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)

Using a combined pharmacological and gene-deletion approach, we have delineated a novel mechanism of neurokinin-1 (NK-1) receptor-dependent hyperalgesia induced by proteinase-activated receptor-2 (PAR2), a G-protein-coupled receptor expressed on nociceptive primary afferent neurons. Injections into the paw of sub-inflammatory doses of PAR2 agonists in rats and mice induced a prolonged thermal and mechanical hyperalgesia and elevated spinal Fos protein expression. This hyperalgesia was markedly diminished or absent in mice lacking the NK-1 receptor, preprotachykinin-A or PAR2 genes, or in rats treated with a centrally acting cyclooxygenase inhibitor or treated by spinal cord injection of NK-1 antagonists. Here we identify a previously unrecognized nociceptive pathway with important therapeutic implications, and our results point to a direct role for proteinases and their receptors in pain transmission.
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PMID:Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway. 1143 34

The proteinase-activated receptor 2 is expressed on a subset of primary afferent neurons and may participate in the neurogenic component of inflammation. We hypothesized that this receptor may also play a role in neuronal sensitization and contribute to the pathogenesis of pain in inflammatory conditions such as pancreatitis. Using a specific proteinase-activated receptor 2 activating peptide, we found evidence of such sensitization in vitro in the form of enhanced capsaicin- and KCl-evoked release of calcitonin gene-related peptide, a marker for nociceptive signaling. We then demonstrated that injection of the proteinase-activated receptor 2 activating peptide into the pancreatic duct can activate and sensitize pancreas-specific afferent neurons in vivo, as measured by Fos expression in the dorsal horn of the spinal cord. These observations suggest that proteinase-activated receptor 2 contributes to nociceptive signaling and may provide a novel link between inflammation and pain.
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PMID:The proteinase-activated receptor 2 is involved in nociception. 1169 14

Measurement of visceral sensitivity in animals is mainly based on 'pseudoaffective' responses, which are brain stem reflexes. For example, in female, but not male rats, acute partial restraint stress induces hypersensitivity to colorectal distension. Mucosal mast cell density increases in rats after nematode infection or maternal deprivation, and both also induce colon hypersensitivity. Significantly, the proximity between nerves and mast cells has been found to be increased in adult rats submitted to maternal deprivation. Protease activation of the proteinase-activated receptor-2 also increases visceral nociception in rats, suggesting that an increase in paracellular permeability may be the primum movens in several animal models of visceral hypersensitivity. Accumulating evidence suggests that sensitization of visceral afferents is not restricted to the presumed nociceptor population, suggesting that most of the mechanosensitive afferent population can contribute to visceral discomfort and pain. Other inflammation-produced changes (e.g. subunit composition of purine-gated P2X channels) in visceral sensory neurones may also contribute to visceral hypersensitivity. This article discusses use of in vivo strategies (and transgenic mouse models) to reveal putative roles in mechanosensitivity and sensitization for molecules not previously considered to have mechanosensory functions.
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PMID:In vivo and transgenic animal models used to study visceral hypersensitivity. 1728 May 83

Camostat mesilate, an orally available proteinase inhibitor, is clinically used for treatment of pancreatitis. Given recent evidence that pancreatic proteinases including trypsin and/or proteinase-activated receptor-2 (PAR2) might be involved in pancreatic pain, we examined if camostat mesilate could suppress spinal Fos expression, a marker for neuronal activation, following specific application of trypsin to the pancreas, and pancreatitis-related referred allodynia. Trypsin, administered into the pancreatic duct, caused delayed expression of Fos proteins in the superficial layer of the bilateral T8 and T9 spinal dorsal horns in rats. The trypsin-induced spinal Fos expression was completely abolished by oral pre-administration of camostat mesilate at 300 mg/kg. After hourly repeated (6 times in total) administration of caerulein, mice showed typical symptoms of pancreatitis, accompanied by mechanical allodynia in the upper abdomen (i.e., referred hyperalgesia/allodynia), as assessed by use of von Frey filaments. Camostat mesilate at 100-300 mg/kg, given orally twice before the 1st and 4th doses of caerulein, abolished the pancreatitis-related abdominal allodynia, while it partially prevented the inflammatory signs. The same doses of camostat mesilate, when administered once after the final dose of caerulein, also revealed significant anti-allodynic effect. These data suggest that camostat mesilate prevents and/or depresses pancreatitis-induced pain and/or referred hyperalgesia/allodynia, in which proteinases including trypsin would play a critical role.
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PMID:The proteinase inhibitor camostat mesilate suppresses pancreatic pain in rodents. 1743 71

Functional somatic syndrome (FSS) is defined as a group of related syndromes characterized more by symptoms, suffering, and disability than by structural or functional abnormality. The diagnostic criteria and/or symptoms of FSS often overlap, and co-morbidity is commonly found among the diseases of FSS. For example, patients with irritable bowel syndrome often suffer from chronic pain, and a high percentage of co-morbidity can be found with fibromyalgia. Accumulating evidence indicates the presence of visceral and somatic hyperalgesia in FSS as a common feature, and the central sensitization mechanism has been suggested to play an important role in the pathophysiology of FSS. In the present article, the authors introduce the concept of FSS focusing on its possible relevance to rheumatology in terms of pain perception. A possible implication of mast cells and proteinase-activated receptor-2 (PAR-2) in FSS is also reviewed.
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PMID:Functional somatic syndrome: how it could be relevant to rheumatologists. 1756 71

It has been demonstrated that trypsin is able to evoke the classical signals of inflammation, mainly via the activation of proteinase-activated receptor-2 (PAR-2). This study was designed to evaluate the inflammatory and nociceptive responses caused by trypsin injection in the mouse paw. Trypsin produced a dose- and time-related paw edema, a response that was markedly reduced in PAR-2-deficient mice compared to wild-type mice, particularly at the early time-points after trypsin injection. In addition, trypsin produced an increase in myeloperoxidase (MPO) activity, which was significantly reduced in PAR-2-deficient mice. The injection of trypsin into the mouse paw also elicited a dose- and time-dependent spontaneous nociception, as well as thermal and mechanical hypernociceptive responses, which were consistently decreased in mice with genetic deletion of PAR-2. Pharmacological evaluation revealed that edema formation and spontaneous nociception caused by trypsin injection in the mouse paw are mediated by a complex range of mediators. Both edema and nociception seem to rely on the production of neuropeptides, probably involving C-fibre activation and vanilloid receptor-1 (TRPV1), besides the stimulation of kinin B(2) receptors. Edematogenic response is also likely related to the production of cyclooxygenase (COX) metabolites, whereas the mast cell activation appears to be greatly associated to spontaneous nociception. Altogether, the present results indicate that trypsin-induced edema and nociception in the mouse paw represent multi-mediated responses that are largely, but not exclusively, related to the activation of PAR-2. These pieces of evidence provide new insights on the role of trypsin in pain and inflammation.
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PMID:Mechanisms underlying the nociceptive and inflammatory responses induced by trypsin in the mouse paw. 1808 62

Inflammatory-related activation and sensitization of meningeal nociceptors is believed to play a key role in promoting the intracranial throbbing pain of migraine. We have shown recently that mast cell activation and various mast cell-derived inflammatory mediators can promote activation and sensitization of meningeal nociceptors. Mast cell tryptase has also been proposed to promote pain hypersensitivity by activating the proteinase-activated receptor 2 (PAR2) that is expressed on nociceptive neurons. In this study using in vivo single-unit recording in the trigeminal ganglion of anaesthetized rats, we found that local meningeal activation of PAR2 using the specific agonist SLIGRL-NH2 promoted sensitization of the threshold response while provoking desensitization of the suprathreshold responses. SLIGRL-NH2 also excited a subpopulation of meningeal nociceptors. Chronic mast cell depletion enhanced the sensitizing effects of PAR2 activation while curbing its desensitizing effects. Mast cell depletion did not change the PAR2-mediated excitatory effect. We propose that by enhancing the mechanical sensitivity of meningeal nociceptors local PAR2 activation could play a role in promoting the throbbing pain of migraine and that local mast cell degranulation may modulate such an effect.
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PMID:Modulation of meningeal nociceptors mechanosensitivity by peripheral proteinase-activated receptor-2: the role of mast cells. 1825 96

It has been reported that proteinase-activated receptor 2 (PAR2) receptor activation enhances the animal's pain response and PAR2 coexpresses with P2X3 in dorsal root ganglion neurons. However, whether PAR2 activation has a direct impact on P2X3 currents is still not clear. In this study, we performed the patch-clamp experiments in cultured dorsal root ganglion neurons and found that when incubated with trypsin or the PAR2 agonist SL-NH2 for a short time (3 min), instead of increasing, P2X3 currents amplitude decreased significantly. Meanwhile, the opening of P2X3 ion channel accelerated. Protein kinase A inhibitor H89 could not reverse above phenomenon, but played a synergistic effect on the contrary. These results suggest that the enhanced pain response caused by PAR2 activation is not through direct increase of the P2X3 current amplitude, and the acceleration of P2X3 opening may participate in the enhanced pain response in a long-time view. Moreover, protein kinase A does not participate in the inhibition of P2X3 currents caused by PAR2 activation.
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PMID:Acute PAR2 activation reduces alpha, beta-MeATP sensitive currents in rat dorsal root ganglion neurons. 2011 42

Noxious stimuli cause prompt phosphorylation of extracellular signal-regulated kinase (ERK) in the spinal dorsal horn that contributes to facilitation of pain sensation and is often used as an immediate marker for excitation of spinal neurons following somatic and colonic nociception. Here we asked whether two distinct pronociceptive stimuli with proteinase-activated receptor-2 (PAR2) agonists and hydrogen sulfide (H(2)S) in the pancreas cause phosphorylation of ERK in the spinal dorsal horn and also examined involvement of their possible downstream signaling molecules, transient receptor potential vanilloid-1 (TRPV1) and T-type Ca(2+) channels, respectively. Capsaicin (a TRPV1 agonist), trypsin (an endogenous PAR2 agonist), SLIGRL-NH(2) (a PAR2-activating peptide), and NaHS (an H(2)S donor) were infused into the pancreatic duct in anesthetized rats, and phosphorylated ERK in the spinal cord was detected by immunohistochemistry. Intraductal administration of capsaicin and trypsin caused prompt phosphorylation of ERK in the superficial layers of T9, but not T5 or T12, spinal dorsal horn. SLIGRL-NH(2) and NaHS, administered in the same manner, also produced ERK phosphorylation in the corresponding spinal regions. Mibefradil, a T-type Ca(2+) channel blocker, abolished the phosphorylation of ERK caused by intraductal NaHS but not SLIGRL-NH(2). In contrast, capsazepine, an inhibitor of TRPV1, suppressed the phosphorylation of ERK caused by intraductal SLIGRL-NH(2) but not NaHS. Our data thus demonstrate that pancreatic pronociceptive stimuli with PAR2 agonists and H(2)S cause ERK phosphorylation in the spinal dorsal horn, through activation of TRPV1 and T-type Ca(2+) channels, respectively, and that those two pronociceptive pathways are independent of each other.
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PMID:Phosphorylation of ERK in the spinal dorsal horn following pancreatic pronociceptive stimuli with proteinase-activated receptor-2 agonists and hydrogen sulfide in rats: evidence for involvement of distinct mechanisms. 2080 5

We examined if TRPA1, like TRPV1, contributes to pancreatic nociceptor excitation following proteinase-activated receptor-2 (PAR2) stimulation and to pancreatitis-related pain in mice. A PAR2-activating peptide, infused into the pancreatic duct, caused spinal Fos expression, which was prevented by AP18, a TRPA1 inhibitor. Repeated administration of cerulein caused referred hyperalgesia accompanying pancreatitis, which was reversed by SB366791, a TRPV1 inhibitor, but not AP18. AP18, administered in combination with a subeffective dose of SB366791, significantly suppressed the referred hyperalgesia. Our findings suggest that TRPA1, like TRPV1, mediates PAR2-triggered pancreatic nociception and that TRPA1 in collaboration with TRPV1 latently contributes to pancreatitis-related pain.
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PMID:Contribution of TRPA1 as a downstream signal of proteinase-activated receptor-2 to pancreatic pain. 2416 21


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