Bradykinin Receptors

Bradykinin is one of the best-established chemical nociceptive stimuli and most physiologically relevant to tissue injury and pain. The direct effects of bradykinin are mediated via two G protein-coupled receptors: Bx, which is highly inducible in states of inflammation or injury (135) and B2, which is constitutively expressed (135,136). Evidence suggests a role for B2 receptors in acute inflammatory events, such as edema and inflammatory pain, whereas B1 receptors appear to be involved in chronic inflammatory responses, including certain forms of persistent hyperalgesia (137). This suggests B2 is a good target in normal conditions while Bj may be a good target of interest in studies of altered afferent function in visceral inflammation. Bradykinin has been shown to be an important mediator of pain and irritation in skin, muscle, joints, vasculature, and all visceral organs (67,73,100-106). Bradykinin excites 55% of skin C-fibers in rat (104), 71% of joint afferents in cat (102), and 100% of cardiac afferents in cat (138). Almost 100% of guinea pig airway vagal afferents responded to bradykinin, with the exception of fast-conducting fibers with cell bodies in the nodose ganglion, which were unresponsive (139). In the gastrointestinal tract, bradykinin powerfully activates all mesenteric spinal afferents tested via B2 receptors in an in vitro rat jejunum preparation (106,140). Some of these effects are also mediated via bradykinin-induced release of prostaglandins (106,140). In the cat colon, bradykinin evokes a response in 67% of LSN afferents recorded in vivo (73), while a study of nine pelvic distension-sensitive colonic afferents in rats in vivo showed that 77% of them responded to bradykinin (69). In mouse colon, bradykinin evoked responses in 66% of serosal afferents (84), an effect that was mediated via B2 receptors, and responses to probing were potentiated after bradykinin. In this study, another group of bradykinin-responsive LSN afferents were mechanically insensitive. Fewer (11%) mouse pelvic nerve serosal afferents responded to bradykinin, and no mechanically insensitive pelvic nerve afferents were recruited by bradykinin. This suggests differences in the way each pathway signals bradykinin activation and reveals a chemospecific population of afferents. Interestingly, Bx but not B2 receptor protein is significantly increased in the intestines of both active ulcerative colitis and Crohn's disease patients compared with controls (116), but the relationship of this to symptoms is not known.

Recently it has been demonstrated that bradykinin activation of afferent fibers may have numerous downstream effects, including the production of 12-lipoxygenase metabolites of arachidonic acid that activate vanilloid (TRPV) receptors (104) and which are involved directly in mechanical, thermal, and pH sensitivity (95,109). A similar mechanism is responsible for bradykinin activation of the mechano- and thermosensitive channel TRPA1 (141).

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