Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase C (PKC) is able to phosphorylate several cellular components that serve as key regulatory components in signal transduction pathways of nociceptor excitation and sensitisation. Therefore, the present study attempted to assess some of the mechanisms involved in the overt nociception elicited by peripheral administration of the PKC activator, phorbol 12-myristate 13-acetate (PMA), in mice. The intraplantar (i.pl.) injection of PMA (16-1600 pmol/paw), but not its inactive analogue alpha-PMA, produced a long-lasting overt nociception (up to 45 min), as well as the activation of PKCalpha and PKCepsilon isoforms in treated paws. Indeed, the local administration of the PKC inhibitor GF109203X completely blocked PMA-induced nociception. The blockade of NK1, CGRP, NMDA, beta1-adrenergic, B2 or TRPV1 receptors with selective antagonists partially decreased PMA-induced nociception. Similarly, COX-1, COX-2, MEK or p38 MAP kinase inhibitors reduced the nociceptive effect produced by PMA. Notably, the nociceptive effect promoted by PMA was diminished in animals treated with an antagonist of IL-1beta receptor or with antibodies against TNFalpha, NGF or BDNF, but not against GDNF. Finally, mast cells as well as capsaicin-sensitive and sympathetic fibres, but not neutrophil influx, mediated the nociceptive effect produced by PMA. Collectively, the results of the present study have shown that PMA injection into the mouse paw results in PKC activation as well as a relatively delayed, but long-lasting, overt nociceptive behaviour in mice. Moreover, these results demonstrate that PKC activation exerts a critical role in modulating the excitability of sensory neurons.
Pain 2005 Sep
PMID:Mechanisms involved in the nociception produced by peripheral protein kinase c activation in mice. 1609 1

Heat sensitivity shows considerable functional variability in humans and laboratory animals, and is fundamental to inflammatory and possibly neuropathic pain. In the mouse, at least, much of this variability is genetic because inbred strains differ robustly in their behavioral sensitivity to noxious heat. These strain differences are shown here to reflect differential responsiveness of primary afferent thermal nociceptors to heat stimuli. We further present convergent behavioral and electrophysiological evidence that the variable responses to noxious heat are due to strain-dependence of CGRP expression and sensitivity. Strain differences in behavioral response to noxious heat could be abolished by peripheral injection of CGRP, blockade of cutaneous and spinal CGRP receptors, or long-term inactivation of CGRP with a CGRP-binding Spiegelmer. Linkage mapping supports the contention that the genetic variant determining variable heat pain sensitivity across mouse strains affects the expression of the Calca gene that codes for CGRPalpha.
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PMID:Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene. 1611 73

The role of neuropeptides in synaptic plasticity is less well understood than that of classical transmitters such as glutamate. Here we report the importance of the G-protein-coupled calcitonin gene-related peptide (CGRP1) receptor as a critical link between amygdala plasticity and pain behavior. A key player in emotionality and affective disorders, the amygdala has been implicated in the well documented, but mechanistically unexplained, relationship between pain and affect. Our electrophysiological and pharmacological in vitro (patch-clamp recordings) and in vivo (extracellular single-unit recordings) data show that selective CGRP1 receptor antagonists (CGRP(8-37) and BIBN4096BS) in the amygdala reverse arthritis pain-related plasticity through a protein kinase A (PKA)-dependent postsynaptic mechanism that involves NMDA receptors. CGRP1 receptor antagonists inhibited synaptic plasticity in the laterocapsular division of the central nucleus of the amygdala (CeLC) in brain slices from arthritic rats compared with normal controls. The effects were accompanied by decreased neuronal excitability and reduced amplitude, but not frequency, of miniature EPSCs; paired-pulse facilitation was unaffected. The antagonist effects were occluded by a PKA inhibitor. CGRP1 receptor blockade also directly inhibited NMDA-evoked, but not AMPA-evoked, membrane currents. Together, these data suggest a postsynaptic site of action. At the systems level, the antagonists reversed the sensitization of nociceptive CeLC neurons in anesthetized rats in the arthritis pain model. Importantly, CGRP1 receptor blockade in the CeLC inhibited spinal (hindlimb withdrawal reflexes) and supraspinal pain behavior of awake arthritic rats, including affective responses such as ultrasonic vocalizations. This study provides direct evidence for the critical dependence of pain behavior on CGRP1-mediated amygdala plasticity.
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PMID:Critical role of calcitonin gene-related peptide 1 receptors in the amygdala in synaptic plasticity and pain behavior. 1629 45

Visceral pain is a prevalent clinical problem and one of the most common ailments for which patients seek medical attention. Recent studies have described many of the physiological properties of visceral afferents, but not much is known regarding their anatomical characteristics. To determine the spinal distribution and neurochemical phenotype of colonic afferents in rodents, Alexa Fluor-conjugated cholera toxin-beta (CTB) was injected subserosally into the proximal and distal portions of the descending colon in Sprague Dawley rats and C57Bl/6 mice. Dorsal root ganglia (T10-S2) were processed for fluorescent immunohistochemistry and visualized by confocal microscopy. In the mouse, CTB-positive neurons were most numerous in the lumbosacral region (LS; L6-S1), with a smaller contribution in the thoracolumbar ganglia (TL; T13-L1). In contrast, CTB-positive neurons in the rat were most numerous in the TL ganglia, with a smaller contribution in the LS ganglia. The vast majority of CTB-positive neurons in both mouse and rat were positive for TRPV1 and CGRP and most likely unmyelinated, in that most colonic afferents were not positive for neurofilament heavy chain. In the mouse, the TL ganglia had a significantly higher percentage of TRPV1- and CGRP-positive neurons than did the LS ganglia, whereas no differences were observed in the rat. The high incidence of TRPV1-positive colonic afferents in rodents suggests that hypersensitivity from the viscera may be partially a TRPV1-mediated event, thereby providing a suitable target for the treatment of visceral pain.
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PMID:Differences in spinal distribution and neurochemical phenotype of colonic afferents in mouse and rat. 1632 Feb 37

For more than a century neurogenic inflammation has been proposed to have a role in various human diseases. The present review will cover the conceptual steps of the itinerary that has led to the conclusion that neurogenic inflammation is important in migraine. Of particular relevance for the object of this article is the observation that tachykin-independent neurogenic inflammatory responses are evident in rodents, but much less pronounced or absent in other mammal species, including man, whereas neurogenic vasodilatation, most likely mediated by CGRP, occurs in most mammalian species and also in man. Recent evidence that a CGRP receptor antagonist was effective in the treatment of migraine attack supports the hypothesis that neurogenic vasodilatation is a major underlying mechanism of migraine.
J Headache Pain 2005 Apr
PMID:CGRP and migraine: neurogenic inflammation revisited. 1636 44

The mechanism of pancreatitis-induced pain is unknown. In other tissues, inflammation activates transient receptor potential vanilloid 1 (TRPV1) on sensory nerves to liberate CGRP and substance P (SP) in peripheral tissues and the dorsal horn to cause neurogenic inflammation and pain, respectively. We evaluated the contribution of TRPV1, CGRP, and SP to pancreatic pain in rats. TRPV1, CGRP, and SP were coexpressed in nerve fibers of the pancreas. Injection of the TRPV1 agonist capsaicin into the pancreatic duct induced endocytosis of the neurokinin 1 receptor in spinal neurons in the dorsal horn (T10), indicative of SP release upon stimulation of pancreatic sensory nerves. Induction of necrotizing pancreatitis by treatment with L-arginine caused a 12-fold increase in the number of spinal neurons expressing the proto-oncogene c-fos in laminae I and II of L1, suggesting activation of nociceptive pathways. L-arginine also caused a threefold increase in spontaneous abdominal contractions detected by electromyography, suggestive of referred pain. Systemic administration of the TRPV1 antagonist capsazepine inhibited c-fos expression by 2.5-fold and abdominal contractions by 4-fold. Intrathecal, but not systemic, administration of antagonists of CGRP (CGRP(8-37)) and SP (SR140333) receptors attenuated c-fos expression in spinal neurons by twofold. Thus necrotizing pancreatitis activates TRPV1 on pancreatic sensory nerves to release SP and CGRP in the dorsal horn, resulting in nociception. Antagonism of TRPV1, SP, and CGRP receptors may suppress pancreatitis pain.
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PMID:Transient receptor potential vanilloid 1, calcitonin gene-related peptide, and substance P mediate nociception in acute pancreatitis. 1639 78

Complex regional pain syndromes (CRPS, type I and type II) are devastating conditions that can occur following soft tissue (CRPS type I) or nerve (CRPS type II) injury. CRPS type I, also known as reflex sympathetic dystrophy, presents in patients lacking a well-defined nerve lesion, and has been questioned as to whether or not it is a true neuropathic condition with an organic basis. As described here, glabrous and hairy skin samples from the amputated upper and lower extremity from two CRPS type I diagnosed patients were processed for double-label immunofluorescence using a battery of antibodies directed against neural-related proteins and mediators of nociceptive sensory function. In CRPS affected skin, several neuropathologic alterations were detected, including: (1) the presence of numerous abnormal thin caliber NF-positive/MBP-negative axons innervating hair follicles; (2) a decrease in epidermal, sweat gland, and vascular innervation; (3) a loss of CGRP expression on remaining innervation to vasculature and sweat glands; (4) an inappropriate expression of NPY on innervation to superficial arterioles and sweat glands; and (5) a loss of vascular endothelial integrity and extraordinary vascular hypertrophy. The results are evidence of widespread cutaneous neuropathologic changes. Importantly, in these CRPS type I patients, the myriad of clinical symptoms observed had detectable neuropathologic correlates.
Pain 2006 Feb
PMID:Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome. 1678 76

Using immunohistochemical methods we determined the presence of SP- and CGRP-immunopositive nerve fibers in the hip joint of patients with femoral neck fracture (controls, group 1), painful osteoarthritis (group 2), and painless failed total hip arthroplasties (group 3). Immunoreactive nerve fibers were found in the soft tissue of the fossa acetabuli as well as in the subintimal part of the synovial layer in the hip joint capsule of groups 1 and 2. In the capsule of controls the innervation density had a median of 5.7fibers/cm(2) for CGRP-ir and 3.2fibers/cm(2) for SP-ir afferents. In the osteoarthritic group, the density significantly increased to a median of 15.6fibers/cm(2) for CGRP-ir and 8.2fibers/cm(2) for SP-ir neurons (p=0.05). Patients with failed hip arthroplasties completely lacked these neuropeptide containing afferents. Innervation density in the fossa acetabuli of osteoarthritc patients showed a median of 14.1fibers/cm(2) for CGRP-ir and 5.9fibers/cm(2) for SP-ir afferents. From these data we assume that the hip joint capsule and the soft tissue of the fossa acetabuli are important triggers of nociception. This is supported by the fact, that patients with loosened total hip arthroplasties, where we failed to detect SP- and CGRP-immunoreactive fibers, did not feel pain. The upregulation of SP- and CGRP-positive neurons in response to arthritic stages suggests a mechanism involving neuropeptides in the maintenance of a painful degenerative joint disease and in mediating noxious stimuli from the periphery. Furthermore, these findings help to explain clinical observations, such as effectiveness of local therapy to control hip pain with intraarticular injection, synovectomy and denervation procedures.
Eur J Pain 2007 Jan
PMID:Localization of SP- and CGRP-immunopositive nerve fibers in the hip joint of patients with painful osteoarthritis and of patients with painless failed total hip arthroplasties. 1646 Sep 74

The involvement of spinal transient receptor potential vanilloid 1 (TRPV1) in formalin-evoked pain has remained unclear, because investigation of this kind of pain with selective antagonists has not been conducted. The purpose of this study is to investigate the participation of spinal TRPV1 in formalin-evoked pain with iodo-resiniferatoxin (I-RTX), a potent TRPV1-selective antagonist. I-RTX given intrathecally dose-dependently and significantly decreased the number of flinching responses in the formalin-evoked 1st and 2nd phase with ID50 values (drug dose producing 50% inhibition of response) of 1.0 and 3.8 microg, respectively, and concentration-dependently suppressed capsaicin-evoked calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) release from rat spinal cord slices with an IC50 value (drug concentration producing 50% inhibition of response) of 86 nM. Capsazepine, a classical non-selective TRPV1 antagonist, given intrathecally also inhibited formalin-evoked flinching in both the 1st and 2nd phase with ID50s of 420 and 200 microg, respectively, and CGRP-LI release from rat spinal cord slices with an IC50 of 7.8 microM. Ratios of in-vivo analgesic potencies of I-RTX and capsazepine well reflected their intrinsic in-vitro activity. These findings suggest that spinal TRPV1 participates in the transduction system of formalin-evoked pain.
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PMID:Participation of the spinal TRPV1 receptors in formalin-evoked pain transduction: a study using a selective TRPV1 antagonist, iodo-resiniferatoxin. 1659 66

Neuropeptide Y (NPY) and its cognate receptors are important modulators of nociception and their expression is significantly altered following injury. In particular, previous studies have demonstrated that the Y1 subtype of NPY receptors inhibits nociceptive transmission from capsaicin-sensitive terminals in the dorsal horn of the spinal cord. The present study evaluated the function of the Y1 receptor on peripheral terminals of primary afferent neurons by testing whether peripherally administered Y1 agonists and antagonists alter capsaicin-evoked mechanical allodynia in rats and capsaicin-evoked immunoreactive calcitonin gene-related peptide (iCGRP) release from isolated superfused rat skin. Treatment with the Y1 agonist [Leu31,Pro34]-NPY (0.5, 1, or 10 nmol) significantly inhibited capsaicin-evoked mechanical allodynia in a dose-dependent manner. This effect was reversible by pretreatment with the Y1 antagonist BIBO3304 (10 nmol). The anti-allodynia produced by the Y1 agonist occurred at a peripheral site of action, because injection into the paw contralateral to the site of the capsaicin injection had no effect on paw withdrawal latencies. In isolated skin, application of [Leu31,Pro34]-NPY (300 nM) significantly inhibited capsaicin-evoked CGRP release. BIBO3304 reversed this inhibition, having itself no effect on capsaicin-evoked iCGRP release. These studies indicate that the activation of peripheral Y1 receptors produces anti-allodynia, possibly via the direct inhibition of capsaicin-sensitive fibers.
Pain 2006 Sep
PMID:Attenuation of capsaicin-evoked mechanical allodynia by peripheral neuropeptide Y Y1 receptors. 1671 86


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