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 (BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) antagonists are potentially useful for treating inflammation, pain and severe trauma. To identify what chemical features might promote effective antagonism, we replaced Arg1 and Pro7 with structurally constrained and proteolytic-resistant residues, such as Bip (biphenylalanine), Dip (diphenylalanine) or 2Ind (indane amino acid). To determine which BK folding might lead to favourable interactions with receptors, the effects of cyclo(3,8) vs. cyclo(5,8) analogues were compared. The resulting BK analogues were examined for their agonistic and antagonistic activities in guinea pig ileum, rat uterus and depressor assays. The results suggest that co-planarity of the residue-7 side chain with its backbone NH is important for potent agonism as well as antagonism, and a D-directed side chain is crucial for antagonism. For residue-1 an L-orientation is important, and Dip1 may mimic a folded Arg1 side chain to elicit agonistic activities, with Bip1 mimicking an extended Arg1 side chain to elicit inhibitory activities. However, ileal and uterine receptors appear to prefer differently folded BK. For ileum, a BK conformation in which residues-3 and -8 are proximal to each other, but apart from residue-5, led to improved pA2.
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PMID:Cyclic and linear bradykinin analogues: implications for B2 antagonist design. 1044 67

In the skin, noxious heating induces an axon reflex response which is commonly accepted to be due to the release of vasodilatory neuropeptides from polymodal nociceptors. In the present study, the quantitative assessment of calcitonin gene-related peptide (CGRP) release from rat skin serves as an integrative measure of primary afferent activation by noxious heat and the presumed sensitising action of bradykinin and an activator of protein kinase C (PKC). The isolated rat hairy skin of either hind paw was mounted on acrylic rods and exposed for 5 min periods to synthetic interstitial fluid of either 32 degrees C for control or of higher temperatures up to 59 degrees C during stimulation. In addition, experiments were performed in calcium free solution (containing 10 mM EGTA) or the skin was preloaded with the membrane permeant calcium chelator BAPTA-AM (1 mM). To look for modulatory effects on the heat responses, bradykinin or polymyristate-acetate (PMA) were added during heat stimulation in further experiments. Heating the skin induced a temperature-dependent release of CGRP from a threshold of 43 degrees C which was absent in calcium free solution. Only at the highest temperatures (55 and 59 degrees C) was a partially calcium-independent release observed. Inhibition of the release was also obtained with the intracellular calcium buffer BAPTA-AM. Bradykinin 10 but not 1 microM as well as PMA 1 and 10 microM significantly facilitated the heat-induced CGRP release at 47 degrees C whereby BK caused a marginal and PMA a significant CGRP release by itself. Our results indicate that moderate noxious heat induces calcium-dependent CGRP release and this can be facilitated by bradykinin and by the activation of PKC. This suggests the same sensitising mechanism that affects nociceptor heat responses.
Pain 1999 Nov
PMID:Heat-induced release of CGRP from isolated rat skin and effects of bradykinin and the protein kinase C activator PMA. 1053 1

Bradykinin and kallidin are released during dermal injury and inflammation as a result of activation of kallikreins which cleave high- and low-molecular weight kininogen (HMW and LMW kininogen, respectively). In the skin, kinins are involved, e.g., as co-mitogens in cellular proliferation or in processes propagating pain and inflammation. The aim of our study was to investigate the specific occurrence of mRNAs for components of the kallikrein-kinin system in normal human skin and in skin biopsies of patients with selected skin diseases (psoriasis, lichenificated atopic eczema, basalioma). In normal skin, reverse transcription polymerase chain reaction (RT-PCR) with specific primer pairs followed by separation of products by polyacrylamide gel electrophoresis (PAGE) revealed the presence of mRNAs for tissue kallikrein, for the B2 and the B1 bradykinin receptors, but not for kininogen. In biopsies of lichenificated atopic eczema and basalioma, additionally, the mRNAs for HMW and LMW kininogen were detected, whereas in psoriatic skin mRNA for HMW kininogen was not expressed. These differences in mRNA expression may reflect the different contribution of kallikrein-kinin system components to the maintenance of chronic skin diseases like psoriasis. In acute dermal reactions occurring in lichenificated atopic eczema or in basalioma, tissue mRNA for HMW kininogen appears to be arisen from sources not pre-existing in normal skin.
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PMID:Identification and occurrence of mRNAs for components of the kallikrein-kinin system in human skin and in skin diseases. 1059 65

Bradykinin (BK) increased carotid blood flow (CBF) and jugular nitric oxide (NO) levels when administered into the common carotid artery of rabbits, and potentiated selectively, when infused together with histamine (HIST) or serotonin (5-HT), their effects on both CBF and jugular NO levels (but not vice versa). Such a potentiation was prevented and reversed only by nitroarginine or 1,10-phenanthroline (PHE) (which also reduced basal jugular NO levels) and did not involve the BK1 or BK2 receptors. Either HIST or 5-HT potentiated (likely involving the H1 and 5-HT2 receptors, respectively) the activating effect of BK on kininase I (K1), thus increasing the availability of L-arginine for the synthesis of NO. In patients with migraine, venous NO and K1 activity were higher during HIST desensitization than in basal conditions; moreover, HIST reduced the activities of prekallikrein (pre-KAL), kallikrein (KAL) and kininase II (K2) in the venous blood of these patients, in which the intensity of pain was related to the levels of plasma NO, and the administration into the humeral artery during circulatory arrest of BK alone (but not HIST) or BK and HIST together caused a strong pain attack. BK was confirmed to interact selectively with other autacoids in regulating systemic and local hemodynamics through the system of NO.
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PMID:Regulatory role of bradykinin in the coronary and cerebral circulations and in systemic hemodynamics. 1060 29

A number of plant species used in traditional medicine for the relief of pain have been selected from the medicinal and scientific literature of China, South America, Asia and West Africa. Extracts were prepared and tested in three in vitro receptor radioligand binding assays to determine whether there was an indication of biological activity, in particular their selectivity to a single receptor implicated in the mediation of pain. The three neuropeptide receptors chosen were Bradykinin (BK II), expressed in Chinese hamster ovary cells (CHO), neurokinin 1 (NK 1) expressed in astrocytoma cells, and calcitonin gene related peptide (CGRP) which were all implicated in the mediation of acute pain in the mammaliancentral nervous system. The plant species chosen to investigate were Ageratum conyzoides, Barringtonia edulis, Croton tiglium, Ipomea pes-caprae, Panax ginseng, Physostigma venenosum, Sinomenium acutum, Solidago virgaurea, Symplocos leptophylla and Typhonium giganteum. The results showed that there was a strong indication of biological activity for some of the plants which are used ethnomedicinally to treat pain, in the three in vitro receptor binding assays used, and particular plant extracts exhibited selective action to a single receptor.
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PMID:Ethnomedicinally selected plants as sources of potential analgesic compounds: indication of in vitro biological activity in receptor binding assays. 1064 Oct 43

The pro-inflammatory, pain producing, and cardiovascular effects of bradykinin B2 receptor activation are well characterized. Bradykinin B1 receptors also produce inflammation and pain. Therefore, antagonists are expected to be anti-inflammatory/analgesic drugs. Other exploitable clinical opportunities may exist. The newly discovered non-peptide B2 receptor antagonists and the equivalent B1 receptor pharmacological agents, which are in the pipeline, are suitable preclinical tools to properly evaluate potential utilities.
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PMID:Bradykinin antagonists: new opportunities. 1095 67

Bradykinin B1 and B2 receptors, members of the G-protein coupled receptor superfamily, are involved in inflammation and pain. Chinese hamster ovary (CHO) cells stably expressing the human B2 bradykinin receptor (CHO-B2) were used to characterize the signal transduction pathways associated with this receptor and its regulation. The selective B2 antagonist [3H]NPC17731 but not the selective B1 antagonist [3,4-prolyl-3,4-(3)H(N)]-[des-Arg10,Leu9]kallidin ([3H]DALKD) bound to CHO-B2 cell membranes with a Kd of 0.77 nM and a Bmax of 1087 fmol/mg protein. [3H]NPC17731 binding was inhibited by bradykinin ligands in the order: NPC17731 > bradykinin > kallidin >> DALKD > [des-Arg10] kallidin (DAKD), consistent with the pharmacological profile of B2 bradykinin receptors. The B2 agonist bradykinin and the B1/B2 agonist kallidin, but not the B1 agonist DAKD, increased [35S]GTP gamma S binding to the CHO-B2 cell membranes. The B2 bradykinin receptors were co-immunoprecipitated with G alpha q/11. In response to bradykinin stimulation, coupling of the B2 receptors to G alpha q/11 was increased by 10-fold. Bradykinin and kallidin, but not DAKD, induced intracellular calcium release in CHO-B2 cells, which was blocked by NPC17731 but not by DALKD. These results demonstrate that B2 bradykinin receptors directly coupled to G alpha q/11 to regulate intracellular calcium release. CHO-B2 cell is a useful system that can be applied to study the effect of potential agents that may influence the B2 receptor function.
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PMID:Functional studies of bradykinin receptors in Chinese hamster ovary cells stably expressing the human B2 bradykinin receptor. 1137 50

Protein extravasation (PE) is known to play an important role in inflammatory conditions. In this study we used dermal microdialysis to apply inflammatory mediators (histamine, bradykinin, serotonin) to human skin. Locally induced PE was compared to pain ratings and axon reflex erythema measured simultaneously. Linear microdialysis capillaries (outer diameter 0.4 mm; cut-off 3000 kDa) were inserted intracutaneously at a length of 1.5 cm in the volar forearm of healthy volunteers. The capillaries were perfused with Ringer's solution at a constant flow rate of 4 microl/min. The perfusate was sampled at 15-min intervals and was analysed for total protein concentration. After a baseline of 60 min, the perfusion was switched to inflammatory mediators for 30 min and then back to vehicle again. Sensations evoked by the stimulation were assessed on a visual analogue scale and visible axon reflex erythema was measured planimetrically.Dose-dependent increases in PE could be assessed for all inflammatory mediators tested. Bradykinin (10(-7)M) induced a significant PE, whereas serotonin was effective only at a concentration of 10(-3)M. While serotonin in lower concentrations induced moderate burning pain and an axon reflex flare but no PE, bradykinin provoked PE without pain or axon reflex flare at a concentration of 10(-7)M. Application of histamine similarly evoked PE at lower concentrations as compared to the induction of itch sensation and axon reflex flare. It is concluded that there is no link between nociceptor activation and protein extravasation induced by inflammatory mediators in healthy human skin.
Eur J Pain 2001
PMID:Nociceptor activation and protein extravasation induced by inflammatory mediators in human skin. 1139 22

Tissue injury generates endogenous factors that heighten our sense of pain by increasing the response of sensory nerve endings to noxious stimuli. Bradykinin and nerve growth factor (NGF) are two such pro-algesic agents that activate G-protein-coupled (BK2) and tyrosine kinase (TrkA) receptors, respectively, to stimulate phospholipase C (PLC) signalling pathways in primary afferent neurons. How these actions produce sensitization to physical or chemical stimuli has not been elucidated at the molecular level. Here, we show that bradykinin- or NGF-mediated potentiation of thermal sensitivity in vivo requires expression of VR1, a heat-activated ion channel on sensory neurons. Diminution of plasma membrane phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) levels through antibody sequestration or PLC-mediated hydrolysis mimics the potentiating effects of bradykinin or NGF at the cellular level. Moreover, recruitment of PLC-gamma to TrkA is essential for NGF-mediated potentiation of channel activity, and biochemical studies suggest that VR1 associates with this complex. These studies delineate a biochemical mechanism through which bradykinin and NGF produce hypersensitivity and might explain how the activation of PLC signalling systems regulates other members of the TRP channel family.
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PMID:Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. 1141 61

Bradykinin is a potent mediator of pain and inflammation. To examine extracellular levels of bradykinin in human dental pulp, CMA/20 microdialysis probes were inserted into the pulp tissue of 22 teeth diagnosed with normal pulp or with irreversible pulpitis before their extraction or endodontic therapy. Probes were perfused with a modified Locke-Ringer's buffer and bradykinin levels in the dialysate evaluated using a radioimmunoassay. Mean extracellular levels of bradykinin within pulp tissue diagnosed with irreversible pulpitis were significantly higher (262.26 +/- 83.79 fmol/ml) than that found within normal pulp (19.41 +/- 6.47 fmol/ml). Highest levels of bradykinin were detected in pulp tissue diagnosed with irreversible pulpitis when the patient had reported pain in the past, compared with patients who were in pain just before their visit. These observations suggest that the bradykinin system is activated during pulpitis and may contribute to pain and inflammation.
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PMID:Bradykinin levels in dental pulp by microdialysis. 1147 46


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