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Tony L. Yaksh - One of the best experts on this subject based on the ideXlab platform.
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Intrathecal Protease-Activated Receptor Stimulation Produces Thermal Hyperalgesia through Spinal Cyclooxygenase Activity
The Journal of pharmacology and experimental therapeutics, 2004Co-Authors: Lee Koetzner, Joshua A. Gregory, Tony L. YakshAbstract:Activation of protease-activated receptors (PARs) in non-neural tissue results in prostaglandin production. Because PARs are found in the spinal cord and increased prostaglandin release in the spinal cord causes Thermal Hyperalgesia, we hypothesized that activation of these spinal PARs would stimulate prostaglandin production and cause a cyclooxygenase-dependent Thermal Hyperalgesia. PARs were activated using either thrombin or peptide agonists derived from the four PAR subtypes, delivered to the lumbar spinal cord. Dialysis experiments were conducted in conscious, unrestrained rats using loop microdialysis probes placed in the lumbar intrathecal space. Intrathecal thrombin stimulated release of prostaglandin E (PGE) 2 but not aspartate or glutamate. Intrathecal delivery of the PAR 1-derived peptide SFLLRN-NH 2 and the PAR 2-derived peptide SLIGRL both stimulated PGE 2 release; PAR 3-derived TFRGAP and PAR 4-derived GYPGQV were inactive. Intrathecal thrombin had no effect upon formalin-induced flinching or tactile sensitivity but resulted in a Thermal Hyperalgesia. Intrathecal SFLLRN-NH 2 and SLIGRL both produced Thermal Hyperalgesia. Consistent with their effects on spinal PGE 2 , Hyperalgesia from these peptides was blocked by pretreatment with the cyclooxygenase inhibitor ibuprofen. SLIGRL-induced Hyperalgesia was also blocked by the selective inhibitors SC 58,560 [5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1 H -pyrazole; cyclooxygenase (COX) 1] and SC 58,125 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1 H -pyrazole; COX 2]. These data indicate that activation of spinal PAR 2 and possibly PAR 1 results in the stimulation of the spinal cyclooxygenase cascade and a prostaglandin-dependent Thermal Hyperalgesia.
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spinal p38 map kinase is necessary for nmda induced spinal pge 2 release and Thermal Hyperalgesia
Neuroreport, 2003Co-Authors: Camilla I Svensson, Xiaoying Hua, Andrew A Protter, Henry C Powell, Tony L. YakshAbstract:Based on previous work, we hypothesized that activation of spinal NMDA-receptor initiates activation of the p38 mitogen-activated protein kinase (p38 MAPK) pathway, leading to spinal release of prostaglandins and Hyperalgesia. Accordingly, we examined the effect of intrathecal SD-282, a selective p38 MAPK inhibitor, on NMDA-induced release of prostaglandin E(2) (PGE(2)) and Thermal Hyperalgesia. Inhibition of spinal p38 MAPK attenuated both NMDA-evoked release of PGE(2) and Thermal Hyperalgesia. NMDA injection led to increased phospho-p38 MAPK immunoreactivity in superficial (I-II) dorsal laminae. Co-labeling studies revealed co-localization of activated p38 MAPK predominantly with microglia but also with a small subpopulation of neurons. Taken together these data suggest a role for p38 MAPK in NMDA-induced PGE(2) release and Hyperalgesia, and that microglia is involved in spinal nociceptive processing.
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Pharmacology of Spinal Glutamatergic Receptors in Post–Thermal Injury–evoked Tactile Allodynia and Thermal Hyperalgesia
Anesthesiology, 2002Co-Authors: Natsuko Nozaki-taguchi, Tony L. YakshAbstract:BACKGROUND After a focal Thermal injury to the heel of a rat, Thermal Hyperalgesia appears at the injury site (primary Thermal Hyperalgesia), and tactile allodynia appears at the off-injury site (secondary tactile allodynia). The pharmacology of spinal glutamatergic receptors in the initiation and maintenance of secondary tactile allodynia was examined. METHODS In rats prepared with chronic intrathecal catheters, the heel of one hind paw was exposed to a 52 degrees C surface for 45 s, resulting in a local erythema without blistering. Intrathecal N-methyl-d-aspartate (NMDA) receptor antagonists (MK-801, AP5) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-kainate (AMPA-KA) receptor antagonists (CNQX, NBQX, NS257, etc.) were administered either before (pretreatment) or after (posttreatment) the induction of the injury. Tactile withdrawal thresholds and Thermal paw withdrawal latencies were assessed. RESULTS Pretreatment and posttreatment with AMPA-KA antagonists produced a dose-dependent blockade of secondary tactile allodynia. However, NMDA antagonists, in doses that effectively block other models of facilitated states, showed little or no effect. Primary Thermal Hyperalgesia was blocked only by high-dose AMPA-KA antagonists. CONCLUSION Spinal AMPA-KA receptors play a major role in the initiation of secondary tactile allodynia induced by focal Thermal injury. In contrast, spinal NMDA receptors play only a minimal role.
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intrathecal substance p induced Thermal Hyperalgesia and spinal release of prostaglandin e2 and amino acids
Neuroscience, 1999Co-Authors: Xiaoying Hua, Ping Chen, Martin Marsala, Tony L. YakshAbstract:Substance P is an important neuromediator in spinal synaptic transmission, particularly in processing nociceptive afferent information. The effects of substance P are mediated by activation of the neurokinin 1 receptor. Evidence has suggested that excitatory amino acids such as glutamate, and prostaglandins including prostaglandin E2 are involved in the enhanced spinal excitability and Hyperalgesia produced by spinal substance P. In the present study, we have demonstrated that intrathecal injection of substance P (20 nmol) in rats chronically implanted with intrathecal dialysis catheters induced a decrease in Thermal paw withdrawal latency (before: 10.4+/-0.3 s; after 7.6+/-0.6 s), which was accompanied by an increase in prostaglandin E2 (362+/-37% of baseline), glutamate (267+/-84%) and taurine (279+/-57%), but not glycine, glutamine, serine or asparagine. Intrathecal injection of artificial cerebrospinal fluid had no effect upon the behavior or release. Substance P-induced Thermal Hyperalgesia and prostaglandin E2 release were significantly attenuated by a selective neurokinin 1 receptor antagonist RP67580, but not by an enantiomer RP68651. However, substance P-induced release of glutamate and taurine was not reduced by treatment with RP67580. SR140333, another neurokinin 1 receptor antagonist, displayed the same effects as RP67580 (i.e. block of Thermal Hyperalgesia and prostaglandin E2 release, but not release of amino acids). These results provide direct evidence suggesting that the spinal substance P-induced Thermal Hyperalgesia is mediated by an increase in spinal prostaglandin E2 via activation of the neurokinin 1 receptor. These findings define an important linkage between small afferents, sensory neurotransmitter release and spinal prostanoids in the cascade of spinally-mediated Hyperalgesia. The evoked release of glutamate is apparently not a result of activation of neurokinin 1 receptors. Accordingly, consistent with other pharmacological data, acute spinal glutamate release does not contribute to the Hyperalgesia induced by activation of spinal neurokinin 1 receptors.
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EFFECT OF COX-1 AND COX-2 INHIBITION ON INDUCTION AND MAINTENANCE OF CARRAGEENAN-EVOKED Thermal Hyperalgesia IN RATS
The Journal of pharmacology and experimental therapeutics, 1998Co-Authors: David M. Dirig, Peter C. Isakson, Tony L. YakshAbstract:Intrathecal administration of nonsteroidal anti-inflammatory drugs in the rat blocks the Thermal Hyperalgesia induced by tissue injury, which suggests a role for spinal cyclooxygenase (COX) products in this facilitated state. Two isozymes of the COX enzyme have been reported, COX-1 and COX-2, but the agents thus far examined are not isozyme selective. We examined the effects of intrathecally (i.t.) or systemically (i.p.) administered S(+)-ibuprofen (a nonselective COX inhibitor) or 1-[(4-methysulfonyl)phenyl]-3-tri-fluoromethyl-5-(4-fluorophenyl) pyrazole (SC58125; a COX-2 selective inhibitor) on carrageenan-induced Thermal Hyperalgesia (reduced hindpaw-withdrawal latency). The following observations were made: 1) Thermal Hyperalgesia otherwise observed during the first 170 min was blocked in a dose-dependent manner by S(+)-ibuprofen or SC58125 administered i.t. or i.p. before carrageenan treatment. 2) Intraperitoneal, but not i.t., administration of either inhibitor after the establishment of Hyperalgesia (170 min after carrageenan injection) reversed Thermal Hyperalgesia in a dose-dependent manner. Thus, the initial component of Thermal Hyperalgesia after tissue injury was blocked by systemic or spinal administration of both COX inhibitors, whereas established Hyperalgesia was reversed only by systemic inhibitors. This study demonstrates that at least spinal COX-2, if not both COX-1 and COX-2, are necessary for the initiation of Thermal Hyperalgesia, whereas nonspinal sources of prostanoids (synthesized by COX-2 and perhaps also COX-1) are important for the maintenance of Thermal Hyperalgesia associated with tissue injury and inflammation.
Tsutomu Suzuki - One of the best experts on this subject based on the ideXlab platform.
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Involvement of a spinal brain-derived neurotrophic factor/full-length TrkB pathway in the development of nerve injury-induced Thermal Hyperalgesia in mice
Brain research, 2002Co-Authors: Yoshinori Yajima, Minoru Narita, Michiko Narita, Nozomi Matsumoto, Tsutomu SuzukiAbstract:Partial sciatic nerve ligation in mice caused a marked and persistent decrease in the latency of paw withdrawal from a Thermal stimulus only on the ipsilateral side. This Thermal Hyperalgesia was abolished by repeated intrathecal pretreatment with a specific antibody to brain-derived neurotrophic factor (BDNF), but not neurotrophin-4, just before and after the nerve ligation. These results provide direct evidence that BDNF within the spinal cord may contribute to the development of Thermal Hyperalgesia caused by nerve injury in mice. We previously reported that protein level of full-length TrkB, which contains the cytoplasmic protein tyrosine kinase domain, were clearly increased on the ipsilateral side of spinal cord membranes obtained from sciatic nerve-ligated mice. In the present study, we further demonstrated that the increased in the protein level of full-length TrkB is completely reversed by concomitant intrathecal injection of BDNF antibody. Furthermore, Thermal Hyperalgesia induced by nerve ligation was completely suppressed by repeated intrathecal injection of a specific antibody to full-length TrkB and an inhibitor of the protein tyrosine kinase activity for the neurotrophin receptor, K-252a. However, repeated intrathecal injection of a specific antibody to truncated TrkB, which lacks the cytoplasmic protein tyrosine kinase domain, failed to reverse Thermal Hyperalgesia observed in nerve-ligated mice. These findings suggest the possibility that the binding of BDNF to full-length TrkB and subsequent its activation may play a critical role in the development of neuropathic pain-like Thermal Hyperalgesia induced by nerve injury in mice.
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involvement of a spinal brain derived neurotrophic factor full length trkb pathway in the development of nerve injury induced Thermal Hyperalgesia in mice
Brain Research, 2002Co-Authors: Yoshinori Yajima, Minoru Narita, Michiko Narita, Nozomi Matsumoto, Tsutomu SuzukiAbstract:Partial sciatic nerve ligation in mice caused a marked and persistent decrease in the latency of paw withdrawal from a Thermal stimulus only on the ipsilateral side. This Thermal Hyperalgesia was abolished by repeated intrathecal pretreatment with a specific antibody to brain-derived neurotrophic factor (BDNF), but not neurotrophin-4, just before and after the nerve ligation. These results provide direct evidence that BDNF within the spinal cord may contribute to the development of Thermal Hyperalgesia caused by nerve injury in mice. We previously reported that protein level of full-length TrkB, which contains the cytoplasmic protein tyrosine kinase domain, were clearly increased on the ipsilateral side of spinal cord membranes obtained from sciatic nerve-ligated mice. In the present study, we further demonstrated that the increased in the protein level of full-length TrkB is completely reversed by concomitant intrathecal injection of BDNF antibody. Furthermore, Thermal Hyperalgesia induced by nerve ligation was completely suppressed by repeated intrathecal injection of a specific antibody to full-length TrkB and an inhibitor of the protein tyrosine kinase activity for the neurotrophin receptor, K-252a. However, repeated intrathecal injection of a specific antibody to truncated TrkB, which lacks the cytoplasmic protein tyrosine kinase domain, failed to reverse Thermal Hyperalgesia observed in nerve-ligated mice. These findings suggest the possibility that the binding of BDNF to full-length TrkB and subsequent its activation may play a critical role in the development of neuropathic pain-like Thermal Hyperalgesia induced by nerve injury in mice.
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Involvement of spinal protein kinase C in Thermal Hyperalgesia evoked by partial sciatic nerve ligation, but not by inflammation in the mouse.
European journal of pharmacology, 2000Co-Authors: M Ohsawa, Minoru Narita, Tsutomu Suzuki, H Mizoguchi, L F TsengAbstract:Activation of several protein kinases contributes to the development of Hyperalgesia evoked by injuries. The present study was designed to investigate the role of protein kinase C in the spinal cord in Thermal Hyperalgesia evoked by sciatic nerve ligation or by intraplantar injection of complete Freund's adjuvant. The paw withdrawal latency on the ipsilateral side, but not on the contralateral side, was markedly decreased after sciatic nerve ligation. Intraplantar injection of complete Freund's adjuvant also caused markedly decreases of the paw withdrawal latency. Intrathecal pretreatment with protein kinase C inhibitor calphostin C (100 and 250 ng) attenuated the decrease of the paw withdrawal latency evoked by sciatic nerve ligation. In contrast, the decrease of the paw withdrawal latency evoked by inflammation was only slightly attenuated by intrathecal pretreatment with calphostin C. The results indicate that protein kinase C in the spinal cord is involved in the development of the Thermal Hyperalgesia evoked by nerve ligation and is much less involved in the Thermal Hyperalgesia by complete Freund's adjuvant's-induced inflammation.
Terence J. Coderre - One of the best experts on this subject based on the ideXlab platform.
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effects of intrathecal administration of nitric oxide synthase inhibitors on carrageenan induced Thermal Hyperalgesia
British Journal of Pharmacology, 1999Co-Authors: Michael G Osborne, Terence J. CoderreAbstract:1. We examined the effects of various nitric oxide synthase (NOS) inhibitors on carrageenan-induced Thermal Hyperalgesia. 2. 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-N(G)-nitro-arginine methyl ester (L-NAME) produces a dose-dependent reduction of carrageenan-induced Thermal Hyperalgesia. 3. Four relatively selective NOS inhibitors were then tested for their efficacy at reducing carrageenan-induced Thermal Hyperalgesia. Initially, the effects of prolonged treatment with inhibitors of neuronal [7-nitroindazole (7-NI) and 3-bromo-7-nitroindazole (3-Br)] and inducible [aminoguanidine (AG) and 2-amino-5,6-dihydro-methylthiazine (AMT)] NOS were examined. All agents were injected three times intrathecally during the course of inflammation caused by the plantar injection of carrageenan, and Thermal Hyperalgesia was measured at 6 h post-carrageenan using a plantar apparatus. 4. All inhibitors, except for 7-NI, were effective at attenuating the carrageenan-induced Thermal Hyperalgesia when compared with vehicle treatment. 5. Finally, the effects of early versus late administration of neuronal and inducible NOS inhibitors on carrageenan-induced Thermal Hyperalgesia were examined. We found that neither 3-Br nor AG significantly affected Thermal Hyperalgesia when administered during the early phase of carrageenan inflammation, while only AG was able to reduce Thermal Hyperalgesia when administered during the late phase of the injury. 6. Our results suggest that inducible NOS contributes to Thermal Hyperalgesia in only the late stages of the carrageenan-induced inflammatory response, while neuronal NOS likely plays a role throughout the entire time course of the injury.
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Effects of intrathecal administration of nitric oxide synthase inhibitors on carrageenan‐induced Thermal Hyperalgesia
British journal of pharmacology, 1999Co-Authors: Michael G Osborne, Terence J. CoderreAbstract:1. We examined the effects of various nitric oxide synthase (NOS) inhibitors on carrageenan-induced Thermal Hyperalgesia. 2. 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-N(G)-nitro-arginine methyl ester (L-NAME) produces a dose-dependent reduction of carrageenan-induced Thermal Hyperalgesia. 3. Four relatively selective NOS inhibitors were then tested for their efficacy at reducing carrageenan-induced Thermal Hyperalgesia. Initially, the effects of prolonged treatment with inhibitors of neuronal [7-nitroindazole (7-NI) and 3-bromo-7-nitroindazole (3-Br)] and inducible [aminoguanidine (AG) and 2-amino-5,6-dihydro-methylthiazine (AMT)] NOS were examined. All agents were injected three times intrathecally during the course of inflammation caused by the plantar injection of carrageenan, and Thermal Hyperalgesia was measured at 6 h post-carrageenan using a plantar apparatus. 4. All inhibitors, except for 7-NI, were effective at attenuating the carrageenan-induced Thermal Hyperalgesia when compared with vehicle treatment. 5. Finally, the effects of early versus late administration of neuronal and inducible NOS inhibitors on carrageenan-induced Thermal Hyperalgesia were examined. We found that neither 3-Br nor AG significantly affected Thermal Hyperalgesia when administered during the early phase of carrageenan inflammation, while only AG was able to reduce Thermal Hyperalgesia when administered during the late phase of the injury. 6. Our results suggest that inducible NOS contributes to Thermal Hyperalgesia in only the late stages of the carrageenan-induced inflammatory response, while neuronal NOS likely plays a role throughout the entire time course of the injury.
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Priming enhances endotoxin-induced Thermal Hyperalgesia and mechanical allodynia in rats
Brain research, 1998Co-Authors: Catherine M. Cahill, Andy Dray, Terence J. CoderreAbstract:Central inflammation is an integral component and contributor of the pathology of many debilitating diseases and has been shown to produce spontaneous pain and Hyperalgesia. Recently, administration of lipopolysaccharide (LPS) into the lateral ventricle of rats was shown to elicit both Thermal Hyperalgesia and tactile allodynia [K. Walker, A. Dray, M. Perkins, Hyperalgesia in rats following intracerebroventricular administration of endotoxin: effect of bradykinin B1 and B2 receptor antagonist treatment, Pain 65 (1996) 211-219]. In this study, we have replicated the LPS model with some adaptations and correlated the nociceptive behaviors with an increased expression of activated macrophages in the central nervous system. We also examined the effects of priming on LPS-induced decreases in Thermal nociceptive thresholds and mechanical response thresholds following either central or peripheral administration. Intracerebroventricular (i.c.v.) administration of LPS (0.2 microgram/rat) did not alter either Thermal (hot plate) or mechanical (von Frey filaments) thresholds compared to baseline values in the first few hours after injection. However, priming rats by pretreating with i.c.v. LPS (0.2 microgram) 24 h prior to testing with i.c.v. LPS (0.2 microgram) produced significant mechanical allodynia and Thermal Hyperalgesia. The mechanical allodynia had an onset of 80 min after injection and a duration of 5 h. A similar time course was observed for Thermal Hyperalgesia, although its expression was less pronounced. Immunohistochemical studies indicated an increased expression of activated macrophages in the brain parenchyma of primed rats but not in unprimed rats. Intraperitoneal (i.p., 2 mg/kg) administration of LPS had no significant effect on either Thermal or mechanical thresholds in the first few hours after injection; however, priming rats via i.p. (0.2 mg/kg) or i.c.v. (0.2 microgram) LPS produced a reduction in both Thermal nociceptive thresholds and mechanical response thresholds in rats given a subsequent i.p. injection of LPS. This study demonstrates that priming is an effective protocol for the induction of central inflammation and increases the duration of these behaviors after i.c. v. administration.
Minoru Narita - One of the best experts on this subject based on the ideXlab platform.
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Involvement of a spinal brain-derived neurotrophic factor/full-length TrkB pathway in the development of nerve injury-induced Thermal Hyperalgesia in mice
Brain research, 2002Co-Authors: Yoshinori Yajima, Minoru Narita, Michiko Narita, Nozomi Matsumoto, Tsutomu SuzukiAbstract:Partial sciatic nerve ligation in mice caused a marked and persistent decrease in the latency of paw withdrawal from a Thermal stimulus only on the ipsilateral side. This Thermal Hyperalgesia was abolished by repeated intrathecal pretreatment with a specific antibody to brain-derived neurotrophic factor (BDNF), but not neurotrophin-4, just before and after the nerve ligation. These results provide direct evidence that BDNF within the spinal cord may contribute to the development of Thermal Hyperalgesia caused by nerve injury in mice. We previously reported that protein level of full-length TrkB, which contains the cytoplasmic protein tyrosine kinase domain, were clearly increased on the ipsilateral side of spinal cord membranes obtained from sciatic nerve-ligated mice. In the present study, we further demonstrated that the increased in the protein level of full-length TrkB is completely reversed by concomitant intrathecal injection of BDNF antibody. Furthermore, Thermal Hyperalgesia induced by nerve ligation was completely suppressed by repeated intrathecal injection of a specific antibody to full-length TrkB and an inhibitor of the protein tyrosine kinase activity for the neurotrophin receptor, K-252a. However, repeated intrathecal injection of a specific antibody to truncated TrkB, which lacks the cytoplasmic protein tyrosine kinase domain, failed to reverse Thermal Hyperalgesia observed in nerve-ligated mice. These findings suggest the possibility that the binding of BDNF to full-length TrkB and subsequent its activation may play a critical role in the development of neuropathic pain-like Thermal Hyperalgesia induced by nerve injury in mice.
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involvement of a spinal brain derived neurotrophic factor full length trkb pathway in the development of nerve injury induced Thermal Hyperalgesia in mice
Brain Research, 2002Co-Authors: Yoshinori Yajima, Minoru Narita, Michiko Narita, Nozomi Matsumoto, Tsutomu SuzukiAbstract:Partial sciatic nerve ligation in mice caused a marked and persistent decrease in the latency of paw withdrawal from a Thermal stimulus only on the ipsilateral side. This Thermal Hyperalgesia was abolished by repeated intrathecal pretreatment with a specific antibody to brain-derived neurotrophic factor (BDNF), but not neurotrophin-4, just before and after the nerve ligation. These results provide direct evidence that BDNF within the spinal cord may contribute to the development of Thermal Hyperalgesia caused by nerve injury in mice. We previously reported that protein level of full-length TrkB, which contains the cytoplasmic protein tyrosine kinase domain, were clearly increased on the ipsilateral side of spinal cord membranes obtained from sciatic nerve-ligated mice. In the present study, we further demonstrated that the increased in the protein level of full-length TrkB is completely reversed by concomitant intrathecal injection of BDNF antibody. Furthermore, Thermal Hyperalgesia induced by nerve ligation was completely suppressed by repeated intrathecal injection of a specific antibody to full-length TrkB and an inhibitor of the protein tyrosine kinase activity for the neurotrophin receptor, K-252a. However, repeated intrathecal injection of a specific antibody to truncated TrkB, which lacks the cytoplasmic protein tyrosine kinase domain, failed to reverse Thermal Hyperalgesia observed in nerve-ligated mice. These findings suggest the possibility that the binding of BDNF to full-length TrkB and subsequent its activation may play a critical role in the development of neuropathic pain-like Thermal Hyperalgesia induced by nerve injury in mice.
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Involvement of spinal protein kinase C in Thermal Hyperalgesia evoked by partial sciatic nerve ligation, but not by inflammation in the mouse.
European journal of pharmacology, 2000Co-Authors: M Ohsawa, Minoru Narita, Tsutomu Suzuki, H Mizoguchi, L F TsengAbstract:Activation of several protein kinases contributes to the development of Hyperalgesia evoked by injuries. The present study was designed to investigate the role of protein kinase C in the spinal cord in Thermal Hyperalgesia evoked by sciatic nerve ligation or by intraplantar injection of complete Freund's adjuvant. The paw withdrawal latency on the ipsilateral side, but not on the contralateral side, was markedly decreased after sciatic nerve ligation. Intraplantar injection of complete Freund's adjuvant also caused markedly decreases of the paw withdrawal latency. Intrathecal pretreatment with protein kinase C inhibitor calphostin C (100 and 250 ng) attenuated the decrease of the paw withdrawal latency evoked by sciatic nerve ligation. In contrast, the decrease of the paw withdrawal latency evoked by inflammation was only slightly attenuated by intrathecal pretreatment with calphostin C. The results indicate that protein kinase C in the spinal cord is involved in the development of the Thermal Hyperalgesia evoked by nerve ligation and is much less involved in the Thermal Hyperalgesia by complete Freund's adjuvant's-induced inflammation.
Akiyoshi Namiki - One of the best experts on this subject based on the ideXlab platform.
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contribution of transient receptor potential vanilloid subfamily 1 to endothelin 1 induced Thermal Hyperalgesia
Neuroscience, 2008Co-Authors: Tomoyuki Kawamata, J. Yamamoto, Yukitoshi Niiyama, Shingo Furuse, Akiyoshi NamikiAbstract: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 (ETA) 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 ETA and protein kinase C (PKC) but not that of ETB. 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 ETA. In the presence of ET-1, capsaicin produced much larger current responses (P<0.05). Mutation at PKC-specific TRPV1 phosphorylation sites (S800A/S502A) and PKC inhibitors inhibited the potentiating effect of ET-1. In addition, ET-1 decreased the temperature threshold for TRPV1 activation in a PKC-dependent manner (from 41.0±0.4 °C to 32.6±0.6 °C). In addition, Western blot analysis was also performed to confirm ET-1-induced phosphorylation of TRPV1. Incubation of ET-1 and intraplantar ET-1 evoked phosphorylation of TRPV1 in HEK293 cells expressing TRPV1 and ETA and the skin, respectively. These results suggest that the sensitization of TRPV1 activity through an ETA-PKC pathway contributes to ET-1-induced Thermal Hyperalgesia.
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Contribution of transient receptor potential vanilloid subfamily 1 to endothelin-1-induced Thermal Hyperalgesia.
Neuroscience, 2008Co-Authors: Tomoyuki Kawamata, J. Yamamoto, Yukitoshi Niiyama, Shingo Furuse, Akiyoshi NamikiAbstract: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 (P
