Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162473 (Frey)
 2,599 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with postherpetic neuralgia often have an increased sensitivity to a tactile stimulus but impaired thermal sensitivity in the same affected dermatomes. We recently found that depletion of capsaicin-sensitive afferents by systemic treatment with a potent TRPV1 agonist, resiniferotoxin, in adult rats produces long-lasting paradoxical changes in mechanical and thermal sensitivities, which resemble the unique clinical features of postherpetic neuralgia. The anticonvulsant gabapentin is effective in reducing the subjective pain score in patients with postherpetic neuralgia. In this study, we quantified the potential effect of systemic and intrathecal gabapentin on tactile allodynia induced by resiniferotoxin in rats. Intraperitoneal injection of 200 microg/kg resiniferotoxin produced a rapid and sustained increase in the paw withdrawal latency to a radiant heat stimulus. Profound tactile allodynia developed in all the resiniferotoxin-treated rats within 3 weeks. Intraperitoneal injection of 30-60 mg/kg of gabapentin in resiniferotoxin-treated rats significantly increased the withdrawal threshold in response to von Frey filaments. Furthermore, intrathecal administration of 10-30 microg of gabapentin also produced a significant effect on the mechanical withdrawal threshold in all resiniferotoxin-treated rats. These data provide complementary new information that gabapentin administered systemically and spinally can effectively relieve tactile allodynia in this animal model of postherpetic neuralgia.
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PMID:Effect of systemic and intrathecal gabapentin on allodynia in a new rat model of postherpetic neuralgia. 1582 59

Molecular and behavioral evidence suggests that acid-sensing ion channels (ASICs) contribute to pain processing, but an understanding of their precise role remains elusive. Existing ASIC knock-out mouse experiments are complicated by the heteromultimerization of ASIC subunits. Therefore, we have generated transgenic mice that express a dominant-negative form of the ASIC3 subunit that inactivates all native neuronal ASIC-like currents by oligomerization. Using whole-cell patch-clamp recordings, we examined the response properties of acutely isolated dorsal root ganglion neurons to protons (pH 5.0). We found that whereas 33% of the proton-responsive neurons from wild-type mice exhibited an ASIC-like transient response, none of the neurons from the transgenic mice exhibited a transient inward current. Capsaicin-evoked responses mediated by the TRPV1 receptor were unaltered in transgenic mice. Adult male wild-type and transgenic mice were subjected to a battery of behavioral nociceptive assays, including tests of thermal, mechanical, chemical/inflammatory, and muscle pain. The two genotypes were equally sensitive to thermal pain and to thermal hypersensitivity after inflammation. Compared with wild types, however, transgenic mice were more sensitive to a number of modalities, including mechanical pain (von Frey test, tail-clip test), chemical/inflammatory pain (formalin test, 0.6% acetic acid writhing test), mechanical hypersensitivity after zymosan inflammation, and mechanical hypersensitivity after intramuscular injection of hypotonic saline. These data reinforce the hypothesis that ASICs are involved in both mechanical and inflammatory pain, although the increased sensitivity of transgenic mice renders it unlikely that they are direct transducers of nociceptive stimuli.
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PMID:Transgenic expression of a dominant-negative ASIC3 subunit leads to increased sensitivity to mechanical and inflammatory stimuli. 1625 36

Subcutaneous endothelin-1 (ET-1; 200 microM, 2 nmoles/paw) injected into the rat hind paw, has been shown to cause robust hind paw flinching (HPF) and paw licking, and to induce impulses selectively in primary nociceptors. Here we report that a much lower [ET-1] sensitizes the paw to a nocifensive withdrawal response to tactile stimulation (by von Frey hairs, VFH), a sensitization that involves local TRPV1 receptors. Injection of 10 microM ET-1 (0.1 nmole/paw) causes only marginal HPF but rapidly (20 mins after injection) lowers the force threshold for paw withdrawal (PWT) to VFH, to approximately 30% of pre-injection baseline. Such tactile allodynia persists for 3 hrs. In rats pre-injected with the TRPV1-antagonists capsazepine (CPZ; 1.33 mM) or 5'-iodoresiniferatoxin (I-RTX; 0.13 microM), 15 min before ET-1, a fast initial drop in PWT, as with ET-1 alone, occurs (to 40% or to 19% of baseline, respectively), but this earliest reduction then regresses back to the pre-injection PWT value more rapidly than with ET-1 alone. The recovery of allodynia from the maximum value is about two times faster for ET-1+CPZ and about 4 times faster for ET-1+ I-RTX, compared with that from ET-1 +vehicle (t(1/2) = 130, 60, and 250 mins, respectively). In contrast, spontaneous pain indicated by overt HPF from ET-1 is not attenuated by TRPV1 antagonists. Tactile allodynia is similarly abbreviated by antagonists of both ET(A) (BQ-123, 32 nmoles/paw) and ET(B) (BQ-788, 30 nmoles/paw) receptors, whereas HPF is abolished by this ET(A) antagonist but enhanced by the ET(B) antagonist. We conclude that low ET-1 causes tactile allodynia, which is characterized by a different time-course and pharmacology than ET-1-induced nociception, and that local TRPV1 receptors are involved in the maintenance of this ET-1-induced allodynia but not in the overt algesic action of ET-1.
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PMID:Tactile allodynia initiated by local subcutaneous endothelin-1 is prolonged by activation of TRPV-1 receptors. 1674 Oct 70

Whether modulation of C afferent fiber activities could relieve peripheral neuropathic pain was tested. After establishment of neuropathic pain induced by L5 and 6 spinal nerve transection (SNT), the sciatic nerve was treated with 2% capsaicin at the level of the midthigh. Mechanical hyperalgesia (von Frey filaments) was significantly alleviated from 7 days to 4 weeks after capsaicin treatment, but cold allodynia (acetone) was unchanged. Immunohistochemical studies showed a significant increase in the number of calcitonin gene-related peptide (CGRP)-positive neurons, but not TRPV1-positive neurons in intact L4 dorsal root ganglia after SNT. Capsaicin treatment decreased TRPV1- and CGRP-positive neurons in L4 DRG of the treated side, but not the opposite side. These results suggest that local application of capsaicin onto the sciatic nerve can alleviate mechanical hyperalgesia, but not cold allodynia, in a peripheral neuropathic pain model and the pain alleviation may result from a decrease of TRPV1- and CGRP-positive sensory neurons of which fibers pass through the sciatic nerve.
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PMID:Local application of capsaicin alleviates mechanical hyperalgesia after spinal nerve transection. 1824 51

Rodents detect visceral pain in response to noxious levels of rectal distension. However, the mechanoreceptors that innervate the rectum and respond to noxious levels of rectal distension have not been identified. Here, we have identified the mechanoreceptors of capsaicin-sensitive rectal afferents and characterized their properties in response to circumferential stretch of the rectal wall. We have also used the lethal spotted (ls/ls) mouse to determine whether rectal mechanoreceptors that respond to capsaicin and stretch may also develop in an aganglionic rectum that is congenitally devoid of enteric ganglia. In wild type (C57BL/6) mice, graded increases in circumferential stretch applied to isolated rectal segments activated a graded increase in firing of slowly-adapting rectal mechanoreceptors. Identical stimuli applied to the aganglionic rectum of ls/ls mice also activated similar graded increases in firing of stretch-sensitive rectal afferents. In both wild type and aganglionic rectal preparations, focal compression of the serosal surface using von Frey hairs identified mechanosensitive "hot spots," that were associated with brief bursts of action potentials. Spritzing capsaicin (10 microM) selectively onto each identified mechanosensitive hot spot activated an all or none discharge of action potentials in 32 of 56 identified hot spots in wild type mice and 24 of 62 mechanosensitive hot spots in the aganglionic rectum of ls/ls mice. Each single unit activated by both capsaicin and circumferential stretch responded to low mechanical thresholds (1-2 g stretch). No high threshold rectal afferents were ever recorded in response to circumferential stretch. Anterograde labeling from recorded rectal afferents revealed two populations of capsaicin-sensitive mechanoreceptor that responded to stretch: one population terminated within myenteric ganglia, the other within the circular and longitudinal smooth muscle layers. In the aganglionic rectum of ls/ls mice, only the i.m. mechanoreceptors were identified. Both myenteric and i.m. mechanoreceptors could be identified by their immunoreactivity to the anti-TRPV1 antibody and the vesicular glutamate transporter, Vglut2. Myenteric mechanoreceptors had a unique morphology, consisting of smooth bulbous nodules that ramified within myenteric ganglia. In summary, the rectum of wild type mice is innervated by at least two populations of capsaicin-sensitive rectal mechanoreceptor, both of which respond to low mechanical thresholds within the innocuous range. These findings suggest that the visceral pain pathway activated by rectal distension is likely to involve low threshold rectal mechanoreceptors that are activated within the normal physiological range.
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PMID:Identification of capsaicin-sensitive rectal mechanoreceptors activated by rectal distension in mice. 1839 92

Post-inflammatory pain is a poorly understood phenomenon. G protein-coupled receptors are involved in regulating pain signaling in the context of inflammation. G protein-coupled receptor kinases (GRK) modulate signaling through these receptors. We investigated whether GRK6 contributes to post-inflammatory visceral hyperalgesia. Colitis was induced in female mice by 1% dextran sodium sulphate in drinking water for 7 days. Disease score, colon length, and colonic cytokines were determined. On day 49, when animals had recovered from colitis, we induced visceral pain by intracolonic capsaicin instillation. Behavioral responses to capsaicin were monitored for 20 min. Referred hyperalgesia was measured using von Frey hairs. Spinal cord c-Fos was visualized by immunohistochemistry. In contrast to our earlier observations in male GRK6-/- and wild type (WT) mice, we did not detect differences in the course of colitis or in expression of colonic cytokines between female GRK6-/- and WT mice. After recovery from colitis, capsaicin-induced behavioral pain responses and spinal cord c-Fos expression were more pronounced in female GRK6-/- than WT mice. Naive GRK6-/- and WT animals did not differ in pain and c-Fos responses to capsaicin. Capsaicin-induced referred hyperalgesia post-colitis was increased in GRK6-/- compared to WT mice. However, referred hyperalgesia post-colitis was not affected by ablation of GRK6. Furthermore, in vitro IL-1beta sensitized the capsaicin receptor TRPV1 and this process was inhibited by over-expression of GRK6. We describe the novel concept that GRK6 inhibits post-inflammatory visceral hyperalgesia but does not contribute to visceral pain in naive animals. We propose that GRK6 regulates inflammation-induced sensitization of TRPV1.
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PMID:G protein-coupled receptor kinase 6 controls post-inflammatory visceral hyperalgesia. 1897 89

The roles of ion channels in sensory neurons were examined in experimental models of muscle pain in the rat. Rats were injected with 50 microl of 4% carrageenan or subjected to an eccentric exercise (ECC) of the gastrocnemius muscle (GM). The Randall-Selitto and von Frey tests were performed on the calves to evaluate mechanical hyperalgesia of the muscle. The changes in expression of four genes and proteins of ion channels in dorsal root ganglia were examined using quantitative PCR and immunohistochemistry, respectively. Effects of antagonists to transient receptor potential (TRP) channels and acid sensing ion channels (ASICs) on the mechanical hyperalgesia induced by carrageenan injection or ECC were evaluated. The mechanical hyperalgesia was observed 6-24h after carrageenan injection and 1-3 days after ECC in the Randall-Selitto test. Infiltrations of the inflammatory cells in the GM were seen in carrageenan-injected animals but not in those subjected to ECC. Expressions of genes and proteins in sensory neurons showed no changes. Intramuscular injection of antagonists to TRPV1 showed an almost complete suppressive effect on ECC-induced muscle hyperalgesia but not a carrageenan-induced one. Antagonists to TRP channels and ASICs showed suppressive effects for both carrageenan- and ECC-induced muscle hyperalgesia. The carrageenan injection and ECC models are useful models of acute inflammatory pain and delayed onset muscle soreness (DOMS), respectively, and the time course and underlying etiology might be different. TRP channels and ASICs are closely related to the development of muscle mechanical hyperalgesia, and TRPV1 is involved in ECC-induced DOMS.
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PMID:TRP channels and ASICs mediate mechanical hyperalgesia in models of inflammatory muscle pain and delayed onset muscle soreness. 1883 67

Lipoxygenase (LO) metabolites are generated in inflamed tissues. However, it is unclear whether the inhibition of the LO activity regulates the expression of c-Fos protein, a pain marker in the spinal cord. Here we used a carrageenan-induced inflammation model to examine the role of LO in the development of c-Fos expression. Intradermally injected carrageenan caused elevated number of cells exhibiting Fos-like immunoreactivity (Fos-LI) in the spinal dorsal horn, and decreased the thermal and mechanical threshold in Hargreaves and von Frey tests. Pretreatment with an inhibitor of phospholipase A2, that generates the LO substrate, prior to the carrageenan injection significantly reduced the number of Fos-(+) cells. A general LO inhibitor NDGA, a 5-LO inhibitor AA-861 and a 12-LO inhibitor baicalein also exhibited the similar effects. Moreover, the LO inhibitors suppressed carrageenan-induced thermal and mechanical hyperalgesic behaviors, which inidcates that the changes in Fos expression correlates with those in the nociceptive behaviors in the inflamed rats. LO products are endogenous TRPV1 activators and pretreatment with BCTC, a TRPV1 antagonist inhibited the thermal but not the mechanical hypersensitivity. Overall, our results from the Fos-LI and behavior tests suggest that LO products released from inflamed tissues contribute to nociception during carrageenan-induced inflammation, indicating that the LO pathway is a possible target for modulating inflammatory pain.
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PMID:Lipoxygenase inhibitors suppressed carrageenan-induced Fos-expression and inflammatory pain responses in the rat. 1939 Aug 22

The vanilloid-1 receptor TRPV1 is known to play a role in extrinsic gastrointestinal afferent function. We investigated the role of TRPV1 in mechanosensitivity in afferents from normal and inflamed tissue. Colonic mechanosensitivity was determined in an in vitro rat colon preparation by recording from attached splanchnic nerves. Recordings were made from serosal/mesenteric afferents responding only at high thresholds to graded mechanical stimulation with von Frey probes. Colonic inflammation was induced by adding 5% dextran sulphate sodium (DSS) to the drinking water for 5 days, and was confirmed by histopathology. The selective TRPV1 antagonist, SB-750364 (10(-8) to 10(-6)M), was tested on mechanosensory stimulus response functions of afferents from normal and inflamed preparations (N=7 each). Mechanosensory responses had thresholds of 1-2g, and maximal responses were observed at 12 g. The stimulus response function was not affected by DSS-induced colitis. SB-750364 had no effect on stimulus response functions in normal preparations, but reduced (up to 60%) in a concentration-dependent manner those in inflammation (2-way ANOVA, p<0.05). Moreover, in inflamed tissue, spontaneous afferent activity showed a dose-dependent trend toward reduction with SB-750364. We conclude that mechanosensitivity of high-threshold serosal colonic splanchnic afferents to graded stimuli is unaffected during DSS colitis. However, there is a positive influence of TRPV1 in mechanosensitivity in inflammation, suggesting up-regulation of excitatory TRPV1-mediated mechanisms.
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PMID:Role of TRPV1 in high-threshold rat colonic splanchnic afferents is revealed by inflammation. 1940 4

The role of ion channels expressed in sensory neurons on mechanical and thermal hyperalgesia was examined in a rat model of cisplatin-induced peripheral neuropathy. The rats were injected with 3mg/kg of cisplatin intraperitoneally once per week for five consecutive weeks. The von Frey test, pin-prick test and plantar test were performed to examine any noxious sensitivity of the skin. The Randall-Selitto test of the gastrocnemius muscle (GM) and the measurement of grip forces were performed to quantify muscle hyperalgesia. Coordination/motor was assessed by Rota-rod testing. Expressions of the ion channels TRPV1, TRPV2, P2X(3) and ASIC3 were examined in dorsal root ganglion (DRG) neurons and the muscle afferent neurons innervating GM. Effects of antagonists against either P2X(3) or ASICs on behavioral responses were evaluated. Mechanical hyperalgesia and allodynia of both skin and muscle were observed in cisplatin-treated animals. Expressions of TRPV2, P2X(3), and ASIC3 increased in all DRG neurons. In addition, expressions of P2X(3) and ASIC3 also increased in muscle afferent neurons in DRGs. Antagonists against P2X(3,2/3) and ASICs showed a suppressive effect on both skin and muscle hyperalgesia induced by cisplatin administration. Upregulation of TRPV2, P2X(3), and ASIC3 may play important roles in the mechanical hyperalgesia induced by cisplatin. Furthermore, cisplatin treatment also induced muscle hyperalgesia in muscle afferent neurons in connection with the upregulation of P2X(3) and ASIC3.
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PMID:Upregulations of P2X(3) and ASIC3 involve in hyperalgesia induced by cisplatin administration in rats. 2037 47


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