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)

Bradykinin receptors are believed to contribute to hyperalgesia under conditions of neuropathic pain. Using calcium imaging we investigated responses to B1 and B2 agonists on isolated rat dorsal root ganglion neurons. No response to the B1 agonist was detected, whereas 12% of neurons responded to the B2 agonist. Northern blot analysis confirmed the lack of B1 receptor expression in dorsal root ganglia, as B1 mRNA was neither detected under normal conditions nor after nerve injury. In the calcium imaging experiments, agonists were applied with an elevated superfusion flow rate to avoid tachyphylaxis to the drug. Normal external solution applied at this flow rate constituted a mechanical stimulus causing a response in some neurons. Thus, in comparable set-ups mechanosensitivity has first to be tested to avoid masking effects.
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PMID:No evidence for bradykinin B1 receptors in rat dorsal root ganglion neurons. 1156 57

Temporomandibular disorders (TMD) represent a family of recurrent conditions that often cause pain in the temporomandibular joint (TMJ) region and muscles of mastication. To determine if TMJ-responsive neurons encoded the intensity of pro-inflammatory chemical signals, dose-effect relationships were assessed after direct injection bradykinin into the joint space and compared with responses after injection of glutamate or saline. Neurons were recorded from superficial laminae of the trigeminal subnucleus caudalis/upper cervical cord junction region (Vc/C(2)) and identified by palpation of the TMJ region in barbiturate-anesthetized male rats. The majority (62 of 84) of units received convergent input from facial skin, while 26% were driven only by deep input from the TMJ region. Conduction-velocity based on the latency to firing after electrical stimulation of the TMJ region indicated 64% of units were driven by A-delta fiber input only. Bradykinin (0.1-10 microM) excited 69% of neurons tested, and 70% (19 of 27) of these units were activated by the lowest dose (0.1 microM). Glutamate (50-200 mM) excited 27% of units; however, when tested after bradykinin, 58% of units were activated by glutamate. Some TMJ units (17%) were excited by saline injection alone and not enhanced further by bradykinin or glutamate. Most (88%) TMJ units were activated by injection of the small fiber excitant, mustard oil (20% solution), into the TMJ region. Units responsive to bradykinin or glutamate were not restricted to particular classes [e.g., wide dynamic range (WDR), nociceptive specific (NS), deep only]. A small percentage of TMJ units (approximately 15%) were activated antidromically from the contralateral posterior thalamus. In parallel studies using c-fos immunocytochemistry, bradykinin (1 microM) injection into the TMJ region produced a greater number of Fos-positive neurons at the Vc/C(2) region than glutamate (200 mM) or saline. These results revealed two broad classes of TMJ units that encoded the intensity of pro-inflammatory chemical stimuli applied to the TMJ region, units that received convergent nociceptive input from facial skin (i.e., WDR and NS units) and units that responded only to deep input from the TMJ region. On the basis of encoding properties and efferent projection status, it is concluded that activation of TMJ units within the superficial laminae at the Vc/C(2) region contribute to the diffuse and spreading nature of TMD pain sensation.
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PMID:Intensity coding by TMJ-responsive neurons in superficial laminae of caudal medullary dorsal horn of the rat. 1169 29

Bradykinin is involved in hyperalgesia (pain hypersensitivity) induced by Bothrops jararaca venom-intraplantar injection of B. jararaca venom (5microg/paw) in rats caused hyperalgesia, which peaked 1h after venom injection. This phenomenon was not modified by promethazine (H(1) receptor antagonist), methysergide (5-HT receptor antagonist), guanethidine (sympathetic function inhibitor), anti-TNF-alpha or anti-interleukin-1 antibodies or by the chelating agent CaNa(2)EDTA. Venom-induced hyperalgesia was blocked by the bradykinin B(2) receptor antagonist HOE 140. On the other hand, des-Arg(9), [Leu(8)]-bradykinin, a bradykinin B(1) receptor antagonist, did not modify the hyperalgesic response. These results suggest that bradykinin, acting on B(2) receptor, is a mediator of hyperalgesia induced by B. jararaca venom.
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PMID:Bradykinin is involved in hyperalgesia induced by Bothrops jararaca venom. 1207 60

Bradykinin (BK) is an inflammatory mediator that plays a pivotal role in pain and hyperalgesia to heat in inflamed tissues by exciting nociceptors and sensitizing them to heat through activation of protein kinase C (PKC). It has been suggested that the capsaicin receptor (VR1), a nociceptor-specific cation channel sensitive to noxious heat, protons, and capsaicin, is a channel that is modified by BK in these effects. In this study, we examined how BK modulates the activity of VR1. We measured VR1 currents using the patch-clamp technique in human embryonic kidney-derived (HEK293) cells expressing VR1 and B2 BK receptor. We found that BK lowered the threshold temperature for activation of VR1 currents in HEK cells down to well below the physiological body temperature in a concentration-dependent manner through PKC activation. We also demonstrated that in capsaicin-sensitive dorsal root ganglion (DRG) neurons the activation threshold of heat-induced current, which is considered to be VR-1 mediated, was lowered by BK and that this effect was also mediated by PKC. These data further support the supposition that modulation of VR1 is a mechanism for the BK-induced excitation of nociceptors and their sensitization to heat.
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PMID:Bradykinin lowers the threshold temperature for heat activation of vanilloid receptor 1. 1209 79

Recent work has addressed the role of vanilloid receptor type 1 (VR1) in pain perception. VR1 activity is regulated both directly and indirectly by endogenous factors. For example, protein kinase C sensitizes human VR1 to mild decreases in pH, which are commonly encountered during inflammation, and renders the endocannabinoid anandamide a more potent 'endovanilloid'. Bradykinin and nerve growth factor release VR1 from the inhibitory control of phosphatidylinositol (4,5)-bisphosphate and anti-VR1 serum ameliorates thermal allodynia and hyperalgesia in diabetic mice. There is strong evidence that not only the sensitivity but also the density of expression of VR1 is enhanced during inflammatory conditions. These observations provide an empirical foundation which could explain the reduced inflammatory hyperalgesia in VR1 knockout mice, and they imply an important role for endovanilloid signaling via VR1 in the development of ongoing pain in humans that occurs in most inflammatory conditions. Conversely, downregulation of VR1 expression and/or activity is a promising therapeutic strategy for novel analgesic drugs.
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PMID:Endovanilloid signaling in pain. 1213 83

Bradykinin is not only a mediator of pain and inflammation but also a potent vasodilator and is likely to contribute to the cardioprotective effects of angiotensin-converting enzyme inhibitors. The B2 receptor (B2-R) mediating most of the inflammatory and cardiovascular effects of bradykinin represents a candidate gene likely involved in the complex genetic causes of common chronic disorders such as hypertension. The C181T polymorphism of the B2-R gene influences the potency of bradykinin and there is evidence of a possible role of this polymorphism in the development of hypertension and end-stage renal disease. We developed and validated a new, rapid, and reliable method for the detection of the C181T polymorphism based on the hybridization probes format on the LightCycler, which is superior to the conventional PCR-RFLP method commonly used to detect this polymorphism. It allows the solid evaluation of large patient populations with the best time.
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PMID:Rapid and reliable genotyping of the C181T polymorphism in the bradykinin B2 receptor gene. 1270 34

Bradykinin and prostaglandins are both local mediators strongly implicated in pain and inflammation. Here, we have investigated the effects of bradykinin on the release of prostaglandin E(2) from cultured neurones derived from adult rat trigeminal ganglia. Bradykinin was a potent inducer of prostaglandin E(2) release, an effect that was likely mediated by bradykinin B(2) receptors, as the bradykinin-induced prostaglandin E(2) release was attenuated by the bradykinin B(2) receptor-selective antagonist, arginyl-L-prolyl-trans-4-hydroxy-L-prolylglycyl-3-(2-thienyl)-L-alanyl-L-seryl-D-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-L-(2 alpha, 3 beta, 7a beta)-octahydro-1H-indole-2-carbonyl-L-arginine (HOE 140), but not by the bradykinin B(1) receptor-selective antagonist, des-Arg(9),[Leu(8)]-bradykinin. Furthermore, bradykinin-induced prostaglandin E(2) release was inhibited following treatment with the phospholipase A(2) inhibitor, arachidonyltrifluoromethyl ketone (AACOCF(3)), the nonselective cyclooxygenase inhibitor, piroxicam, the mitogen-activated protein kinase kinase-1 (MEK1) inhibitor, 2'-amino-3'-methoxyflavone (PD98059), and the protein kinase C inhibitor, bisindolylmaleimide XI (Ro320432). Taken together, these data suggest that bradykinin, acting via bradykinin B(2) receptors, induces prostaglandin E(2) release from trigeminal neurones through the protein kinase C and mitogen-activated protein kinase-dependent activation of phospholipase A(2) and consequent stimulation of cyclooxygenases.
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PMID:Characterization of bradykinin-induced prostaglandin E2 release from cultured rat trigeminal ganglion neurones. 1278 82

Bradykinin (BK) is an important mediator of hyperalgesia, inflammatory diseases, asthma and cancer. It is a pro-inflammatory polypeptide that can cause pain, inflammation, increased vascular permeability, vasodilation, contraction of various smooth muscles and cell proliferation by stimulating B(1)and B(2)receptors. B(1) receptors are formed in vitro during trauma, inflammatory reactions and injury. B(2) receptors are most commonly distributed in the vascular and non-vascular smooth muscle, and in the heart. Numerous BK antagonists have been developed in recent years with the prime aim of treating diseases resulting from excessive BK formation. Non-peptide B(2) receptor antagonists are now being synthesized and are under intense experimental investigation at various research centers. The most clinically useful peptide and non-peptide BK antagonists must be stable against all BK-inactivating enzymes, orally active, and have a long half-life with minimal side effects. These BK receptor antagonists may have future novel therapeutic applications in various pathological conditions associated with the abnormal kinin system.
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PMID:Bradykinin receptor antagonists: therapeutic implications. 1281 81

Bradykinin (BK) plays an important role in the pathophysiological processes accompanying pain and inflammation. Selective bradykinin B1 receptor antagonists have been shown to be anti-nociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. We have explored chemical modifications in a series of dihydroquinoxalinone sulfonamides to evaluate the effects of various structural changes on biological activity. The optimization of a screening lead compound, facilitated by a homology model of the BK B1 receptor, culminated in the discovery of a potent human BK B1 receptor antagonist. Results from site-directed mutagenesis studies and experiments in an animal pain model are presented.
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PMID:Discovery of a potent, non-peptide bradykinin B1 receptor antagonist. 1281 82

Metalloendopeptidases of the M13 family were shown to play critical roles in normal physiological processes such as pain control, hypertension and phosphate metabolism, and in pathological states such as Alzheimer's disease. Recently, NL1, a novel member of the family, has been identified and shown to be expressed in several tissues both as a membrane-bound and a secreted protein. As a further step to understand the physiological role(s) of NL1 in mouse, we mapped NL1 mRNA expression pattern in embryos and in young animals at postnatal days p1 and p3, and in adult nervous tissue, using in situ hybridization at the cellular level. No expression could be detected in embryos and young animals. In contrast, NL1 expression was evident in adult brain, pituitary gland and spinal cord. In the central nervous system (CNS), NL1 mRNA was predominantly found in the ventro-posterior regions, which are mostly associated with vegetative functions. At the cellular level, NL1 mRNA was non-uniformly distributed within subpopulations of neurons. In the spinal cord, specific signal was observed in the gray matter. Then, in order to identify putative relevant substrates for NL1, we studied its enzymatic activity towards peptides known to be co-expressed in the NL1-positive domains. Our study showed that NL1 degrades several of these peptides in vitro, the most readily degraded peptides being Bradykinin and Substance P. These results suggest that NL1 is likely to play a critical role in the central nervous system.
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PMID:The neuropeptide-degrading enzyme NL1 is expressed in specific neurons of mouse brain. 1449 88


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