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)

We recently described a novel endogenous mechanism of peripheral antinociception, possibly involving activation of muscarinic M2 acetylcholine receptors that are expressed on nociceptive nerve endings and decrease their sensitivity. In the present study, this mechanism was scrutinized in skin taken from mice with targeted deletions of the muscarinic M2 receptor gene and, for control purposes, of the M4 receptor gene. Two different approaches were taken. Electrophysiologically the effects of muscarine on nociceptive afferents were investigated using the mouse skin-saphenous nerve preparation, in vitro. Muscarine did not excite nociceptors in the wild-type littermates (WT) and M4 knock-out (M4 KO) mice, but almost all fibers exhibited marked desensitization to mechanical and heat stimuli. Surprisingly, in the M2 KO mice, muscarine was able to excite C-nociceptors and to induce a mild sensitization to heat but caused no alteration in mechanical responsiveness tested with von Frey hairs. In the second, neurochemical approach, the heat-induced cutaneous release of calcitonin gene-related peptide (CGRP) was investigated to gain comparative data on the neurosecretory (vasodilatory) functions of the primary afferent neurons. The substantial increase of CGRP release evoked by noxious heat (47 degrees C) was diminished under muscarine by >50% in the WT and M4 KO animals but remained unaltered in the M2 KO mice. Together, these data provide direct evidence that M2 receptors on cutaneous nerve endings mediate effective depression of nociceptive responsiveness. This observation should be of interest for the development of novel classes of analgesic agents.
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PMID:Muscarinic M2 receptors on peripheral nerve endings: a molecular target of antinociception. 1204 34

This study was designed to assess the role of calcitonin gene-related peptide (CGRP) and its receptor in the generation and maintenance of secondary mechanical allodynia and hyperalgesia induced by intradermal injection of capsaicin in rats. Paw withdrawal responses (PWRs) to von Frey hairs with different bending forces applied on the rat paw were tested in this study. CGRP(8-37), a specific antagonist of CGRP 1 receptors, was delivered through a microdialysis fiber inserted across the dorsal horn. Post- and pretreatment paradigms were followed. When CGRP(8-37) was administered 1h after capsaicin injection, the mechanical allodynia and hyperalgesia were partially reversed in a dose-dependent manner. On the other hand, when rats were treated with CGRP(8-37) prior to capsaicin injection, the PWRs to von Frey applications were significantly reduced as compared to control animals. Collectively, these results suggest that CGRP receptors present in the dorsal horn are involved in the generation and maintenance of nociceptive behaviors associated with cutaneous inflammation.
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PMID:The role of calcitonin gene-related peptide (CGRP) in the generation and maintenance of mechanical allodynia and hyperalgesia in rats after intradermal injection of capsaicin. 1285 30

Although pain is a cardinal feature of pancreatitis, its pathogenesis is poorly understood and treatment remains difficult. Nociceptive sensitization in several somatic pain models has been associated with activation of protein kinases including trkA, protein kinase C, and protein kinase A. We therefore tested the hypothesis that systemic treatment with a kinase inhibitor, k252a, known to inhibit all of these kinases would alleviate pain in an animal model of pancreatitis. Von Frey filament testing of somatic referral regions was evaluated as a method to measure referred pain in a rat model of acute necrotizing pancreatitis induced by L-arginine. Rats with pancreatitis showed increased sensitivity to abdominal stimulation with Von Frey filament. This referred mechanical sensitivity was associated with an 8-fold increase in levels of phosphorylated trkA in the pancreas and with significant up-regulation of both calcitonin gene-related peptide and preprotachykinin mRNA expression in thoracic dorsal root ganglia and with increased calcitonin gene-related peptide and substance P immunoreactivity in spinal cord segment T10. Treatment with the kinase inhibitor k252a suppressed the phosphorylation of trkA in the pancreas as well as reversed both the behavioral changes and the increase in neuropeptide expression associated with pancreatitis.
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PMID:Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor k252a. 1462 90

It is well known that following peripheral nerve injury, there are numerous changes in neurotransmitter and neuropeptide expression in the superficial dorsal horn, the dorsal root ganglion and the periphery. Of particular interest are the relative contributions of two sub-types of unmyelinated C-fibers in the initiation and maintenance of chronic pain, the peptidergic, and the non-peptidergic. Evidence gathered in recent years has led researchers to believe that the non-peptidergic nociceptive primary afferents are functionally distinct from their peptidergic counterpart. For our study, we used a well-established animal model of constriction neuropathy (the Kruger model) and studied Wistar rats at 5, 7, 10, 15 and 21 days after nerve lesion caused by the application of a fixed-diameter polyethylene cuff to the left sciatic nerve. Animals were assessed for the onset and evolution of mechanical allodynia using calibrated von Frey filaments and were additionally tested for thermal (heat and cold) hypersensitivity. Immunocytochemical detection of calcitonin gene-related peptide (CGRP) and isolectin B4 (IB4) binding was used to visualize the dorsal horn distribution of the boutons from the peptidergic and non-peptidergic fibers respectively. Using confocal microscopy and image analysis, we detected a significant decrease in the density of IB4-labeled boutons, ipsilateral to the lesion, at seven and 10 days following nerve injury. The density of IB4-labeled varicosities retuned to control levels by 15 days. There were no significant changes in the density of CGRP-labeled varicosities at all time points examined. Applying electron microscopy, we initially detected degenerative changes in the central elements of type I glomeruli and then a considerable reduction in their number followed by recovery at 15 days post-lesion. As the central boutons of type Ia represent varicosities from the fibers which bind IB4, the ultrastructural changes confirmed that there was a bona fide transient loss of varicosities, not simply a loss of IB4 binding. These data indicate that, in this animal model, morphological changes in the nociceptive C-fiber input of the rat dorsal horn are restricted to the non-peptidergic sub-population and are transient in nature. Furthermore, such changes do not correlate with the time-course of the allodynia.
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PMID:Transient loss of terminals from non-peptidergic nociceptive fibers in the substantia gelatinosa of spinal cord following chronic constriction injury of the sciatic nerve. 1641 31

The main purpose of this study was to evaluate the effects of early dexamethasone treatment on pain-related peptides at an early stage in the development of neuropathic pain induced by implantation of a sciatic nerve cuff in Sprague Dawley rats (body weight 250 to 350 g). The rats were tested for touch sensitivity with the use of von Frey filaments before and 3 d after cuff implantation (n = 12) or sham surgery (n = 6). Half of the cuff-implanted rats received dexamethasone, 1 mg/kg intraperitoneally, 1 h after surgery. Spinal cords were collected on the 3rd day after surgery, and the lumbar enlargement was processed for the detection of selected peptides (neurotensin, substance P, cholecystokinin [CCK], vasoactive intestinal peptide, and calcitonin gene-related peptide) by means of liquid chromatography and tandem mass spectrometry. The right sciatic nerve of each rat was collected, fixed, and stained for histopathological evaluation. Except for neurotensin, all the peptides showed an increased concentration with neuropathic pain; however, the differences were significant (P < 0.05) only for substance P and CCK. In the animals treated with dexamethasone, mechanical allodynia was less pronounced (P < 0.01), and only the concentration of substance P was decreased significantly (P < 0.05). Sciatic nerve sections showed a decrease in C (P < 0.01) and Adelta (P < 0.03) fibres with neuropathic pain and a nearly normal percentage of C fibres after dexamethasone treatment. The dexamethasone-treated animals also had less inflammation detectable microscopically at the nerve constriction site compared with cuff-implanted animals that were not treated with dexamethasone. Our results suggest that in the early stages of neuropathic pain induced by an inflammatory process, dexamethasone may be a useful treatment and that substance P plays an important role in pain perception.
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PMID:Early dexamethasone treatment after implantation of a sciatic-nerve cuff decreases the concentration of substance P in the lumbar spinal cord of rats with neuropathic pain. 1747 71

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

The acid sensing ion channel 3 (ASIC3) is critical for the development of secondary hyperalgesia as measured by mechanical stimulation of the paw following muscle insult. We designed experiments to test whether ASIC3 was necessary for the development of both primary and secondary mechanical hyperalgesia that develops after joint inflammation. We used ASIC3 -/- mice and examined the primary (response to tweezers) and secondary hyperalgesia (von-Frey filaments) that develops after joint inflammation comparing to ASIC3 +/+ mice. We also examined the localization of ASIC3 to the knee joint afferents innervating the synovium using immunohistochemical techniques before and after joint inflammation. We show that secondary mechanical hyperalgesia does not develop in ASIC3 -/- mice. However, the primary mechanical hyperalgesia of the inflamed knee joint still develops in ASIC3 -/- mice and is similar to ASIC3 +/+ mice. In knee joint synovium from ASIC3 +/+ mice without joint inflammation, ASIC3 was not localized to joint afferents that were stained with an antibody to protein gene product (PGP) 9.5 or calcitonin gene-related peptide (CGRP). ASIC3 was found, however, in synoviocytes of the knee joint of uninflamed mice. In ASIC3 +/+ mice with joint inflammation, ASIC3 co-localized with PGP 9.5 or CGRP in joint afferents innervating the synovium. We conclude that the decreased pH that occurs after inflammation would activate ASIC3 on primary afferent fibers innervating the knee joint, increasing the input to the spinal cord resulting in central sensitization manifested behaviorally as secondary hyperalgesia of the paw.
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PMID:Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation in mice. 1834 37

Painful neuropathy is a common complication of diabetes. Particularly in the early stage of diabetic neuropathy, patients are characterized by burning feet, hyperalgesia to heat, and mechanical stimuli, as if residual nociceptors were sensitized. Such symptoms are barely explained by common pathophysiological concepts of diabetic neuropathy. Diabetes was induced in Wistar rats by streptozotocin (STZ). After 4 weeks behavioral testing (Plantar test, Randall-Selitto) was conducted. Basal and stimulated release of calcitonin gene-related peptide (CGRP), Substance P (SP) and prostaglandin E(2) (PGE(2)) from isolated skin and sciatic nerve were assessed by enzyme immunoassays. Electrophysiological properties of identified nociceptors under hyperglycemic, hypoxic, and acidotic conditions were investigated using the skin-nerve preparation. The diabetic rats showed hyperalgesia to heat and pressure stimulation. The basal CGRP/SP release was reduced, but chemical stimulation with bradykinin induced greater release of SP, CGRP and PGE(2) than in control animals. In contrast, capsaicin-stimulated CGRP release was reduced in sciatic nerves. Hypoxia per se lowered von Frey thresholds of most C-nociceptors to half. Hyperglycemic hypoxia induced ongoing discharge in all diabetic but not control C-fibers which was further enhanced under acidosis. Sensory and neurosecretory nociceptor functions are sensitized in diabetes. Diabetic C-fibers show exaggerated sensitivity to hyperglycemic hypoxia with and without additional acidosis, conditions that are thought to mimic ischemic episodes in diabetic nerves. Ongoing C-fiber discharge is known to induce spinal sensitization. Together with altered receptor and ion channel expressions this may contribute to painful episodes in diabetic neuropathy.
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PMID:Sensitized peripheral nociception in experimental diabetes of the rat. 2083 42

The purpose of this study was to compare the gait parameters recorded on the CatWalk and the mechanical sensitivity with von Frey filaments of two putative models of osteoarthritis over a one month period, and to evaluate the effect of celecoxib on these parameters. Animals underwent either a surgical sectioning of the anterior cruciate ligament with partial medial menisectomy (ACLT+pMMx) to create a joint instability model or received an intra-articular injection of monoiodoacetate (MIA) as a putative inflammatory joint pain model. Animals were assessed for four consecutive weeks and knee joints were then evaluated histologically. Spinal cord lumbar enlargements were harvested for selected neuropeptide analysis (substance P (SP) and calcitonin gene related peptide (CGRP)). With the MIA model, significant changes persisted in selected dynamic gait parameters throughout the study in the injured limb as well as with the von Frey filaments. The ACLT+pMMx model in contrast showed no clear differential response between both hind limb for both gait parameters and pain-related behavior with von Frey filaments occurred only on the last day of the study. Neuropeptide analysis of spinal cord lumbar enlargements revealed a significant increase in CGRP concentration in both models and an increase in SP concentration only in the MIA model. Histological evaluation confirmed the presence of articular cartilage lesions in both models, but they were much more severe in the MIA model. Celecoxib had an effect on all selected gait parameters at the very beginning of the study and had an important alleviating effect on mechanical allodynia. These results suggest that the MIA model may be more appropriate for the evaluation of short term pain studies and that celecoxib may modulate mechanical allodynia through central sensitization mechanisms.
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PMID:Gait analysis and pain response of two rodent models of osteoarthritis. 2111 52

Previous studies showed that 5-hydroxytryptamine (5-HT)(1B/1D) receptor stimulation by triptans alleviates neuropathic pain caused by chronic constriction injury to the infraorbital nerve (CCI-ION) but not the sciatic nerve (CCI-SN) in rats. To assess whether such differential effects in the cephalic vs extracephalic territories is a property shared by other antimigraine drugs, we used the same models to investigate the effects of olcegepant, which has an antimigraine action mediated through calcitonin gene-related peptide (CGRP) receptor blockade. Adult male rats underwent unilateral CCI to the ION or the SN, and subsequent allodynia and/or hyperalgesia were assessed in ipsilateral vibrissal territory or hindpaw, respectively, using von Frey filaments and validated nociceptive tests. c-Fos expression was quantified by immunohistochemistry and interleukin 6 and activating transcription factor 3 (ATF3) mRNAs by real-time quantitative reverse transcriptase-polymerase chain reaction. Like naratriptan (0.1 to 0.3mg/kg, subcutaneously), olcegepant (0.3 to 0.9mg/kg, intravenously) markedly reduced mechanical allodynia in CCI-ION rats. In contrast, in CCI-SN rats, mechanical allodynia was completely unaffected and hyperalgesia was only marginally reduced by these drugs. A supra-additive antiallodynic effect was observed in CCI-ION rats treated with olcegepant (0.3mg/kg intravenously) plus naratriptan (0.1mg/kg subcutaneously), whereas this drug combination remained inactive in CCI-SN rats. Olcegepant (0.6mg/kg, intravenously) significantly reduced the number of c-Fos immunolabeled cells in spinal nucleus of the trigeminal nerve and upregulation of ATF3 transcript (a marker of neuron injury) but not that of interleukin-6 in trigeminal ganglion of CCI-ION rats. These findings suggest that CGRP receptor blockade might be of potential interest to alleviate trigeminal neuropathic pain.
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PMID:Differential effects of calcitonin gene-related peptide receptor blockade by olcegepant on mechanical allodynia induced by ligation of the infraorbital nerve vs the sciatic nerve in the rat. 2279 18


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