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)

Activation of the kinin-kallikrein system and stimulation of bradykinin (BK) B2 receptors are thought to play an important role in the pathophysiology of inflammation and pain. In the present study, we report the pharmacological properties of a novel nonpeptide bradykinin B2 receptor antagonist, LF 16-0335C, (1-[[3-[(2,4-dimethylquinolin-8-yl) oxymethyl]-2,4-dichloro-phenyl]sulfonyl]-2(S)-[[4-[4- (aminoiminomethyl)-phenylcarbonyl]piperazin-1-yl]carbo nyl]pyrrolidine, 2HCl). In binding studies, LF 16-0335C competed with [3H]bradykinin giving Ki values of 1.65 +/- 0.36 nM and 2.20 +/- 0.30 nM in membrane preparations from rat uterus (RU) and guinea-pig ileum (GPI), respectively. In functional experiments, LF 16-0335C inhibited in a competitive manner BK-induced contractions of both isolated RU and GPI, leading to calculated pA2 values of 7.70 +/- 0.70 and 8.30 +/- 0.30, respectively. The inhibitory effect of LF 16-0335C was fully reversible by washing in the guinea-pig ileum. In vivo, LF 16-0335C given intravenously inhibited in a dose-dependent manner BK-induced hypotension in both animal species, although it was more potent in the guinea-pig than in the rat (ED50, 2.5 +/- 1.6 micrograms/kg versus 22.6 +/- 2.3 micrograms/kg). BK is a potent constrictor of guinea-pig airways and this effect was markedly attenuated by LF 16-0335C. In contrast, LF 16-0335C did not affect histamine- and acetylcholine-induced hypotensive response in the rat. We conclude that LF 16-0335C is a potent and selective nonpeptide B2 receptor antagonist which equally binds to the rat and guinea-pig receptor but displays a different in vivo potency in the two species. Therefore, this drug represents a useful tool to better assess the role of bradykinin in pathophysiological conditions.
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PMID:In vitro and in vivo effects of the new nonpeptide bradykinin B2 receptor antagonist, LF 16-0335C, on guinea-pig and rat kinin receptors. 1002 91

Biologically active kinin peptides are released from precursor kininogens by kallikreins. Kinins act on kinin receptors to mediate diverse biological functions including smooth muscle contraction, inflammation, pain and mitogenicity. All components of the kallikrein-kinin system exist in human male genital secretions suggesting that these molecules participate in physiological and pathophysiological genitourinary function. The objective of this study was to assess the consequences of kinin action on prostate cells. Primary cultures of prostate secretory epithelial (PE) and prostate fibromuscular stromal (PS) cells were established from human prostate tissue. Transcripts encoding both the human B1 and B2 bradykinin receptor subtypes were detected in human prostate transition-zone tissue and in cultured cells by RT-PCR. In receptor binding assays, the B1 subtype predominated on PE cell membranes and the B2 subtype predominated on PS cell membranes. In PS cells, but not in PE cells, BK induced significant inositol phosphate accumulation and [3H]-thymidine uptake. These responses were mediated through the B2 receptor subtype. The use of signal transduction inhibitors indicated that mitogenic activation by BK occurred through both protein kinase C (PKC) and protein tyrosine kinase dependent mechanisms. PMA (phorbol 12-myristate 13-acetate) produced maximal [3H]-thymidine uptake by PS cells, resulted in cell elongation and caused the alpha-actin fibres present in PS smooth muscle cells to became organized into parallel arrays along the length of the elongated cells. In summary, the prostate contains a functional kallikrein-kinin system, which could be significant in physiological and pathophysiological prostate function.
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PMID:Mitogenic activation of human prostate-derived fibromuscular stromal cells by bradykinin. 1036 76

Tumour necrosis factor-alpha (TNF alpha) was studied in the carrageenin (CG) induced knee-joint incapacitation, and also in mediating recurrent incapacitation response in knee-joints previously exposed to an inflammatory attack. CG or TNF alpha intra-articular injection into CG-primed knee-joints induced an intense and long-lasting (>8 h) peaking incapacitation response. TNF alpha injected in naive joints did not elicit incapacitation. Anti-TNF alpha serum in situ treatment specifically inhibited CG-induced incapacitation in naive joints, and also TNF alpha-induced incapacitation in primed joints. Hoe-140 (D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin, a bradykinin B2 receptor antagonist, given before CG, abolished incapacitation, but was without effect when injected 3 h after. Hoe-140 given before or after the CG injection in primed joints was without effect, but it produced a partial inhibitory effect in the early phase (1 h) of TNF alpha-induced incapacitation. Des-Arg9[Leu3]-bradykinin, a bradykinin B1 receptor antagonist, given intra-articularly after CG or TNF alpha, reversed incapacitation either in naive or primed joints. Indomethacin abolished the incapacitation induced by CG in naive joints, but only the 5-lipoxygenase inhibitor MK-886 plus indomethacin blocked the response in primed joints. MK-886 did not modify CG-induced incapacitation in naive joints, but lately reversed CG-induced incapacitation in primed joints, and blocked TNF alpha-induced response. Substance P or prostaglandin E2 did not induce incapacitation in either naive or primed joints. Our results support the conclusion that TNF alpha is a mediator of CG-induced inflammatory incapacitation, and is able to induce the further release of kinins and leukotrienes, which is suggested to have an important role in the maintenance of long-lasting nociceptive response.
Pain 1999 Jul
PMID:Tumour necrosis factor-alpha mediates carrageenin-induced knee-joint incapacitation and also triggers overt nociception in previously inflamed rat knee-joints. 1042 63

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

Mediators produced during inflammation are responsible for hyperalgesia and expression of neurotransmitters and receptors in the nervous system. The production of bradykinin (BK) and the prostaglandins (PGs) may regulate initiation of pain. This study tested the hypothesis that BK and prostaglandin E2 (PGE2) have a positive interaction in evoking neurosecretion of immunoreactive calcitonin gene-related peptide (iCGRP). Bovine dental pulp was prepared and stimulated by the superfusion method with BK alone and in combination with PGE2. Kinin receptor antagonists to bradykinin-evoked release of iCGRP were also tested. Also tested was the hypothesis that dental pulp contains either the B1 or B2 or both BK receptors. Results showed that PGE2 enhanced BK-evoked iCGRP release by more than 50%. Western immunoblots revealed detectable B2 receptor protein with no detectable B1 receptor protein. We conclude that BK evokes iCGRP release from bovine dental pulp which is enhanced by a positive interaction with PGE2. Neurosecretion is evoked from isolated terminals of dental pulp fibers via the bradykinin B2 receptor-dependent mechanism.
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PMID:Prostaglandin E2 enhances bradykinin-evoked iCGRP release in bovine dental pulp. 1102 82

Inflammatory pain was induced following an intradermal injection of carrageenin into rat paws, and the hyperalgesia was measured in terms of withdrawal time following thermal pain stimulation of the inflamed paw. This hyperalgesia was significantly less in kininogen-deficient Brown Norway (B/N)-Katholiek rats, which also showed less swelling in carrageenin-induced paw edema, than in normal B/N-Kitasato rats at 1 approximately 4 hr after the carrageenin injection (at the early phase). However, 24 hr after the injection, hyperalgesia and the swelling volume of the kininogen-deficient rats were almost the same as those in normal rats. The bradykinin B2 receptor antagonist FR173657, (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-[(2-methyl-8-quinolinyl)oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide, attenuated the carrageenin-induced swelling and hyperalgesia of the normal rats at the early phase to almost the levels of the B/N-Katholiek rats. Pretreatment with indomethacin, a cyclooxygenase inhibitor, also inhibited the carrageenin-induced responses significantly in normal rats. These results indicate that bradykinin, acting on the B2 receptor, is the main mediator at the early phase of inflammatory pain of carrageenin edema and that prostaglandins, produced by cyclooxygenase, potentiate the effects of bradykinin.
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PMID:Evidence for bradykinin mediation of carrageenin-induced inflammatory pain: a study using kininogen-deficient Brown Norway Katholiek rats. 1127 77

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

We found that intraperitoneal injection of organic acids, such as propionic and lactic acid, are able to develop writhing responses in mice similarly as that of acetic acid. These acid-induced writhing reactions were significantly attenuated by capsazepine, a VR1 receptor-specific antagonist, but the phenylbenzoquinone-induced one was not, suggesting that the acids but not phenylbenzoquinone activate the VR1 receptor, which is involved in polymodal pain perception. Hoe 140, a bradykinin B2 receptor antagonist, also suppressed the acid-induced writhing response. Furthermore, these writhing responses were significantly suppressed after neonatal treatment with capsaicin, which treatment is known to destroy peripheral sensory afferent C-fibers. Capsazepine and Hoe 140 did not further attenuate the already reduced writhing responses of capsaicin-treated mice, suggesting that the acids stimulate the VR1 and the bradykinin B2 receptor in the pathway comprising sensory afferent C-fibers. On the other hand, indomethacin further significantly suppressed the writhing number of the capsaicin-treated animals, suggesting that the acid-induced pain perception requires prostanoid receptors not only in the pathway via capsaicin-sensitive C-fibers but also in other sensory pathways. These results provide the first evidence for the involvement of the vanilloid receptor in the acid-induced inflammatory pain perception via sensory C-fibers in addition to the known mediators bradykinin, neurokinins, and prostanoids.
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PMID:Involvement of vanilloid receptor VR1 and prostanoids in the acid-induced writhing responses of mice. 1172 94

Roles for the kallikrein-kinin system in inflammation have been investigated extensively, and many reviews on this topic have been published during the 50 years since the discovery of bradykinin in 1949. Recent progress in the field has been remarkable with the help of experiments using gene-targetted transgenic or knockout mice, which have added further valuable information in addition to previous results obtained from pharmacological and biochemical studies using purified and isolated components of the system. Furthermore, much knowledge has been accumulated as a result of the development of various bradykinin agonists and antagonists. In this review, we focused on the data obtained from the kininogen-deficient rat, which is a natural mutant, and discuss the results in comparison with those from bradykinin receptor knockout mice. These data have clarified that endogenous bradykinin exerts a most important role in inflammatory exudation along with prostanoids, preferentially to histamine, serotonin, or neuropeptides. In inflammatory pain perception also, bradykinin produced in the local perivascular spaces stimulates polymodal pain receptors in conjunction with co-helpers such as prostanoids, vanilloids, and neuropeptides. These important roles are concluded based on consistent results obtained from experiments using several antagonists of bradykinin, kininogen-deficient rats, and bradykinin receptor knockout mice.
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PMID:Roles for the kallikrein-kinin system in inflammatory exudation and pain: lessons from studies on kininogen-deficient rats. 1450 Nov 45

Bradykinin-induced mechanical hyperalgesia is sympathetically dependent and B(2)-type bradykinin receptor-mediated in the rat; however, a sympathetically independent component of bradykinin hyperalgesia is shown after subdiaphragmatic vagotomy. We evaluated the mechanism of this bradykinin-induced sympathetic-independent mechanical hyperalgesia. The dose-response curve for bradykinin mechanical hyperalgesia in sympathectomized plus vagotomized rats was similar in magnitude to that for sympathetically dependent bradykinin hyperalgesia in normal rats. Although bradykinin mechanical hyperalgesia was mediated by the B(2)-type bradykinin receptors after sympathectomy plus vagotomy, it had a much more rapid latency to onset. This hyperalgesia was significantly attenuated by inhibition of protein kinase A but not protein kinase C, similar to the hyperalgesia produced by prostaglandin E(2), an agent that directly sensitizes primary afferent nociceptors. However, unlike prostaglandin E(2)-induced mechanical hyperalgesia in normal rats, after sympathectomy plus vagotomy, bradykinin-induced hyperalgesia was not attenuated by inhibition of nitric oxide synthesis. Peripheral administration of a mu opioid agonist, [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin, significantly attenuated bradykinin mechanical hyperalgesia after sympathectomy plus vagotomy. These data suggest that after sympathectomy plus subdiaphragmatic vagotomy, bradykinin acts directly on primary afferents to produce mechanical hyperalgesia via a novel protein kinase A-dependent signaling mechanism.
J Pain 2002 Oct
PMID:Sympathetic-independent bradykinin mechanical hyperalgesia induced by subdiaphragmatic vagotomy in the rat. 1462 40


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