B2 receptor-mediated enhanced bradykinin sensitivity of rat cutaneous C-fiber nociceptors during persistent inflammation

Bradykinin (BK), which has potent algesic and sensitizing effect on nocicep tors, is of current interest in understanding the mechanisms of chronic pai n. BK response is mediated by B2 receptor in normal conditions; however, fi ndings that B1 receptor blockade alleviated hyperalgesia in inflammation ha ve been highlighting the role of B1 receptor in pathological conditions. It has not yet been clear whether nociceptor activities are modified by B1 re ceptor agonists or antagonists during inflammation. In addition, previous s tudies reported the change in BK sensitivity of nociceptors during short-la sting inflammation, and data in persistent inflammation are lacking. Theref ore we investigated whether an experimentally induced persistent inflammato ry state modulates the BK sensitivity of nociceptors and which receptor sub type plays a more important role in this condition. Complete Freund's adjuv ant was injected into the rat-tail and after 2-3 wk, persistent inflammatio n developed, which was prominent in the ankle joint. Using an in vitro skin -saphenous nerve preparation, single-fiber recordings were made from mechan o-heat sensitive C-fiber nociceptors innervating rat hairy hindpaw skin, an d their responses were compared with those obtained from C-fibers tested si milarly in normal animals. BK at 10(-8) M excited none of the 10 C-fibers i n normal animals while it excited 5 of 11 (45%) C-fibers of inflamed animal s, and at 10(-6) M BK excited all of the 11 inflamed C-fibers (or 94% of 36 tested C-fibers) but only 4 of 10 (or 45% of 58 tested C-fibers) in normal animals. Thus the concentration-response curves based on the incidence of BK induced excitation, and the total number of impulses evoked in response to BK were significantly shifted to the left. Moreover, an increased percen tage of the inflamed C-fibers responded to 10(-6) M BK with bursting or hig h-frequency discharges. Thirty-percent of inflamed C-fibers had spontaneous activity, and these fibers showed comparatively less tachyphylaxis to cons ecutive second and third 10(-6) M BK stimulation. A B2 receptor antagonist (D-Arg-[Hyp(3), Thi(5,8),D-phe(7)]-BK) completely eliminated BK responses i n inflamed rats, while B1 receptor antagonists (B 9958 and Des-Arg(9)-[Leu( 8)]-BK) had no effect. Selective B1 receptor agonist (Des-Arg(10)-Kallidin) excited 46% (n = 13) of inflamed C-fibers at 10(-5) M concentration, which is 1,000 times higher than that of BK needed to excite the same percentage of inflamed C-fibers. We conclude that in chronically inflamed tissue, sen sitivity of C-fiber nociceptors to BK, which is B2 receptor mediated, is st rongly increased and that B1 receptor may not be important to a persistent inflammatory state, at least at the primary afferent level.