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)

Proteinase-activated receptor (PAR) 2 is expressed on a subset of primary afferent neurons and involved in inflammatory nociception. Transient receptor potential vanilloid subfamily 1 (TRPV1) is a sensory neuron-specific cation channel that responds to capsaicin, protons, or heat stimulus. Here, we show that TRPV1 is coexpressed with PAR2 but not with PAR1 or PAR3, and that TRPV1 can functionally interact with PAR2. In human embryonic kidney 293 cells expressing TRPV1 and PAR2, PAR2 agonists increased capsaicin- or proton-evoked TRPV1 currents through a PKC-dependent pathway. After application of PAR2 agonists, temperature threshold for TRPV1 activation was reduced from 42 degrees C to well below the body temperature. PAR2-mediated Fos expression in spinal cord was decreased in TRPV1-deficient mice. The functional interaction was also observed in mouse DRG neurons and proved at a behavioral level. These represent a novel mechanism through which trypsin or tryptase released in response to tissue inflammation might trigger the sensation of pain by PAR2 activation.
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PMID:Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinase-induced inflammatory pain. 1512 43

We report a case of an acute allergic reaction to rectal diclofenac following elective caesarean section in a patient taking ibuprofen. The reaction presented as severe angio-oedema affecting the face and tongue. Serial blood samples failed to show the rise in tryptase levels characteristic of an anaphylactic or anaphylactoid reaction. Diclofenac is widely used for postoperative pain relief in women undergoing caesarean section. To our knowledge this is the first time that an adverse reaction to diclofenac given via this route has been reported in an obstetric patient.
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PMID:Angio-oedema following rectal diclofenac after caesarean section. 1532 29

Kinins are released from kininogens through the activation of the Hageman factor-prekallikrein system or by tissue kallikrein. These peptides exert various biological activities, such as vascular permeability increase, smooth muscle contraction, pain sensation and induction of hypotension. In many instances kinins are thought to be involved in the pathophysiology of various diseases. Recent studies have revealed that microbial and human cell proteinases activate Hageman factor and/or prekallikrein, or directly release kinin from kininogens. This review discusses the activation of the kinin-release system by mast-cell tryptase and microbial proteinases, including gingipains, which are cysteine proteinases from Porphyromonas gingivalis , the major pathogen of periodontal disease. Each enzyme is evaluated in the context of its association to allergy and infectious diseases, respectively. Furthermore, a novel system of kinin generation directly from kininogens by the concerted action of two proteinases is described. An interesting example of this system with implications to bacterial pathogenicity is the release of kinins from kininogens by neutrophil elastase and a synergistic action of cysteine proteinases from Staphylococcus aureus . This alternative production of kinins by proteinases present in diseased sites indicates a significant contribution of proteinases other than kallikreins in kinin generation. Therefore kinin receptor antagonists and proteinase inhibitors may be useful as therapeutic agents.
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PMID:Activation of the kallikrein-kinin system and release of new kinins through alternative cleavage of kininogens by microbial and human cell proteinases. 1557 18

Migraine may affect as many as 9% of all schoolchildren and often presents with abdominal symptoms of pain, nausea, and vomiting. Even though the pathophysiology of migraine remains unknown, self-regulation techniques appear to be more effective in prevention of childhood migraine than conventional pharmacotherapy which is often associated with adverse effects. Mast cells have been implicated in the pathogenesis of migraine in adults, but have not been previously studied in children with migraine. Mast cells are found close to the vessels and nerves in the meninges where they can release multiple vasoactive, neurosensitizing, and pro-inflammatory mediators. Therefore, we investigated whether children with migraine may have increased urinary levels of mast cell mediators and whether practicing relaxation imagery exercises has an effect on the frequency of headache, as well as on mast cell activation. Urine was collected for 24 hours from children with and without migraine after a 5-day amine-restricted diet. Children with migraine also collected urine during migraine episodes. The mean levels of urinary histamine, its main metabolite, methylhistamine, and the mast cell enzyme, tryptase, were higher in children than generally found in adults, but they did not differ statistically in any of the categories studied. However, in 8 of 10 children who practiced relaxation imagery techniques and successfully reduced the number of migraines, the urine tryptase levels were also significantly lower. There was no relationship between successful practice and sex or age of the child. These results suggest that stress may activate mast cells which could be involved in the pathophysiology of migraine.
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PMID:Mast cell activation in children with migraine before and after training in self-regulation. 1561 2

Certain serine proteases from the circulation (e.g., coagulation factors), inflammatory cells (e.g., mast-cell tryptase, neutrophil proteinase 3), and from many other cell types (e.g., trypsins) can specifically signal to cells by cleaving protease-activated receptors (PARs), a family of four G protein-coupled receptors. Proteases cleave PARs at specific sites within the extracellular amino-terminus to expose amino-terminal tethered ligand domains that bind to and activate the cleaved receptors. The proteases that activate PARs are often generated and released during injury and inflammation, and activated PARs orchestrate tissue responses to injury, including hemostasis, inflammation, pain, and repair. This review concerns protease and PAR signaling in the nervous system. Neurons of the central and peripheral nervous systems express all four PARs. Proteases that may derive from the circulation, inflammatory cells, or neural tissues can cleave PARs on neurons and thereby activate diverse signaling pathways that control survival, morphology, release of neurotransmitters, and activity of ion channels. In this manner proteases and PARs regulate neurodegeneration, neurogenic inflammation, and pain transmission. Thus, PARs may participate in disease states and PAR antagonists or agonists may be useful therapies for certain disorders.
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PMID:Protease-activated receptors: regulation of neuronal function. 1605 40

The pathophysiology of functional gastrointestinal disorders is poorly understood. Accepted common mechanisms include psychosocial factors, abnormal gastrointestinal motility and disturbed visceral sensory perception, but the underlying causes remain unclear. Mast cells (MCs) are immunocytes widely distributed throughout the gastrointestinal tract. Several stimuli (e.g. allergens, neuropeptides and stress) lead to MC activation with consequent mediator release (e.g. histamine, tryptase and prostanoids). The MC mediators interact with nerves supplying the gut leading to altered gut physiology and increased sensory perception. The intestinal mucosa of irritable bowel syndrome patients contains on average an increased number of MCs. These cells release an increased amount of mediators in close vicinity to mucosal innervation. The MC activation and their close proximity to nerve fibres is correlated with the severity of perceived abdominal painful sensations. These data provide a strong basis for considering MCs as important participants in visceral hypersensitivity and pain perception in irritable bowel syndrome. Inhibition of MC function may ameliorate irritable bowel symptoms. Novel drugs with an increased potential in the control of MC function (e.g., anti-IgE antibodies, the intracellular protein tyrosine kinase inhibitor Syk) and mediator release (e.g., second generation antihistamines, proteinase-activated receptor antagonists) may be useful pharmacological tools for these common disorders.
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PMID:Functional gastrointestinal disorders and mast cells: implications for therapy. 1637 Oct 78

1 Proteinase-activated receptor-2 (PAR2), a receptor activated by trypsin and tryptase, is abundantly expressed in the gastrointestinal tract including the C-fiber terminal, and might play a role in processing of visceral pain. In the present study, we examined and characterized the roles of PAR2 in pancreatitis-related abdominal hyperalgesia/allodynia in mice. 2 Caerulein, administered i.p. once, caused a small increase in abdominal sensitivity to stimulation with von Frey hairs, without causing pancreatitis, in PAR2-knockout (KO) mice, but not wild-type (WT) mice. 3 Caerulein, given hourly six times in total, caused more profound abdominal hyperalgesia/allodynia in PAR2-KO mice, as compared with WT mice, although no significant differences were detected in the severity of pancreatitis between the KO and WT animals. 4 The PAR2-activating peptide, 2-furoyl-LIGRL-NH(2), coadministered repeatedly with caerulein six times in total, abolished the caerulein-evoked abdominal hyperalgesia/allodynia in WT, but not PAR2-KO, mice. Repeated doses of 2-furoyl-LIGRL-NH(2) moderately attenuated the severity of caerulein-induced pancreatitis in WT animals. 5 Our data from experiments using PAR2-KO mice provide evidence that PAR2 functions to attenuate pancreatitis-related abdominal hyperalgesia/allodynia without affecting pancreatitis itself, although the PAR2AP applied exogenously is not only antinociceptive but also anti-inflammatory.
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PMID:Suppression of pancreatitis-related allodynia/hyperalgesia by proteinase-activated receptor-2 in mice. 1652 Jul 45

Certain serine proteases that originate from the circulation (coagulation factors), inflammatory cells (mast cell tryptase, neutrophil granzyme A, and proteinase 3), and epithelial and neuronal tissues (trypsins) can specifically regulate cells by cleaving protease-activated receptors (PARs), a family of four G-protein-coupled receptors. Proteases cleave PARs on multiple cell types to reveal tethered ligand domains that bind to and activate the cleaved receptors. The proteases that activate PARs are often generated and secreted during injury and inflammation, and PARs orchestrate tissue responses to these insults, including hemostasis, inflammation, nociception, and repair mechanisms. Agonists of PARs, notably PAR2, induce inflammation in many tissues that is characterized by hyperemia, extravasation of plasma proteins, granulocyte infiltration, and alterations in epithelial permeability. These effects are mediated in part by the release of neuropeptides substance P and calcitonin gene-related peptide from sensory nerve fibers in peripheral tissues. Proteases that activate PAR2 also induce the release of neuropeptides from the central projections of these nerves in the dorsal horn of the spinal cord, where they participate in pain transmission. Accumulating evidence from PAR-deficient mice indicates that these mechanisms may contribute to experimental models of disease and raise the possibility that protease inhibitors and PAR antagonists may be useful therapies for a variety of inflammatory and painful conditions.
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PMID:Protease-activated receptors: how proteases signal to cells to cause inflammation and pain. 1667 65

The mast-cell sarcoma of a bone is described here for the first time. The tumour presented in a 4-year-old boy, with pain, oedema and deformation of his right lower leg. Radiological findings revealed a destructive tumourous mass. Histopathological examination showed the tumour to be composed of large, atypical cells, with hyperchromatic oval and polygonal nuclei. The cytoplasm around them was eosinophilic with many basophilic and toluidine-blue-positive granules. These atypical mast cells were positive for chloroacetate esterase, c-kit, tryptase and negative for myeloperoxidase. The primary disease quickly progressed to mast-cell leukaemia, and despite intensive chemotherapy the patient died 18 months after first symptoms.
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PMID:Mast-cell sarcoma of the tibia. 2177 98

Interstitial cystitis (IC) is a syndrome of bladder hypersensitivity with symptoms of urgency, frequency, and chronic pelvic pain. Although no consensus has been reached on the underlying cause of IC, several pathophysiologic mechanisms, including epithelial dysfunction, mast cell activation, and neurogenic inflammation, have been proposed. Despite multiple different causes of urinary cystitis, the bladder's response to cystitis is limited and typical. Animal experiments have shown upregulation of proteinase-activated receptors, tryptase, beta-nerve growth factor, inducible nitric oxide synthase, nuclear transcription factor-kappaB, c-Fos, phosphodiesterase 1C, cyclic adenosine monophosphate (cAMP)-dependent protein kinase, and proenkephalin B. After the noxious stimulus has abated, downregulation of genes appears to follow. Distention of the bladder results in the release of adenosine triphosphate (ATP) from urothelial cells, which activates purinergic P2X3 receptors. Activation by ATP of P2X3-expressing afferents is a fundamental signaling factor in bladder sensation and appears to play a role in bladder reflexes. Fos proteins present in spinal cord neurons have been shown to be upregulated in animals that have undergone cyclophosphamide-induced chemical cystitis. These and other findings suggest that neural upregulation occurs both peripherally and centrally in subjects with chronic cystitis. It is unclear whether neural mechanisms and inflammation are the cause of IC or the result of other initiating events. Neural upregulation is known to play a role in the chronicity of pain, urgency, and frequency and represents an exciting area of research that may lead to additional treatments and a better understanding of IC.
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PMID:Neural upregulation in interstitial cystitis. 1746 76


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