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Bradykinin is an endogenous nonapeptide known to induce pain and hyperalgesia to heat and mechanical stimulation. Correspondingly, it excites nociceptors in various tissues and sensitizes them to heat, whereas sensitizing effect on the mechanical response of nociceptors is not well established. Protein kinase C and TRPV1 contribute to the sensitizing mechanism of bradykinin to heat. In addition, TRPA1 and other ion channels appear to contribute to excitation caused by bradykinin. Finally, prostaglandins sensitize bradykinin-induced excitation in normal tissues by restoring desensitized responses due to the inhibition of protein kinase A.

Bradykinin (BK), a major inflammatory mediator, excites and sensitizes nociceptor neurons/fibers, thus evoking pain and hyperalgesia. The cellular signaling mechanisms underlying these actions have remained unsolved, especially in regard to the identity of channels that mediate acute excitation. Here, to clarify the contribution of transient receptor potential vanilloid 1 (TRPV1), a heat-sensitive ion channel, to the BK-evoked nociceptor excitation and pain, we examined the behavioral and physiological BK-responses in TRPV1-deficient (KO) mice. A nocifencive behavior after BK injection (100 pmol/site) into mouse sole was reduced in TRPV1-KO mice compared with wild-type (WT). A higher dose of BK (1 nmol/site), however, induced the response in TRPV1-KO mice indistinguishable from that in the WT. BK-evoked excitation of cutaneous C-fibers in TRPV1-KO mice was comparable to that in WT. BK clearly increased intracellular calcium in cultured dorsal root ganglion (DRG) neurons of TRPV1-KO mice, although the incidence of BK-sensitive neurons was reduced. BK has been reported to activate TRPA1 indirectly, yet a considerable part of BK-sensitive DRG neurons did not respond to a TRPA1 agonist, mustard oil. These results suggest that BK-evoked nociception/nociceptor response would not be simply explained by activation of TRPV1 and A1, and that BK-evoked nociceptor excitation would be mediated by several ionic mechanisms.

Many inflammatory chemical mediators excite or sensitize nociceptors, which had led some researchers to believe that they may interact with each other to maintain a persistent painful state. We examined how the excitatory mediators norepinephrine (NE) and bradykinin (BK) interact, using single fiber recordings from cutaneous nociceptors. We observed that NE augmented the BK-induced response in both control and adjuvant-inflamed rats in a way different from NE-induced excitation in inflamed animals only. BK also tended to augment the NE-induced response (examined only in inflamed rats). Our results provide the first evidence that BK and NE synergistically interact on nociceptors.

Bradykinin (BK), which has potent algesic and sensitizing effect on nociceptors, is of current interest in understanding the mechanisms of chronic pain. BK response is mediated by B2 receptor in normal conditions; however, findings that B1 receptor blockade alleviated hyperalgesia in inflammation have been highlighting the role of B1 receptor in pathological conditions. It has not yet been clear whether nociceptor activities are modified by B1 receptor agonists or antagonists during inflammation. In addition, previous studies reported the change in BK sensitivity of nociceptors during short-lasting inflammation, and data in persistent inflammation are lacking. Therefore we investigated whether an experimentally induced persistent inflammatory state modulates the BK sensitivity of nociceptors and which receptor subtype plays a more important role in this condition. Complete Freund's adjuvant was injected into the rat-tail and after 2-3 wk, persistent inflammation developed, which was prominent in the ankle joint. Using an in vitro skin-saphenous nerve preparation, single-fiber recordings were made from mechano-heat sensitive C-fiber nociceptors innervating rat hairy hindpaw skin, and their responses were compared with those obtained from C-fibers tested similarly in normal animals. BK at 10(-8) M excited none of the 10 C-fibers in normal animals while it excited 5 of 11 (45%) C-fibers of inflamed animals, 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 percentage of the inflamed C-fibers responded to 10(-6) M BK with bursting or high-frequency discharges. Thirty-percent of inflamed C-fibers had spontaneous activity, and these fibers showed comparatively less tachyphylaxis to consecutive second and third 10(-6) M BK stimulation. A B2 receptor antagonist (D-Arg-[Hyp3, Thi5,8,D-phe7]-BK) completely eliminated BK responses in inflamed rats, while B1 receptor antagonists (B 9958 and Des-Arg9-[Leu8]-BK) had no effect. Selective B1 receptor agonist (Des-Arg10-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, sensitivity of C-fiber nociceptors to BK, which is B2 receptor mediated, is strongly increased and that B1 receptor may not be important to a persistent inflammatory state, at least at the primary afferent level.