口痛大鼠痛觉过敏时脊髓趋化因子配体3 (CCL3)和趋化因子CC亚族受体5(CCRS)表达水平的变化.方法 雄性SD大鼠32只,体重240~ 260 g,2~3月龄,采用随机数字表法,分为4组(n=8):对照组(C组)、切口痛组(I组)、瑞芬太尼组(R组)和瑞

  16. Effect of changes of PKC activity on iNOS in posterior horn neurons of spinal cord in rats after formalin-induced inflammatory pain and hyperalgesia%甲醛足底致痛大鼠脊髓后角神经元内蛋白激酶C活性改变对一氧化氮合酶的影响

    Institute of Scientific and Technical Information of China (English)

    吕兴业

    2011-01-01

    目的 通过改变蛋白激酶C(protein kinase C,PKC)的活性观察其对甲醛炎性痛及痛觉过敏时大鼠脊髓后角一氧化氮合酶(nitric oxide synthase,NOS)尤其是对诱生型NOS(induciable NOS,iNOS)的影响,以探讨在该过程中PKC的作用机制.方法 将实验动物54只分为9组,每组6只,分男q为正常组、甲醛12 h组、甲醛24 h组、甲醛12 h加0.9%氯化钠溶液组、甲醛24 h加0.9%氯化钠溶液组、甲醛12 h加佛波醇脂(PMA)组、甲醛24 h加PMA组、甲醛12 h加灯盏花素乙(CH)组和甲醛24 h加CH组.先进行疼痛行为学检测,然后分别于注射甲醛后12、24 h将大鼠麻醉后取材,采用免疫组织化学方法观察脊髓后角iNOS阳性神经元数目及染色深度,以探讨PKC时NOS的影响.结果 与甲醛12 h组比较,甲醛12 h加PMA组iNOS阳性细胞数明显增加(P<0.01),神经细胞及神经纤维染色也明显加深(P<0.01);甲醛12 h加CH组iNOS阳性细胞数明显减少(P<0.01),神经细胞及神经纤维染色明显变浅(P<0.01).同时产生相应的行为痛觉过敏变化.结论 鞘内注射PKC兴奋荆PMA能显著增加L5脊髓后角神经元NOS的活性;鞘内注射PKC抑制剂CH能显著抑制L5脊髓后角神经元iNOS的活性.在甲醛炎性痛及痛觉过敏中,脊髓后角iNOS活性在一定程度上受PKC调控.%Objective To observe the effect of changes of protein kinase C (PKC) activity on nitric oxide synthase (NOS) and inducible NOS (iNOS) in posterior horn neurons of spinal cord in rats after formalin-induced inflammatory pain and hyperalgesia in order to explore the action mechanism of PKC during the process. Methods Fifty-four SD rats were randomly divided into 9 groups:control group, formalin 12h, formalin 24h, formalin 12h +NS,formalin 24 h + N, formalin 12h + PMA, formalin 24h + PMA, formalin 12h + CH and formalin 24h + CH groups. The mechanical and thermal pain threshold was measured by paw withdrawal latencies to yon Frey hair and radiant heat

  17. Role of central and peripheral sensitization in remifentanil- induced hyperalgesia in a rat model of inflammatory pain%中枢敏化和外周敏化在瑞芬太尼诱发炎性痛大鼠痛觉过敏中的作用

    Institute of Scientific and Technical Information of China (English)

    邓立琴; 王建珍; 孟尽海

    2011-01-01

    h and 1-7 d after carrageenan injection. Bilateral paw withdrawal latency to noxious thermal stimuli (PWL) was measured before and at 2 h, 4 h and 1-7 d after carrageenan injection. The thickness of the plantar surface of left hindpaw was measured before and at 1 h, 4 h and 1-7 d after carrageenan injection. Results Bilateral PWT was significantly lower at day 1 after carrageenan injection in R, and R2 groups than in group C. The right PWT was significantly lower at 2 d and 4-7 d after carrageenan injection in group R2 than in group R, . There was no significant difference in PWL and thickness of the plantar surface of left hindpaw among the 3 groups. Conclusion Central sensitization is involved in developing and maintaining the remifentanil-induced hyperalgesia in a rat model of inflammatory pain, while peripheral sensitization is not.

  18. Quantum Thermal Transistor.

    Science.gov (United States)

    Joulain, Karl; Drevillon, Jérémie; Ezzahri, Younès; Ordonez-Miranda, Jose

    2016-05-20

    We demonstrate that a thermal transistor can be made up with a quantum system of three interacting subsystems, coupled to a thermal reservoir each. This thermal transistor is analogous to an electronic bipolar one with the ability to control the thermal currents at the collector and at the emitter with the imposed thermal current at the base. This is achieved by determining the heat fluxes by means of the strong-coupling formalism. For the case of three interacting spins, in which one of them is coupled to the other two, that are not directly coupled, it is shown that high amplification can be obtained in a wide range of energy parameters and temperatures. The proposed quantum transistor could, in principle, be used to develop devices such as a thermal modulator and a thermal amplifier in nanosystems.

  19. Quantum thermal transistor

    CERN Document Server

    Joulain, Karl; Ezzahri, Younès; Ordonez-Miranda, Jose

    2016-01-01

    We demonstrate that a thermal transistor can be made up with a quantum system of 3 interacting subsystems , coupled to a thermal reservoir each. This thermal transistor is analogous to an electronic bipolar one with the ability to control the thermal currents at the collector and at the emitter with the imposed thermal current at the base. This is achieved determining the heat fluxes by means of the strong-coupling formalism. For the case of 3 interacting spins, in which one of them is coupled to the other 2, that are not directly coupled, it is shown that high amplification can be obtained in a wide range of energy parameters and temperatures. The proposed quantum transistor could, in principle, be used to develop devices such as a thermal modulator and a thermal amplifier in nano systems.

  20. 大鼠背根节慢性压迫或急性分离引起的cGMP-PKG信号通路持续激活介导背根节神经元的异常兴奋性和痛觉过敏%Activation of cGMP-PKG signaling pathway contributes to neuronal hyperexcitability and hyperalgesia after in vivo prolonged compression or in vitro acute dissociation of dorsal root ganglion in rats

    Institute of Scientific and Technical Information of China (English)

    黄志江; 李浩川; 刘苏; 宋学军

    2012-01-01

    Injury or inflammation affecting sensory neurons in the dorsal root ganglia (DRG) causes hyperexcitability of DRG neurons that can lead to spinal central sensitization and neuropathic pain.Recent studies have indicated that,following chronic compression of DRG (CCD) or acute dissociation of DRG (ADD) treatment,both hyperexcitability of neurons in intact DRG and behaviorally expressed hyperalgesia are maintained by activity in cGMP-PKG signaling pathway.Here,we provide evidence supporting the idea that CCD or ADD treatment activates cGMP-PKA signaling pathway in the DRG neurons.The results showed that CCD or ADD results in increase of levels of cGMP concentration and expression of PKG-I mRNA,as well as PKG-I protein in DRG.CCD or ADD treatedDRG neurons become hyperexcitable and exhibit increased responsiveness to the activators of cGMP-PKG pathway,8-Br-cGMP and Sp-cGMP.Hyperexcitability of the injured neurons is inhibited by cGMP-PKG pathway inhibitors,ODQ and Rp-8-pCPT-cGMPS.In vivo delivery of Rp-8-pCPT-cGMPS into the compressed ganglion within the intervertebral foramen suppresses CCD-induced thermal hyperalgesia.These findings indicate that the in vivo CCD or in vitro ADD treatment can activate the cGMP-PKG signaling pathway,and that continuing activation of cGMP-PKG pathway is required to maintain DRG neuronal hyperexcitability and/or hyperalgesia after these two dissimilar forms of injury-related stress.%背根节(dorsal root ganglion,DRG)损伤或炎症可导致DRG神经元兴奋性异常增强和痛觉过敏.我们近期研究显示,长期慢性在体压迫(chronic compression of DRG,CCD)或急性离体分离(acute dissociation of DRG,ADD)背根节导致的神经元兴奋性异常增强和痛觉过敏受环鸟苷酸(cGMP)-蛋白激酶G(PKG)信号通路活动的调控.本研究采用大鼠CCD模型和ADD模型,直接在DRG上检测cGMP浓度和PKG mRNA及其蛋白质的表达,进一步证明了cGMP-PKG信号通路活动在CCD和ADDDRG所致神经元兴奋性

  1. Pharmacological activation of 5-HT7 receptors reduces nerve injury-induced mechanical and thermal hypersensitivity.

    Science.gov (United States)

    Brenchat, Alex; Nadal, Xavier; Romero, Luz; Ovalle, Sergio; Muro, Asunción; Sánchez-Arroyos, Ricard; Portillo-Salido, Enrique; Pujol, Marta; Montero, Ana; Codony, Xavier; Burgueño, Javier; Zamanillo, Daniel; Hamon, Michel; Maldonado, Rafael; Vela, José Miguel

    2010-06-01

    The involvement of the 5-HT(7) receptor in nociception and pain, particularly chronic pain (i.e., neuropathic pain), has been poorly investigated. In the present study, we examined whether the 5-HT(7) receptor participates in some modulatory control of nerve injury-evoked mechanical hypersensitivity and thermal (heat) hyperalgesia in mice. Activation of 5-HT(7) receptors by systemic administration of the selective 5-HT(7) receptor agonist AS-19 (1 and 10mg/kg) exerted a clear-cut reduction of mechanical and thermal hypersensitivities that were reversed by co-administering the selective 5-HT(7) receptor antagonist SB-258719. Interestingly, blocking of 5-HT(7) receptors with SB-258719 (2.5 and 10mg/kg) enhanced mechanical (but not thermal) hypersensitivity in nerve-injured mice and induced mechanical hypersensitivity in sham-operated mice. Effectiveness of the treatment with a 5-HT(7) receptor agonist was maintained after repeated systemic administration: no tolerance to the antiallodynic and antihyperalgesic effects was developed following treatment with the selective 5-HT(7) receptor agonist E-57431 (10mg/kg) twice daily for 11 days. The 5-HT(7) receptor co-localized with GABAergic cells in the dorsal horn of the spinal cord, suggesting that the activation of spinal inhibitory GABAergic interneurons could contribute to the analgesic effects of 5-HT(7) receptor agonists. In addition, a significant increase of 5-HT(7) receptors was found by immunohistochemistry in the ipsilateral dorsal horn of the spinal cord after nerve injury, suggesting a "pain"-triggered regulation of receptor expression. These results support the idea that the 5-HT(7) receptor subtype is involved in the control of pain and point to a new potential use of 5-HT(7) receptor agonists for the treatment of neuropathic pain.

  2. Specific involvement of atypical PKCζ/PKMζ in spinal persistent nociceptive processing following peripheral inflammation in rat

    Directory of Open Access Journals (Sweden)

    Marchand Fabien

    2011-11-01

    Full Text Available Abstract Background Central sensitization requires the activation of various intracellular signalling pathways within spinal dorsal horn neurons, leading to a lowering of activation threshold and enhanced responsiveness of these cells. Such plasticity contributes to the manifestation of chronic pain states and displays a number of features of long-term potentiation (LTP, a ubiquitous neuronal mechanism of increased synaptic strength. Here we describe the role of a novel pathway involving atypical PKCζ/PKMζ in persistent spinal nociceptive processing, previously implicated in the maintenance of late-phase LTP. Results Using both behavioral tests and in vivo electrophysiology in rats, we show that inhibition of this pathway, via spinal delivery of a myristoylated protein kinase C-ζ pseudo-substrate inhibitor, reduces both pain-related behaviors and the activity of deep dorsal horn wide dynamic range neurons (WDRs following formalin administration. In addition, Complete Freund's Adjuvant (CFA-induced mechanical and thermal hypersensitivity was also reduced by inhibition of PKCζ/PKMζ activity. Importantly, this inhibition did not affect acute pain or locomotor behavior in normal rats and interestingly, did not inhibited mechanical allodynia and hyperalgesia in neuropathic rats. Pain-related behaviors in both inflammatory models coincided with increased phosphorylation of PKCζ/PKMζ in dorsal horn neurons, specifically PKMζ phosphorylation in formalin rats. Finally, inhibition of PKCζ/PKMζ activity decreased the expression of Fos in response to formalin and CFA in both superficial and deep laminae of the dorsal horn. Conclusions These results suggest that PKCζ, especially PKMζ isoform, is a significant factor involved in spinal persistent nociceptive processing, specifically, the manifestation of chronic pain states following peripheral inflammation.

  3. Seasonal thermal energy storage

    Science.gov (United States)

    Allen, R. D.; Kannberg, L. D.; Raymond, J. R.

    1984-05-01

    Seasonal thermal energy storage (STES) using heat or cold available from surplus, waste, climatic, or cogeneration sources show great promise to reduce peak demand, reduce electric utility load problems, and contribute to establishing favorable economics for district heating and cooling systems. Heated and chilled water can be injected, stored, and recovered from aquifers. Geologic materials are good thermal insulators, and potentially suitable aquifers are distributed throughout the United States. Potential energy sources for use in an aquifer thermal energy storage system include solar heat, power plant cogeneration, winter chill, and industrial waste heat source. Topics covered include: (1) the U.S. Department of Energy seasonal thermal energy storage program; (2) aquifer thermal energy storage technology; (3) alternative STES technology; (4) foreign studies in seasonal thermal energy storage; and (5) economic assessment.

  4. TFAWS: Ares Thermal Overview

    Science.gov (United States)

    Sharp, John R.

    2007-01-01

    As part of a Constellation session at the 2007 Thermal & Fluids Analysis Workshop (TFAWS), an overview of the Crew Launch Vehicle (CLV), Crew Exploration Vehicle (CEV) and Lunar Lander systems will be given. This presentation provides a general description of the CLV (also known as Ares-I)and Ares-V vehicles portion of the session. The presentation will provide an overview of the thermal requirements, design environments, challenges and thermal modeling examples.

  5. Solid state thermal rectifier

    Energy Technology Data Exchange (ETDEWEB)

    None

    2016-07-05

    Thermal rectifiers using linear nanostructures as core thermal conductors have been fabricated. A high mass density material is added preferentially to one end of the nanostructures to produce an axially non-uniform mass distribution. The resulting nanoscale system conducts heat asymmetrically with greatest heat flow in the direction of decreasing mass density. Thermal rectification has been demonstrated for linear nanostructures that are electrical insulators, such as boron nitride nanotubes, and for nanostructures that are conductive, such as carbon nanotubes.

  6. Solar Thermal Propulsion

    Science.gov (United States)

    Gerrish, Harold P., Jr.

    2003-01-01

    This paper presents viewgraphs on Solar Thermal Propulsion (STP). Some of the topics include: 1) Ways to use Solar Energy for Propulsion; 2) Solar (fusion) Energy; 3) Operation in Orbit; 4) Propulsion Concepts; 5) Critical Equations; 6) Power Efficiency; 7) Major STP Projects; 8) Types of STP Engines; 9) Solar Thermal Propulsion Direct Gain Assembly; 10) Specific Impulse; 11) Thrust; 12) Temperature Distribution; 13) Pressure Loss; 14) Transient Startup; 15) Axial Heat Input; 16) Direct Gain Engine Design; 17) Direct Gain Engine Fabrication; 18) Solar Thermal Propulsion Direct Gain Components; 19) Solar Thermal Test Facility; and 20) Checkout Results.

  7. Thermal Performance Benchmarking

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Xuhui; Moreno, Gilbert; Bennion, Kevin

    2016-06-07

    The goal for this project is to thoroughly characterize the thermal performance of state-of-the-art (SOA) in-production automotive power electronics and electric motor thermal management systems. Information obtained from these studies will be used to: evaluate advantages and disadvantages of different thermal management strategies; establish baseline metrics for the thermal management systems; identify methods of improvement to advance the SOA; increase the publicly available information related to automotive traction-drive thermal management systems; help guide future electric drive technologies (EDT) research and development (R&D) efforts. The thermal performance results combined with component efficiency and heat generation information obtained by Oak Ridge National Laboratory (ORNL) may then be used to determine the operating temperatures for the EDT components under drive-cycle conditions. In FY16, the 2012 Nissan LEAF power electronics and 2014 Honda Accord Hybrid power electronics thermal management system were characterized. Comparison of the two power electronics thermal management systems was also conducted to provide insight into the various cooling strategies to understand the current SOA in thermal management for automotive power electronics and electric motors.

  8. Urban thermal diversity

    Institute of Scientific and Technical Information of China (English)

    KoenSTEEMERS; MarylisRAMOS; MariaSINOU

    2003-01-01

    This paper introduces the interrelationships between urban form, microclimate and thermal comfort. It draws on recent research of monitoring, surveying and modelling urban thermal characteristics and proposes a method of mapping urban diversity. Because the urban context provides a rich and varied environment that influences the way we use urban spaces (movement, sequence, activity) and how we feel in them (stimulation, thermal comfort), the aim here is to highlight the notion of diversity. Thus thermal diversity is used as a measure of the urban environment, rather than more conventional spatially or temporally fixed average values.

  9. Thermal Properties, Thermal Shock, and Thermal Cycling Behavior of Lanthanum Zirconate-Based Thermal Barrier Coatings

    Science.gov (United States)

    Guo, Xingye; Lu, Zhe; Jung, Yeon-Gil; Li, Li; Knapp, James; Zhang, Jing

    2016-06-01

    Lanthanum zirconate (La2Zr2O7) coatings are newly proposed thermal barrier coating (TBC) systems which exhibit lower thermal conductivity and potentially higher thermal stability compared to other traditional thermal barrier systems. In this work, La2Zr2O7 and 8 wt pct yttria stabilized zirconia (8YSZ) single-layer and double-layer TBC systems were deposited using the air plasma spray technique. Thermal properties of the coatings were measured. Furnace heat treatment and jet engine thermal shock tests were implemented to evaluate coating performance during thermal cycling. The measured average thermal conductivity of porous La2Zr2O7 coating ranged from 0.59 to 0.68 W/m/K in the temperature range of 297 K to 1172 K (24 °C to 899 °C), which was approximately 25 pct lower than that of porous 8YSZ (0.84 to 0.87 W/m/K) in the same temperature range. The coefficients of thermal expansion values of La2Zr2O7 were approximately 9 to 10 × 10-6/K from 400 K to 1600 K (127 °C to 1327 °C), which were about 10 pct lower than those of porous 8YSZ. The double-layer coating system consisting of the porous 8YSZ and La2Zr2O7 layers had better thermal shock resistance and thermal cycling performance than those of single-layer La2Zr2O7 coating and double-layer coating with dense 8YSZ and La2Zr2O7 coatings. This study suggests that porous 8YSZ coating can be employed as a buffer layer in La2Zr2O7-based TBC systems to improve the overall coating durability during service.

  10. Thermal energy storage

    Science.gov (United States)

    1980-01-01

    The planning and implementation of activities associated with lead center management role and the technical accomplishments pertaining to high temperature thermal energy storage subsystems are described. Major elements reported are: (1) program definition and assessment; (2) research and technology development; (3) industrial storage applications; (4) solar thermal power storage applications; and (5) building heating and cooling applications.

  11. Thermally exfoliated graphite oxide

    Science.gov (United States)

    Prud'Homme, Robert K. (Inventor); Aksay, Ilhan A. (Inventor); Abdala, Ahmed (Inventor)

    2011-01-01

    A modified graphite oxide material contains a thermally exfoliated graphite oxide with a surface area of from about 300 sq m/g to 2600 sq m/g, wherein the thermally exfoliated graphite oxide displays no signature of the original graphite and/or graphite oxide, as determined by X-ray diffraction.

  12. Paradoxes of Thermal Radiation

    Science.gov (United States)

    Besson, U.

    2009-01-01

    This paper presents an analysis of the thermal behaviour of objects exposed to a solar-type flux of thermal radiation. It aims to clarify certain apparent inconsistencies between theory and observation, and to give a detailed exposition of some critical points that physics textbooks usually treat in an insufficient or incorrect way. In particular,…

  13. High Thermal Conductivity Materials

    CERN Document Server

    Shinde, Subhash L

    2006-01-01

    Thermal management has become a ‘hot’ field in recent years due to a need to obtain high performance levels in many devices used in such diverse areas as space science, mainframe and desktop computers, optoelectronics and even Formula One racing cars! Thermal solutions require not just taking care of very high thermal flux, but also ‘hot spots’, where the flux densities can exceed 200 W/cm2. High thermal conductivity materials play an important role in addressing thermal management issues. This volume provides readers a basic understanding of the thermal conduction mechanisms in these materials and discusses how the thermal conductivity may be related to their crystal structures as well as microstructures developed as a result of their processing history. The techniques for accurate measurement of these properties on large as well as small scales have been reviewed. Detailed information on the thermal conductivity of diverse materials including aluminum nitride (AlN), silicon carbide (SiC), diamond, a...

  14. Thermal flow micro sensors

    NARCIS (Netherlands)

    Elwenspoek, M.

    1999-01-01

    A review is given on sensors fabricated by silicon micromachining technology using the thermal domain for the measurement of fluid flow. Attention is paid especially to performance and geometry of the sensors. Three basic types of thermal flow sensors are discussed: anemometers, calorimetric flow se

  15. Conceptual thermal design

    NARCIS (Netherlands)

    Strijk, R.

    2008-01-01

    Present thermal design tools and methods insufficiently support the development of structural concepts engaged by typical practicing designers. Research described in this thesis identifies the main thermal design problems in practice. In addition, models and methods are developed that support an eff

  16. 慢性疼痛治疗中阿片类药物引起痛觉过敏的机制及临床防治进展%Opioid-induced hyperalgesia in chronic pain management

    Institute of Scientific and Technical Information of China (English)

    郭雪娇; 冯智英; 过建国

    2014-01-01

    背景 阿片类药物是临床上治疗慢性癌痛和非癌性疼痛最常用的药物之一.其副作用之一,阿片类药物诱导的痛觉过敏(opioid-induced hyperalgesia,OIH)正越来越受到研究者们的关注,然而其具体的发生机制和治疗方法尚不明确.目的 探讨OIH在动物和人体中的可能表现形式和发生机制,寻找有效的预防和治疗OIH的方法,提高对慢性疼痛患者治疗的临床疗效. 内容 已有大量动物和临床实验报道了OIH的可能表现形式并证实了OIH的存在.OIH的发生机制主要包括腺苷酸环化酶的活性增强、离子通道瞬时受体电位香草醛亚家族1(transient receptor potential vanilloid 1,TRPV1)基因转录的增加、内源性感觉神经肽的增多等.对于预防和治疗OIH学者们提出了多种方法,其中有些方法的疗效已在临床研究中得到证实. 趋向 我们还需进一步研究OIH的机制,探索更加有效和持久的治疗和护理方法,更好地为患者造福.%Background Opioid is one of the most common drugs being used in cancer pain or chronic non-cancer pain.Opioid-induced hyperalgesia (OIH),one of opioid side effects,is increasing nowadays.Objective Discussion on the possible patterns of manifestation and mechanism of OIH on animals or human.To find effective ways to preventing and treating OIH.To improve the outcomes of chromic pain management.Content A large amount of animal or clinical researches had demonstrated the possible manifestation of OIH.The mechanisms of OIH are related to increasing activity of adenylate cyclase,up-regulation of the transient receptor potential vanilloid 1 (TRPV1) channel's expression and increasing number of endogenous neuropeptides.Many researchers put forward different ways to preventing and treating OIH.Trend It is needed for further study of the mechanisms and treatments of OIH.

  17. Effect of overactivation of stem cell factor/c-kit on hyperalgesia in rats with irritable bowel syndrome%SCF/c-kit过度激活在肠易激综合征内脏敏化中的作用

    Institute of Scientific and Technical Information of China (English)

    张静瑜; 黄裕新; 秦明; 王景杰

    2012-01-01

    Objective To explore the role of overactivation of stem cell factor( SCF)/c-kit in the hyperalgesia of rats with irritable bowel syndrome (IBS). Methods Thirty rats were gavaged with Triehinella spiralis to establish the irritable bowel syndrome model. The model rats were randomly divided into IBS group,IBS + colon distension group and IBS + STI-571(a specific SCF/c-kit inhibitor) + colon distension group. Twenty normal rats were chosen to randomized into normal group and normal + colon distension group. Immu-nofluorescent double staining and electrophysiological method were used to observe the activity of interstitial cells of Cajal( ICC) ,the e-lectro-activity of the rectus abdominis and the discharge frequency in dorsal commissural nucleus ( DCN ). Results The activity of ICC,the electro-activity of the rectus abdominis and the discharge frequency in DCN were significantly higher in IBS + colon distension group than those in normal group,normal + colon distension group,IBS group and IBS + STI-571 + colon distension group. Conclusion The overactivation of SCF/c-kit could induce the changes of ICC,which may be the most important factor for the hyperalgesia in IBS rats.%目的 研究SCF/c-kit通路过度激活在肠易激综合征(irritable bowel syndrome,IBS)内脏敏化中的作用. 方法 用旋毛虫感染大鼠致肠易激综合征模型30只,随机分为3组:IBS组、IBS结肠扩张组和IBS给予甲磺酸伊马替尼(imatinib mesylate,STI-571)干预加结肠扩张组.另外选择20只正常大鼠,随机分为正常组和正常结肠扩张组.采用免疫荧光组织化学和电生理学的方法观察各组大鼠肠道ICC活化及其腹直肌肌电和骶髓后连合核(dorsal commissural nucleus,DCN)放电频率的变化. 结果 IBS结肠扩张组的肠道Cajal间质细胞(interstitial cells of Cajal,ICC)活化程度、腹直肌肌电变化及DCN放电频率比正常组、正常结肠扩张组、IBS组和IBS结肠扩张并给予STI-571组均显著增强.

  18. Solar thermal aircraft

    Science.gov (United States)

    Bennett, Charles L.

    2007-09-18

    A solar thermal powered aircraft powered by heat energy from the sun. A heat engine, such as a Stirling engine, is carried by the aircraft body for producing power for a propulsion mechanism, such as a propeller. The heat engine has a thermal battery in thermal contact with it so that heat is supplied from the thermal battery. A solar concentrator, such as reflective parabolic trough, is movably connected to an optically transparent section of the aircraft body for receiving and concentrating solar energy from within the aircraft. Concentrated solar energy is collected by a heat collection and transport conduit, and heat transported to the thermal battery. A solar tracker includes a heliostat for determining optimal alignment with the sun, and a drive motor actuating the solar concentrator into optimal alignment with the sun based on a determination by the heliostat.

  19. Lecture on Thermal Radiation

    Science.gov (United States)

    Dennis, Brian R.

    2006-01-01

    This lecture will cover solar thermal radiation, particularly as it relates to the high energy solar processes that are the subject of this summer school. After a general review of thermal radiation from the Sun and a discussion of basic definitions, the various emission and absorption mechanisms will be described including black-body emission, bremsstrahlung, free-bound, and atomic line emissions of all kinds. The bulk of the time will be spent discussing the observational characteristics of thermal flare plasma and what can be learned about the flare energy release process from observations of the thermal radiation at all wavelengths. Information that has been learned about the morphology, temperature distribution, and composition of the flare plasma will be presented. The energetics of the thermal flare plasma will be discussed in relation to the nonthermal energy of the particles accelerated during the flare. This includes the total energy, the radiated and conductive cooling processes, and the total irradiated energy.

  20. Battery Pack Thermal Design

    Energy Technology Data Exchange (ETDEWEB)

    Pesaran, Ahmad

    2016-06-14

    This presentation describes the thermal design of battery packs at the National Renewable Energy Laboratory. A battery thermal management system essential for xEVs for both normal operation during daily driving (achieving life and performance) and off-normal operation during abuse conditions (achieving safety). The battery thermal management system needs to be optimized with the right tools for the lowest cost. Experimental tools such as NREL's isothermal battery calorimeter, thermal imaging, and heat transfer setups are needed. Thermal models and computer-aided engineering tools are useful for robust designs. During abuse conditions, designs should prevent cell-to-cell propagation in a module/pack (i.e., keep the fire small and manageable). NREL's battery ISC device can be used for evaluating the robustness of a module/pack to cell-to-cell propagation.

  1. Thermal backflow in CFTs

    CERN Document Server

    Banks, Elliot; Gauntlett, Jerome P; Griffin, Tom; Melgar, Luis

    2016-01-01

    We study the thermal transport properties of general CFTs on curved spacetimes in the leading order viscous hydrodynamic limit. At the level of linear response, we show that the thermal transport is governed by a system of forced linearised Navier-Stokes equations on a curved space. Our setup includes CFTs in flat spacetime that have been deformed by spatially dependent temperature gradients or strains that have been applied to the CFT, and hence is relevant to CFTs arising in condensed matter systems at zero charge density. We provide specific examples of deformations which lead to thermal backflow driven by a DC source: that is, the thermal currents locally flow in the opposite direction to the applied DC thermal source.

  2. Tunable thermal link

    Science.gov (United States)

    Chang, Chih-Wei; Majumdar, Arunava; Zettl, Alexander K.

    2014-07-15

    Disclosed is a device whereby the thermal conductance of a multiwalled nanostructure such as a multiwalled carbon nanotube (MWCNT) can be controllably and reversibly tuned by sliding one or more outer shells with respect to the inner core. As one example, the thermal conductance of an MWCNT dropped to 15% of the original value after extending the length of the MWCNT by 190 nm. The thermal conductivity returned when the tube was contracted. The device may comprise numbers of multiwalled nanotubes or other graphitic layers connected to a heat source and a heat drain and various means for tuning the overall thermal conductance for applications in structure heat management, heat flow in nanoscale or microscale devices and thermal logic devices.

  3. Low thermal conductivity oxides

    Energy Technology Data Exchange (ETDEWEB)

    Pan, Wei; Phillpot, Simon R.; Wan, Chunlei; Chernatynskiy, Aleksandr; Qu, Zhixue

    2012-10-09

    Oxides hold great promise as new and improved materials for thermal-barrier coating applications. The rich variety of structures and compositions of the materials in this class, and the ease with which they can be doped, allow the exploration of various mechanisms for lowering thermal conductivity. In this article, we review recent progress in identifying specific oxides with low thermal conductivity from both theoretical and experimental perspectives. We explore the mechanisms of lowering thermal conductivity, such as introducing structural/chemical disorder, increasing material density, increasing the number of atoms in the primitive cell, and exploiting the structural anisotropy. We conclude that further systematic exploration of oxide crystal structures and chemistries are likely to result in even further improved thermal-barrier coatings.

  4. 应用他克莫司后的阿片类药物相关痛觉超敏与快速脱毒%Opioid-Induced Hyperalgesia and Rapid Opioid Detoxification After Tacrolimus Administration

    Institute of Scientific and Technical Information of China (English)

    Antonio Siniscalchi; Emanuele Piraccini; Zuzana Miklosova; Stefania Taddei; Stefano Faenza; Gerardo Martinelli; 石金山

    2009-01-01

    阿片类药物能促使中枢敏化及诱导痛觉超敏,称之为阿片类药物诱导的痛觉超敏(Opioid-Induced Hyperalgesia).本文报道1例女性患者在接受肠移植手术后发生了与免疫抑制剂相关的神经病理性疼痛.在对其疼痛治疗的3年时间里,我们选择了包括静脉注射吗啡在内的不同镇痛方法,可是收效甚微.该患者产生了阿片类药物诱导的痛觉超敏现象,然而此现象在全身麻醉下通过快速脱毒得以成功治疗.脱毒疗法改善了她的生活质量,包括能够重新接受物理治疗.治疗后6个月,仍无需使用阿片类药物.我们的经验表明,全身麻醉下快速脱毒,可能是治疗阿片类药物诱导的痛觉超敏的一种有效方法,值得和传统的脱毒方法进行比较.

  5. NMDAR在瑞芬太尼引起痛觉过敏机制和防治的研究进展%The Role of N-methyl-D-aspartate Receptor in the Mechanism and Prevention of Remifentanil Induced Hyperalgesia

    Institute of Scientific and Technical Information of China (English)

    李燕; 王国年; 林鹰; 杨光; 徐德生

    2015-01-01

    阿片类药物引起痛觉过敏(opioid-induced hyperalgesia,OIH)是指暴露于阿片类药物的患者出现一种痛阈降低和对正常疼痛刺激的超敏反应为特点的感觉异常现象.瑞芬太尼是一种μ受体激动剂,且由于起效迅速,时量半衰期短而恒定,重复用药亦无蓄积,这些良好的药代动力学特点导致它发生的痛觉过敏现象也明显频于、强于其他阿片类药物. N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor,NMDAR)激活在产生超敏现象中是非常重要的.但是关于NMDAR在瑞芬太尼诱发痛觉过敏的机制尚未完全清楚,仍然缺乏系统的预防和治疗方案.本文简要介绍了NMDAR,总结了NMDAR在瑞芬太尼引起痛觉过敏的机制中的作用,归纳了临床上一些NMDAR拮抗药物来预防瑞芬太尼引起的痛觉过敏现象,以期对后续的围术期的疼痛管理提供理论依据.

  6. Roles of cyclooxygenase inhibitors in the prevention and treatment of opioid-induced postoperative hyperalgesia%环氧化酶抑制剂在防治阿片类药物诱发的术后痛觉过敏中的作用

    Institute of Scientific and Technical Information of China (English)

    张婧; 李乐; 张粒子; 姜珊; 徐世元

    2014-01-01

    背景 使用阿片类药物停药后,可导致患者疼痛敏感性增加,即阿片类药物诱发的痛觉过敏(opioid-induced hyperalgesia,OIH),参与术后疼痛的组成.环氧化酶(cyclooxygenase,COX)抑制剂具有抗炎及抗痛觉过敏的作用,广泛用于术后镇痛治疗. 目的 了解COX抑制剂在防治OIH中的作用并进行归纳总结. 内容 COX抑制剂预防OIH的基础及临床研究现状. 趋向 COX抑制剂特别是COX-2抑制剂可有效减轻OIH,其作用机制还需进一步研究.%Background Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids,which partially contributes to the postoperative pain.Cyclooxygenase (COX) inhibitors are widely used medications for postoperative pain control in clinic due to their anti-inflammatory and anti-hyperalgesia properties.Objective To review and summarize the roles of COX inhibitors in the prevention and treatment of OIH.Content This article reviews the latest basic and clinical research of COX inhibitors in the prevention and treatment of OIH.Trend COX inhibitors,especially COX-2 inhibitors can significantly attenuate OIH.However,further research is needed to dissect the mechanism of COX inhibitors in attenuating OIH.

  7. Thermal properties of nanofluids.

    Science.gov (United States)

    Philip, John; Shima, P D

    2012-11-15

    Colloidal suspensions of fine nanomaterials in the size range of 1-100 nm in carrier fluids are known as nanofluids. For the last one decade, nanofluids have been a topic of intense research due to their enhanced thermal properties and possible heat transfer applications. Miniaturization and increased operating speeds of gadgets warranted the need for new and innovative cooling concepts for better performance. The low thermal conductivity of conventional heat transfer fluid has been a serious impediment for improving the performance and compactness of engineering equipments. Initial studies on thermal conductivity of suspensions with micrometer-sized particles encountered problems of rapid settling of particles, clogging of flow channels and increased pressure drop in the fluid. These problems are resolved by using dispersions of fine nanometer-sized particles. Despite numerous experimental and theoretical studies, it is still unclear whether the thermal conductivity enhancement in nanofluids is anomalous or within the predictions of effective medium theory. Further, many reports on thermal conductivity of nanofluids are conflicting due to the complex issues associated with the surface chemistry of nanofluids. This review provides an overview of recent advances in the field of nanofluids, especially the important material properties that affect the thermal properties of nanofluids and novel approaches to achieve extremely high thermal conductivities. The background information is also provided for beginners to better understand the subject.

  8. Thermal Giant Gravitons

    CERN Document Server

    Armas, Jay; Obers, Niels A; Orselli, Marta; Pedersen, Andreas Vigand

    2012-01-01

    We study the giant graviton solution as the AdS_5 X S^5 background is heated up to finite temperature. The analysis employs the thermal brane probe technique based on the blackfold approach. We focus mainly on the thermal giant graviton corresponding to a thermal D3-brane probe wrapped on an S^3 moving on the S^5 of the background at finite temperature. We find several interesting new effects, including that the thermal giant graviton has a minimal possible value for the angular momentum and correspondingly also a minimal possible radius of the S^3. We compute the free energy of the thermal giant graviton in the low temperature regime, which potentially could be compared to that of a thermal state on the gauge theory side. Moreover, we analyze the space of solutions and stability of the thermal giant graviton and find that, in parallel with the extremal case, there are two available solutions for a given temperature and angular momentum, one stable and one unstable. In order to write down the equations of mot...

  9. Negative thermal expansion

    Energy Technology Data Exchange (ETDEWEB)

    Barrera, G D [Departamento de QuImica, Universidad Nacional de la Patagonia SJB, Ciudad Universitaria, 9000 Comodoro Rivadavia (Argentina); Bruno, J A O [Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de QuImica Inorganica, AnalItica y QuImica FIsica, Pabellon 2, Ciudad Universitaria, 1428 Buenos Aires (Argentina); Barron, T H K [School of Chemistry, University of Bristol, Cantock' s Close, Bristol BS8 1TS (United Kingdom); Allan, N L [School of Chemistry, University of Bristol, Cantock' s Close, Bristol BS8 1TS (United Kingdom)

    2005-02-02

    There has been substantial renewed interest in negative thermal expansion following the discovery that cubic ZrW{sub 2}O{sub 8} contracts over a temperature range in excess of 1000 K. Substances of many different kinds show negative thermal expansion, especially at low temperatures. In this article we review the underlying thermodynamics, emphasizing the roles of thermal stress and elasticity. We also discuss vibrational and non-vibrational mechanisms operating on the atomic scale that are responsible for negative expansion, both isotropic and anisotropic, in a wide range of materials. (topical review)

  10. Hyperbolic thermal antenna

    CERN Document Server

    Barbillon, Grégory; Biehs, Svend-Age; Ben-Abdallah, Philippe

    2016-01-01

    A thermal antenna is an electromagnetic source which emits in its surrounding, a spatially coherent field in the infrared frequency range. Usually, its emission pattern changes with the wavelength so that the heat flux it radiates is weakly directive. Here, we show that a class of hyperbolic materials, possesses a Brewster angle which is weakly dependent on the wavelength, so that they can radiate like a true thermal antenna with a highly directional heat flux. The realization of these sources could open a new avenue in the field of thermal management in far-field regime.

  11. Advanced thermal management materials

    CERN Document Server

    Jiang, Guosheng; Kuang, Ken

    2012-01-01

    ""Advanced Thermal Management Materials"" provides a comprehensive and hands-on treatise on the importance of thermal packaging in high performance systems. These systems, ranging from active electronically-scanned radar arrays to web servers, require components that can dissipate heat efficiently. This requires materials capable of dissipating heat and maintaining compatibility with the packaging and dye. Its coverage includes all aspects of thermal management materials, both traditional and non-traditional, with an emphasis on metal based materials. An in-depth discussion of properties and m

  12. Compliant thermal microactuators

    DEFF Research Database (Denmark)

    Jonsmann, Jacques; Sigmund, Ole; Bouwstra, Siebe

    1999-01-01

    Two dimensional compliant metallic thermal microactuators are designed using topology optimisation, and microfabricated using rapid prototyping techniques. Structures are characterised using advanced image analysis, yielding a very high precision. Characterised structures behave in a way which can...

  13. Thermal springs of Wyoming

    Energy Technology Data Exchange (ETDEWEB)

    Breckenridge, R.M.; Hinckley, B.S.

    1978-01-01

    This bulletin attempts, first, to provide a comprehensive inventory of the thermal springs of Wyoming; second, to explore the geologic and hydrologic factors producing these springs; and, third, to analyze the springs collectively as an indicator of the geothermal resources of the state. A general discussion of the state's geology and the mechanisms of thermal spring production, along with a brief comparison of Wyoming's springs with worldwide thermal features are included. A discussion of geothermal energy resources, a guide for visitors, and an analysis of the flora of Wyoming's springs follow the spring inventory. The listing and analysis of Wyoming's thermal springs are arranged alphabetically by county. Tabulated data are given on elevation, ownership, access, water temperature, and flow rate. Each spring system is described and its history, general characteristics and uses, geology, hydrology, and chemistry are discussed. (MHR)

  14. Thermal cloak-concentrator

    Science.gov (United States)

    Shen, Xiangying; Li, Ying; Jiang, Chaoran; Ni, Yushan; Huang, Jiping

    2016-07-01

    For macroscopically manipulating heat flow at will, thermal metamaterials have opened a practical way, which possesses a single function, such as either cloaking or concentrating the flow of heat even though environmental temperature varies. By developing a theory of transformation heat transfer for multiple functions, here we introduce the concept of intelligent thermal metamaterials with a dual function, which is in contrast to the existing thermal metamaterials with single functions. By assembling homogeneous isotropic materials and shape-memory alloys, we experimentally fabricate a kind of intelligent thermal metamaterials, which can automatically change from a cloak (or concentrator) to a concentrator (or cloak) when the environmental temperature changes. This work paves an efficient way for a controllable gradient of heat, and also provides guidance both for arbitrarily manipulating the flow of heat and for efficiently designing similar intelligent metamaterials in other fields.

  15. Thermal hyperbolic metamaterials.

    Science.gov (United States)

    Guo, Yu; Jacob, Zubin

    2013-06-17

    We explore the near-field radiative thermal energy transfer properties of hyperbolic metamaterials. The presence of unique electromagnetic states in a broad bandwidth leads to super-planckian thermal energy transfer between metamaterials separated by a nano-gap. We consider practical phonon-polaritonic metamaterials for thermal engineering in the mid-infrared range and show that the effect exists in spite of the losses, absorption and finite unit cell size. For thermophotovoltaic energy conversion applications requiring energy transfer in the near-infrared range we introduce high temperature hyperbolic metamaterials based on plasmonic materials with a high melting point. Our work paves the way for practical high temperature radiative thermal energy transfer applications of hyperbolic metamaterials.

  16. Thermal Acoustic Fatigue Apparatus

    Data.gov (United States)

    Federal Laboratory Consortium — The Thermal Acoustic Fatigue Apparatus (TAFA) is a progressive wave tube test facility that is used to test structures for dynamic response and sonic fatigue due to...

  17. Thermal Expansion "Paradox."

    Science.gov (United States)

    Fakhruddin, Hasan

    1993-01-01

    Describes a paradox in the equation for thermal expansion. If the calculations for heating a rod and subsequently cooling a rod are determined, the new length of the cool rod is shorter than expected. (PR)

  18. Thermal Cameras and Applications

    DEFF Research Database (Denmark)

    Gade, Rikke; Moeslund, Thomas B.

    2014-01-01

    Thermal cameras are passive sensors that capture the infrared radiation emitted by all objects with a temperature above absolute zero. This type of camera was originally developed as a surveillance and night vision tool for the military, but recently the price has dropped, significantly opening up...... a broader field of applications. Deploying this type of sensor in vision systems eliminates the illumination problems of normal greyscale and RGB cameras. This survey provides an overview of the current applications of thermal cameras. Applications include animals, agriculture, buildings, gas detection......, industrial, and military applications, as well as detection, tracking, and recognition of humans. Moreover, this survey describes the nature of thermal radiation and the technology of thermal cameras....

  19. Thermal Properties Measurement Report

    Energy Technology Data Exchange (ETDEWEB)

    Carmack, Jon [Idaho National Lab. (INL), Idaho Falls, ID (United States); Braase, Lori [Idaho National Lab. (INL), Idaho Falls, ID (United States); Papesch, Cynthia [Idaho National Lab. (INL), Idaho Falls, ID (United States); Hurley, David [Idaho National Lab. (INL), Idaho Falls, ID (United States); Tonks, Michael [Idaho National Lab. (INL), Idaho Falls, ID (United States); Zhang, Yongfeng [Idaho National Lab. (INL), Idaho Falls, ID (United States); Gofryk, Krzysztof [Idaho National Lab. (INL), Idaho Falls, ID (United States); Harp, Jason [Idaho National Lab. (INL), Idaho Falls, ID (United States); Fielding, Randy [Idaho National Lab. (INL), Idaho Falls, ID (United States); Knight, Collin [Idaho National Lab. (INL), Idaho Falls, ID (United States); Meyer, Mitch [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2015-08-01

    The Thermal Properties Measurement Report summarizes the research, development, installation, and initial use of significant experimental thermal property characterization capabilities at the INL in FY 2015. These new capabilities were used to characterize a U3Si2 (candidate Accident Tolerant) fuel sample fabricated at the INL. The ability to perform measurements at various length scales is important and provides additional data that is not currently in the literature. However, the real value of the data will be in accomplishing a phenomenological understanding of the thermal conductivity in fuels and the ties to predictive modeling. Thus, the MARMOT advanced modeling and simulation capability was utilized to illustrate how the microstructural data can be modeled and compared with bulk characterization data. A scientific method was established for thermal property measurement capability on irradiated nuclear fuel samples, which will be installed in the Irradiated Material Characterization Laboratory (IMCL).

  20. Compliant thermal microactuators

    DEFF Research Database (Denmark)

    Jonsmann, Jacques; Sigmund, Ole; Bouwstra, Siebe

    1999-01-01

    Two dimensional compliant metallic thermal microactuators are designed using topology optimisation, and microfabricated using rapid prototyping techniques. Structures are characterised using advanced image analysis, yielding a very high precision. Characterised structures behave in accordance...

  1. 大麻素受体2激动剂JWH015对瑞芬太尼诱发痛觉过敏的影响%The effect of cannabinoid receptor 2 agonist JWH015 on the hyperalgesia induced by remifentanil

    Institute of Scientific and Technical Information of China (English)

    张威; 张伟; 刘晓杰; 张娟; 蒋明; 马正良; 顾小萍

    2012-01-01

    ):control groups ( C1 and C2 ),incisional pain groups (I1 and I2),incisional pain plus JWHO15 groups (QI and FI),remifentanil groups (R1 and R2),and JWHO15 plus remifentanil groups ( QR and FR).Rats in group QL/QR and FI/FR were intrathecal injection with 10μg JWHO15 ( diluted in 10μl 20% DMSO solution) and intraperitoneal administration with 100μg JWHO15 ( diluted in 10μl 4% DMSO solution) respectively 30 min before plantar incision while rats in group C,I and R were received with the same volume of DMSO solution.Plantar incision surgery was operated in rats of group I,R,QI/FI,and QR/FR.In group R and QR/FR,remifentanil (0.04 mg/kg) was infused subcutaneously to rats with a pump for 30 min at the moment of surgical incision.The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) at 24 h before incision and at 2 h,6 h,24 h and 48 h after incision were tested to evaluate the behavioral changes.Results Compared with group C and baseline,the level of PWMT and PWTL decreased at 2 h,6 h,24 h and 48h after incision in group Ⅰ (P< 0.01 ) ;Compared with group Ⅰ,the significant decrease of PWMT and PWTL were observed after incision in group R (P < 0.05 ) ; Compared with group R,the significant increase of PWMT (7.78 ± 1.09) and PWTL ( 17.28 ± 1.58) were observed from 6 h after incision in group QR(P<0.05).And the increase of PWMT (7.79 ±0.72,9.50 ± 1.17,7.86 ± 1.16) and PWTL ( 16.23 ± 1.50,19.53 ± 1.63,18.10 ± 0.93) were observed at 6 h,24 h and 48 h after incision in group FR(P<0.05).Conclusion Intrathecal and intraperitoneal administration of JWHO15 in this investigation dose could relief remifentanil-induced hyperalgesia in a rat model of postoperative pain.

  2. ThermalTracker Software

    Energy Technology Data Exchange (ETDEWEB)

    2016-08-10

    The software processes recorded thermal video and detects the flight tracks of birds and bats that passed through the camera's field of view. The output is a set of images that show complete flight tracks for any detections, with the direction of travel indicated and the thermal image of the animal delineated. A report of the descriptive features of each detected track is also output in the form of a comma-separated value text file.

  3. Thermal conveyance systems

    Energy Technology Data Exchange (ETDEWEB)

    Meador, J.T.

    1978-09-01

    The purpose of the evaluation is to characterize modern technology for long-distance, large-diameter, underground steam and high-temperature water (HTW) transport systems and for hot-water and chilled-water systems that distribute thermal energy within communities. Data on the status of existing systems have been compiled and compared with recommended design factors for fluid flow to aid in parameter selection for assessing performance in transporting and distributing thermal energy.

  4. Thermal flow micro sensors

    OpenAIRE

    Elwenspoek, M.

    1999-01-01

    A review is given on sensors fabricated by silicon micromachining technology using the thermal domain for the measurement of fluid flow. Attention is paid especially to performance and geometry of the sensors. Three basic types of thermal flow sensors are discussed: anemometers, calorimetric flow sensors and time of flight flow sensors. Anemometers may comprise several heaters and temperature sensors and from a geometric point of view are similar sometimes for calorimetric flow sensors. We fi...

  5. Thermal axion production

    OpenAIRE

    Salvio, Alberto; Strumia, Alessandro; Xue, Wei

    2014-01-01

    We reconsider thermal production of axions in the early universe, including axion couplings to all Standard Model (SM>) particles. Concerning the axion coupling to gluons, we find that thermal effects enhance the axion production rate by a factor of few with respect to previous computations performed in the limit of small strong gauge coupling. Furthermore, we find that the top Yukawa coupling induces a much larger axion production rate, unless the axion couples to SM particles only via anom...

  6. Thermal radiation heat transfer

    CERN Document Server

    Howell, John R; Siegel, Robert

    2016-01-01

    Further expanding on the changes made to the fifth edition, Thermal Radiation Heat Transfer, 6th Edition continues to highlight the relevance of thermal radiative transfer and focus on concepts that develop the radiative transfer equation (RTE). The book explains the fundamentals of radiative transfer, introduces the energy and radiative transfer equations, covers a variety of approaches used to gauge radiative heat exchange between different surfaces and structures, and provides solution techniques for solving the RTE.

  7. Thermal Activated Envelope

    DEFF Research Database (Denmark)

    Foged, Isak Worre; Pasold, Anke

    2015-01-01

    search procedure, the combination of materials and their bonding temperature is found in relation to the envelope effect on a thermal environment inside a defined space. This allows the designer to articulate dynamic composites with time-based thermal functionality, related to the material dynamics......, environmental dynamics and occupancy dynamics. Lastly, a physical prototype is created, which illustrates the physical expression of the bi-materials and the problems related to manufacturing of these composite structures....

  8. Nanoscale thermal probing

    Directory of Open Access Journals (Sweden)

    Yanan Yue

    2012-03-01

    Full Text Available Nanoscale novel devices have raised the demand for nanoscale thermal characterization that is critical for evaluating the device performance and durability. Achieving nanoscale spatial resolution and high accuracy in temperature measurement is very challenging due to the limitation of measurement pathways. In this review, we discuss four methodologies currently developed in nanoscale surface imaging and temperature measurement. To overcome the restriction of the conventional methods, the scanning thermal microscopy technique is widely used. From the perspective of measuring target, the optical feature size method can be applied by using either Raman or fluorescence thermometry. The near-field optical method that measures nanoscale temperature by focusing the optical field to a nano-sized region provides a non-contact and non-destructive way for nanoscale thermal probing. Although the resistance thermometry based on nano-sized thermal sensors is possible for nanoscale thermal probing, significant effort is still needed to reduce the size of the current sensors by using advanced fabrication techniques. At the same time, the development of nanoscale imaging techniques, such as fluorescence imaging, provides a great potential solution to resolve the nanoscale thermal probing problem.

  9. Thermal Mud Molecular Overview

    Directory of Open Access Journals (Sweden)

    Ersin Odabasi

    2014-06-01

    Full Text Available Thermal mud (peloids, which are frequently used for thermal therapy purposes consist of organic and inorganic (minerals compounds in general. Organic structure is formed after a variety of chemical processes occurring in decades and comprise of a very complex structure. Stagnant water environment, herbal diversity, microorganism multiplicity and time are crucial players to form the structure. Data regarding description of organic compounds are very limited. Nowadays, it was clearly understood that a variety of compounds those are neglected in daily practice are found in thermal mud after GC-MS and similar methods are being frequently used. Those compounds which are biologically active are humic compounds, carboxylic acids, terpenoids, steroids and fatty acids. By comprising the thermal mud, these different compound groups which are related to divers areas from cosmetology to inflammation, make the thermal mud very meaningful in the treatment of human disease. In this review, it was tried to put forward the effects of several molecule groups those consisting of the thermal mud structure. [TAF Prev Med Bull 2014; 13(3.000: 257-264

  10. LISA thermal design

    Energy Technology Data Exchange (ETDEWEB)

    Peabody, Hume [Swales Aerospace, Inc., 5050 Powder Mill Road, Beltsville, MD 20705 (United States); Merkowitz, Stephen [NASA' s Goddard Space Flight Center, Greenbelt, MD 20771 (United States)

    2005-05-21

    The Laser Interferometer Space Antenna (LISA) mission, a space-based gravitational wave detector, uses laser metrology to measure distance fluctuations between proof masses aboard three spacecraft. The total acceleration disturbance to each proof mass is required to be below 3 x 10{sup -15} m s{sup -2} Hz{sup -1/2} at 0.1 mHz. Optical path length variations on each optical bench must be kept below about 40 pm Hz{sup -1/2} over 1-100 mHz. Noise due to spacecraft thermal distortions, temperature difference variations across the proof mass housing and other thermal effects are expected to be significant contributors to these noise budgets. The LISA Integrated Modelling team developed a detailed thermal model that is currently being used to drive the design of LISA. Several new thermal analysis techniques are also being developed in order to achieve model accuracies to LISA levels. We present here an overview of the LISA thermal design and modelling efforts. The latest thermal results calculated using the current baseline design of LISA are also discussed.

  11. Thermal management of space stations

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Thermal management aims at making full use of energy resources available in the space station to reduce energy consumption, waste heat rejection and the weight of the station. It is an extension of the thermal control. This discussion introduces the concept and development of thermal management, presents the aspects of thermal management and further extends its application to subsystems of the space station.

  12. EVIDENCE FOR INVOLVEMENT OF SPINAL VANILLOID RECEPTOR 1(VR1) IN THERMAL SENSITIVITY:A COMBINED BEHAVIORAL AND IMMUNOHISTOCHEMICAL STUDY IN AGED RATS%脊髓辣椒素受体1(VR1)参与热敏感性的证据:老龄大鼠行为学和形态学相结合观察结果

    Institute of Scientific and Technical Information of China (English)

    李会莉; 李昌林; 陈军

    2004-01-01

    Previous study has shown that peripheral heat nociceptor, vanilloid receptor 1 (VR1, also termed as TRPV1) is critically involved in nociceptive thermal sensation, however, the role of spinal VR1 is not clear. To study the spinal role of VR1 in thermal sensitivity under peripheral tissue injury and inflammatory pain state in aged rats, bee venom (BV) model was used due to its behavioral feature of time course dissociation between heat hyperalgesia (lasting only for 24 h) and mechanical hyperalgesia (lasting for more than 1 month) in aged rats. Immunohistochemical staining of VR1 was carried out in the spinal cord after identification of both heat (to radiant heat) and mechanical (to von Frey filaments) sensitivity at 4 h after BV when both heat and mechanical hyperalgesia existed, 2 weeks after BV when only mechanical hyperalgesia existed, and 2 months after BV when both types of hyperalgesia disappeared. The results were as follows: (1) in the untreated aged rats, the spatial distribution of VR1like immunoreactivity (LI) was mainly localized in lamina Ⅰ and Ⅱ of the spinal cord; (2) in the BV-treated aged rats, VR1-LI in the spinal dorsal horn was slightly increased 4 h after peripheral injury, however, it was decreased 2 weeks after BV compared to the control. Moreover, the decreased level of spinal VR1-LI did not recover to the control level when both types of hyperalgesia disappeared 2 months after BV injection. The present results suggest that spatial distribution of VR1-LI in the spinal cord is not changed with aging under normal state, however, under peripheral chemical tissue injury or inflammation, the level of its expression is likely to be dynamically associated with the changes of thermal sensitivity. Taken together, we propose that besides peripheral sites, VR1 in the spinal cord dorsal horn is likely to be also involved in maintenance of thermal pain threshold level as well as in generation of heat hyperalgesia.%以往的研究表明外周热伤

  13. Thermal conductivity of thermal barrier coatings

    Energy Technology Data Exchange (ETDEWEB)

    Klemens, P.G.; Gell, M. [Connecticut Univ., Storrs, CT (United States). Inst. of Materials Science

    1998-05-01

    In thermal barrier coatings and other ceramic oxides, heat is conducted by lattice waves, and also by a radiative component which becomes significant at high temperatures. The theory of heat conduction by lattice waves is reviewed in the equipartition limit (above room temperature). The conductivity is composed of contributions from a spectrum of waves, determined by the frequency dependent attenuation length. Interaction between lattice waves (intrinsic processes), scattering by atomic scale point defects and scattering by extended imperfections such as grain boundaries, each limit the attenuation length in different parts of the spectrum. Intrinsic processes yield a spectral conductivity which is independent of frequency. Point defects reduce the contribution of the high frequency spectrum, grain boundaries and other extended defects that of the low frequencies. These reductions are usually independent of each other. Estimates will be given for zirconia containing 7wt% Y{sub 2}O{sub 3}, and for yttrium aluminum garnet. They will be compared to measurements. The effects of grain size, cracks and porosity will be discussed both for the lattice and the radiative components. While the lattice component of the thermal conductivity is reduced substantially by decreasing the grain size to nanometers, the radiative component requires pores or other inclusions of micrometer scale. (orig.) 9 refs.

  14. Thermal Arc Spray Overview

    Science.gov (United States)

    Hafiz Abd Malek, Muhamad; Hayati Saad, Nor; Kiyai Abas, Sunhaji; Mohd Shah, Noriyati

    2013-06-01

    Usage of protective coating for corrosion protection was on highly demand during the past decade; and thermal spray coating played a major part during that time. In recent years, the thermal arc spray coating becomes a popular coating. Many big players in oil and gas such as PETRONAS, EXXON MOBIL and SHELL in Malaysia tend to use the coating on steel structure as a corrosion protection. Further developments in coating processes, the devices, and raw materials have led to expansion of functional coatings and applications scope from conventional coating to specialized industries. It is widely used because of its ability to withstand high process temperature, offer advantages in efficiency, lower cost and acts as a corrosion protection. Previous research also indicated that the thermal arc spray offers better coating properties compared to other methods of spray. This paper reviews some critical area of thermal spray coating by discussing the process/parameter of thermal arc spray technology and quality control of coating. Coating performance against corrosion, wear and special characteristic of coating are also described. The field application of arc spray technology are demonstrated and reviewed.

  15. Thermal Magnifier and Minifier

    Science.gov (United States)

    Shen, Xiang-Ying; Chen, Yi-Xuan; Huang, Ji-Ping

    2016-03-01

    For thermal conduction cases, one can detect the size of an object explicitly by measuring the temperature distribution around it. If the temperature is the only signature we can obtain, we will give an incorrect judgment on the shape or size of the object by disturbing the distribution of it. According to this principle, in this article, we develop a transformation method and design a dual-functional thermal device, which can create a thermal illusion that the object inside it “seems” to appear bigger or smaller than its original size. This device can functionally switch among magnifier and minifier at will. The proposed device consists of two layers: the cloak and the complementary material. A thermal cloak can make the internal region thermally “invisible” while the complementary layer offsets this effect. The combination leads to the illusion of magnification and minification. As a result of finite element simulations, the performances of the illusions are confirmed. Support by the National Natural Science Foundation of China under Grant No. 11222544, by the Fok Ying Tung Education Foundation under Grant No. 131008, by the Program for New Century Excellent Talents in University (NCET-12-0121), and by the Chinese National Key Basic Research Special Fund under Grant No. 2011CB922004

  16. Thermal transport in graphene

    Science.gov (United States)

    Sadeghi, Mir Mohammad; Pettes, Michael Thompson; Shi, Li

    2012-08-01

    The recent advances in graphene isolation and synthesis methods have enabled potential applications of graphene in nanoelectronics and thermal management, and have offered a unique opportunity for investigation of phonon transport in two-dimensional materials. In this review, current understanding of phonon transport in graphene is discussed along with associated experimental and theoretical investigation techniques. Several theories and experiments have suggested that the absence of interlayer phonon scattering in suspended monolayer graphene can result in higher intrinsic basal plane thermal conductivity than that for graphite. However, accurate experimental thermal conductivity data of clean suspended graphene at different temperatures are still lacking. It is now known that contact of graphene with an amorphous solid or organic matrix can suppress phonon transport in graphene, although further efforts are needed to better quantify the relative roles of interface roughness scattering and phonon leakage across the interface and to examine the effects of other support materials. Moreover, opportunities remain to verify competing theories regarding mode specific scattering mechanisms and contributions to the total thermal conductivity of suspended and supported graphene, especially regarding the contribution from the flexural phonons. Several measurements have yielded consistent interface thermal conductance values between graphene and different dielectrics and metals. A challenge has remained in establishing a comprehensive theoretical model of coupled phonon and electron transport across the highly anisotropic and dissimilar interface.

  17. On the possible thermal tachyons

    OpenAIRE

    Kozlowski, Miroslaw; Marciak-Kozlowska, Janina

    2006-01-01

    In this paper the existence of the thermal tachyons i.e. quanta of temperature field, with is described in the theoretical frame of hyperbolic thermal equation. The modified Lorentz transformation are developed. It is argued that thermal tachyons can exist in accordance with modified Lorentz transformation after change . The thermal tachyons fulfill the hyperbolic heat transport equation and in principle can be created by attosecond laser pulses. Key words: Tachyons; Thermal processes; Attose...

  18. Thermal Diffusivity Measurements in Edible Oils using Transient Thermal Lens

    Science.gov (United States)

    Valdez, R. Carbajal.; Pérez, J. L. Jiménez.; Cruz-Orea, A.; Martín-Martínez, E. San.

    2006-11-01

    Time resolved thermal lens (TL) spectrometry is applied to the study of the thermal diffusivity of edible oils such as olive, and refined and thermally treated avocado oils. A two laser mismatched-mode experimental configuration was used, with a He Ne laser as a probe beam and an Ar+ laser as the excitation one. The characteristic time constant of the transient thermal lens was obtained by fitting the experimental data to the theoretical expression for a transient thermal lens. The results showed that virgin olive oil has a higher thermal diffusivity than for refined and thermally treated avocado oils. This measured thermal property may contribute to a better understanding of the quality of edible oils, which is very important in the food industry. The thermal diffusivity results for virgin olive oil, obtained from this technique, agree with those reported in the literature.

  19. Highly Thermal Conductive Nanocomposites

    Science.gov (United States)

    Sun, Ya-Ping (Inventor); Connell, John W. (Inventor); Veca, Lucia Monica (Inventor)

    2015-01-01

    Disclosed are methods for forming carbon-based fillers as may be utilized in forming highly thermal conductive nanocomposite materials. Formation methods include treatment of an expanded graphite with an alcohol/water mixture followed by further exfoliation of the graphite to form extremely thin carbon nanosheets that are on the order of between about 2 and about 10 nanometers in thickness. Disclosed carbon nanosheets can be functionalized and/or can be incorporated in nanocomposites with extremely high thermal conductivities. Disclosed methods and materials can prove highly valuable in many technological applications including, for instance, in formation of heat management materials for protective clothing and as may be useful in space exploration or in others that require efficient yet light-weight and flexible thermal management solutions.

  20. Concepts in Thermal Physics

    CERN Document Server

    Blundell, Stephen J

    2006-01-01

    This modern introduction to thermal physics contains a step-by-step presentation of the key concepts. The text is copiously illustrated and each chapter contains several worked examples. - ;An understanding of thermal physics is crucial to much of modern physics, chemistry and engineering. This book provides a modern introduction to the main principles that are foundational to thermal physics, thermodynamics, and statistical mechanics. The key concepts are carefully presented in a clear way, and new ideas are illustrated with copious worked examples as well as a description of the historical background to their discovery. Applications are presented to subjects as. diverse as stellar astrophysics, information and communication theory, condensed matter physics, and climate change. Each chapter concludes with detailed exercises. -

  1. Thermally stable deployable structure

    Science.gov (United States)

    Kegg, Colleen M.

    1988-01-01

    A deployable structure which meets stringent thermal and strength requirements in a space environment was developed. A mast with a very low coefficient of thermal expansion (CTE) was required to limit the movement from thermal distortion over the temperature range of -200 C to 80 C to .064 cm (.025 in). In addition, a high bending strength over the temperature range and weight less than 18.1 kg (40 lbs) was needed. To meet all of the requirements, a composite, near-zero CTE structure was developed. The measured average CTE over the temperature range for the mast was .70 x .000001/C (.38 x .000001/F). The design also has the advantage of being adjustable to attain other specific CTE if desired.

  2. THERMAL NEUTRON BACKSCATTER IMAGING.

    Energy Technology Data Exchange (ETDEWEB)

    VANIER,P.; FORMAN,L.; HUNTER,S.; HARRIS,E.; SMITH,G.

    2004-10-16

    Objects of various shapes, with some appreciable hydrogen content, were exposed to fast neutrons from a pulsed D-T generator, resulting in a partially-moderated spectrum of backscattered neutrons. The thermal component of the backscatter was used to form images of the objects by means of a coded aperture thermal neutron imaging system. Timing signals from the neutron generator were used to gate the detection system so as to record only events consistent with thermal neutrons traveling the distance between the target and the detector. It was shown that this time-of-flight method provided a significant improvement in image contrast compared to counting all events detected by the position-sensitive {sup 3}He proportional chamber used in the imager. The technique may have application in the detection and shape-determination of land mines, particularly non-metallic types.

  3. Thermal Nanosystems and Nanomaterials

    CERN Document Server

    Volz, Sebastian

    2009-01-01

    Heat transfer laws for conduction, radiation and convection change when the dimensions of the systems in question shrink. The altered behaviours can be used efficiently in energy conversion, respectively bio- and high-performance materials to control microelectronic devices. To understand and model those thermal mechanisms, specific metrologies have to be established. This book provides an overview of actual devices and materials involving micro-nanoscale heat transfer mechanisms. These are clearly explained and exemplified by a large spectrum of relevant physical models, while the most advanced nanoscale thermal metrologies are presented.

  4. The attenuate hyperalgesia effect of intrathecal U0126 in a rat model of bone cancer pain%骨癌痛大鼠鞘内注射U0126的抗痛觉过敏作用

    Institute of Scientific and Technical Information of China (English)

    李彩芳; 杨建平; 王丽娜; 刘磊; 胡计嬅; 刘思兰

    2011-01-01

    目的 研究鞘内注射(it)U0126对骨癌痛大鼠机械痛敏的影响和对脊髓背角磷酸化cAMP反应元件结合蛋白(pCREB)表达的影响,探讨ERK-CREB信号转导通路在骨癌痛中的作用.方法 ① 40只成年♀SD大鼠分为5组,假模型组Ⅰ和骨癌痛模型组Ⅱ、Ⅲ、Ⅳ、Ⅴ.建模后d 10每只大鼠分别it 10 μg U0126、5%二甲亚砜10 μl和U0126 0.1、1、10 μg(U0126溶于10 μl 5%二甲亚砜中),测机械性缩爪阈值(MWT)和双下肢负重差(WBD);② 25只成年♀SD大鼠分为5组,T1、T2和T3组在制作骨癌痛模型后d 10,it U0126 10 μg后1、6、24 h处死大鼠,M组为模型对照组,it 5%二甲亚砜10 μl后6 h处死大鼠,S组为空白对照组.免疫组化方法测定L4-6术侧脊髓背角pCREB免疫反应阳性神经元数量.结果 鞘内注射U0126 1 μg和10 μg明显逆转了骨癌痛引起的机械痛敏;鞘内注射10 μg U0126明显减少脊髓背角pCREB表达,且效果至少可持续6 h.结论 ERK-CREB通路可能参与骨癌痛.%Aim To investigate the effect of intrathecal ( i. t. ) U0126( MAPK kinase inhibitor ) on the mechanical hyperalgesia and the expression of phosphorylated cAMP response element binding protein( pCREB ) in the dorsal horn of spinal cord following bone cancer pain in rats , trying to evaluate the role played by ERKCREB signal transmission pathway in the mechanism of bone cancer pain. Methods ① 40 adult female SD rats were divided into five groups. Sham group Ⅰ and bone cancer pain ( BCP ) group rats Ⅱ . Ⅲ , Ⅳ , Ⅴ received a bolus of 10 μg U0126. 5% DMSO 10 μl,U0126 0. 1, 1, 10 μg i. t. respectively on the 10th day after the model was made. Mechanical withdrawal threshold ( MWT ) and weight bearing difference ( WBD ) were measured;②25 adult female SD rats were divided into five groups. On the lOth day after the model was made, BCP rats of group T1 , T2 and T3 were killed at 1, 6. 24 h after i. t. U0126 10 μg respectively. In group M, rats produced bone

  5. 鞘内注射KN93或艾芬地尔对瑞芬太尼致痛觉过敏的镇痛作用%The preventive effect of intrathecal KN93 or Ifenprodil administration on remifentanil-induced incisional hyperalgesia

    Institute of Scientific and Technical Information of China (English)

    张兢; 顾小萍; 程崇学; 马正良

    2014-01-01

    subcutaneously 30 min in R group,K group and F group,30 min before incisional model,20 μl dimethyl sulfoxide (DMSO,10%),20 μl KN93 (50 μg/10 μl) and 20 μl Ifenprodil (10 μg/20 μl) were intrathecally injected to rats in R group,K group or F group respectively.Paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were tested on 24 h before and 2,6,24,48 h after operation.Results The PWTL and PMWT on the ipsilateral side significantly decreased after operation in Ⅰ group compared with C group; and evenshortenin R group than that in Ⅰ group.Compared with R group,the PWTL(15.32±0.73),(15.79±0.32),(14.86±0.98),(14.76±0.82) s and PMWT (31.8±1.4),(29.3±1.2),(30.8±1.0),(30.5±1.2) g significantly increased in K group(P<0.05) at each time point.Meanwhile,the PWTL(14.24±0.79),(15.33±0.29),(15.29±0.74),(15.21±0.45) s and PMWT(29.3±1.8),(30.2±2.1),(29.5±1.5),(30.2±1.0) g obviously increased in F group(P<0.05) at each time point.Conclusions Intrathecal injection of KN93 or Ifenprodil coulde effectively alleviate remifentanil-induced hyperalgesia.

  6. Shape memory thermal conduction switch

    Science.gov (United States)

    Vaidyanathan, Rajan (Inventor); Krishnan, Vinu (Inventor); Notardonato, William U. (Inventor)

    2010-01-01

    A thermal conduction switch includes a thermally-conductive first member having a first thermal contacting structure for securing the first member as a stationary member to a thermally regulated body or a body requiring thermal regulation. A movable thermally-conductive second member has a second thermal contacting surface. A thermally conductive coupler is interposed between the first member and the second member for thermally coupling the first member to the second member. At least one control spring is coupled between the first member and the second member. The control spring includes a NiTiFe comprising shape memory (SM) material that provides a phase change temperature <273 K, a transformation range <40 K, and a hysteresis of <10 K. A bias spring is between the first member and the second member. At the phase change the switch provides a distance change (displacement) between first and second member by at least 1 mm, such as 2 to 4 mm.

  7. Thermal management for LED applications

    CERN Document Server

    Poppe, András

    2014-01-01

    Thermal Management for LED Applications provides state-of-the-art information on recent developments in thermal management as it relates to LEDs and LED-based systems and their applications. Coverage begins with an overview of the basics of thermal management including thermal design for LEDs, thermal characterization and testing of LEDs, and issues related to failure mechanisms and reliability and performance in harsh environments. Advances and recent developments in thermal management round out the book with discussions on advances in TIMs (thermal interface materials) for LED applications, advances in forced convection cooling of LEDs, and advances in heat sinks for LED assemblies. This book also: Presents a comprehensive overview of the basics of thermal management as it relates to LEDs and LED-based systems Discusses both design and thermal management considerations when manufacturing LEDs and LED-based systems Covers reliability and performance of LEDs in harsh environments Has a hands-on applications a...

  8. Ecology: Insect thermal baggage

    Science.gov (United States)

    Williams, Caroline

    2016-06-01

    Strong positive selection on cold hardiness and relaxed selection on heat hardiness experienced by range-expanding populations may help to explain why ectothermic animals generally have broader thermal tolerance towards the poles, and shed new light on their climate vulnerabilities.

  9. Advanced Thermal Conversion Systems

    Science.gov (United States)

    2015-03-18

    Research Triangle Park , NC 27709-2211 PETE process, Solar , thermal isolation, optimal cathode-anode separation REPORT DOCUMENTATION PAGE 11...SECURITY CLASSIFICATION OF: This project evaluated the scientific and technical feasibility of a solar energy converter based on photon enhanced...demonstrating that a structurally stable solar -enhanced converters can be created using microfabrication techniques and (2) Identifying materials that

  10. Thermal Analysis of Plastics

    Science.gov (United States)

    D'Amico, Teresa; Donahue, Craig J.; Rais, Elizabeth A.

    2008-01-01

    This lab experiment illustrates the use of differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) in the measurement of polymer properties. A total of seven exercises are described. These are dry exercises: students interpret previously recorded scans. They do not perform the experiments. DSC was used to determine the…

  11. Thermal Reactor Safety

    Energy Technology Data Exchange (ETDEWEB)

    1980-06-01

    Information is presented concerning fire risk and protection; transient thermal-hydraulic analysis and experiments; class 9 accidents and containment; diagnostics and in-service inspection; risk and cost comparison of alternative electric energy sources; fuel behavior and experiments on core cooling in LOCAs; reactor event reporting analysis; equipment qualification; post facts analysis of the TMI-2 accident; and computational methods.

  12. Optical Thermal Ratchet

    Science.gov (United States)

    Faucheux, L. P.; Bourdieu, L. S.; Kaplan, P. D.; Libchaber, A. J.

    1995-02-01

    We present an optical realization of a thermal ratchet. Directed motion of Brownian particles in water is induced by modulating in time a spatially periodic but asymmetric optical potential. The net drift shows a maximum as a function of the modulation period. The experimental results agree with a simple theoretical model based on diffusion.

  13. Photon thermal Hall effect

    CERN Document Server

    Ben-Abdallah, Philippe

    2015-01-01

    A near-field thermal Hall effect (i.e.Righi-Leduc effect) in lattices of magneto-optical particles placed in a constant magnetic field is predicted. This effect is related to a symetry breaking in the system induced by the magnetic field which gives rise to preferential channels for the heat-transport by photon tunneling thanks to the particles anisotropy tuning.

  14. Thermally assisted MRAM

    Energy Technology Data Exchange (ETDEWEB)

    Prejbeanu, I L [Spintec, URA 2512 CEA/CNRS, CEA-Grenoble, 17 r. des Martyrs, 38054 Grenoble Cedex 9 (France); Kerekes, M [Spintec, URA 2512 CEA/CNRS, CEA-Grenoble, 17 r. des Martyrs, 38054 Grenoble Cedex 9 (France); Sousa, R C [Spintec, URA 2512 CEA/CNRS, CEA-Grenoble, 17 r. des Martyrs, 38054 Grenoble Cedex 9 (France); Sibuet, H [LIMN, DRT/Leti/DIHS, CEA-Grenoble, 17 r. des Martyrs, 38054 Grenoble Cedex 9 (France); Redon, O [LIMN, DRT/Leti/DIHS, CEA-Grenoble, 17 r. des Martyrs, 38054 Grenoble Cedex 9 (France); Dieny, B [Spintec, URA 2512 CEA/CNRS, CEA-Grenoble, 17 r. des Martyrs, 38054 Grenoble Cedex 9 (France); Nozieres, J P [Crocus Technology, 5 Place Robert Schumann, BP 1510, 38025 Grenoble Cedex 1 (France)

    2007-04-23

    Magnetic random access memories (MRAMs) are a new non-volatile memory technology trying establish itself as a mainstream technology. MRAM cell operation using a thermally assisted writing scheme (TA-MRAM) is described in this review as well as its main design challenges. This approach is compared to conventional MRAM, highlighting the improvements in write selectivity, power consumption and thermal stability. The TA-MRAM writing was tested and validated in the dynamic regime down to 500 ps write pulses. The heating process was investigated for the influence of the voltage pulse width, junction area and lead volume looking at the required write power density. The possibilities to control and reduce the write power density are described. The most promising solution to optimize the heating process and reduce the power consumption is to insert two thermal barrier layers at both ends of the MTJ layer stack, between the junction and the electrical leads, using low thermal conductivity materials. This minimizes the heating losses and improves the heating efficiency.

  15. Occupant thermal comfort evaluation

    Science.gov (United States)

    Ghiardi, Gena L.

    1999-03-01

    Throughout the automotive industry there has been an increasing concern and focus on the thermal comfort of occupants. Manufacturers are continuously striving to improve heating and air conditioning performance to comply with expanding customer needs. To optimize these systems, the technology to acquire data must also be enhanced. In this evaluation, the standard use of isolated thermocouple location technology is compared to utilizing infrared thermal vision in an air conditioning performance assessment. Infrared data on an actual occupant is correlated to breath and air conditioning output temperatures measured by positioned thermocouples. The use of infrared thermal vision highlights various areas of comfort and discomfort experienced by the occupant. The evaluation involves utilizing an infrared thermal vision camera to film an occupant in the vehicle as the following test procedure is run. The vehicle is soaked in full sun load until the interior temperature reaches a minimum of 150 degrees F (65.6 degrees Celsius). The occupant enters the vehicle and takes an initial temperature reading. The air conditioning is turned on to full cold, full fan speed, and recirculation mode. While being filmed, the driver drives for sixty minutes at 30 miles per hour (48.3 kph). The thermocouples acquire data in one minute intervals while the infrared camera films the cooling process of the occupant.

  16. Solar thermal financing guidebook

    Energy Technology Data Exchange (ETDEWEB)

    Williams, T.A.; Cole, R.J.; Brown, D.R.; Dirks, J.A.; Edelhertz, H.; Holmlund, I.; Malhotra, S.; Smith, S.A.; Sommers, P.; Willke, T.L.

    1983-05-01

    This guidebook contains information on alternative financing methods that could be used to develop solar thermal systems. The financing arrangements discussed include several lease alternatives, joint venture financing, R and D partnerships, industrial revenue bonds, and ordinary sales. In many situations, alternative financing arrangements can significantly enhance the economic attractiveness of solar thermal investments by providing a means to efficiently allocate elements of risk, return on investment, required capital investment, and tax benefits. A net present value approach is an appropriate method that can be used to investigate the economic attractiveness of alternative financing meth