INFLAMMATION MODULATES THE CONTRIBUTION OF RECEPTOR-SUBTYPES TO BRADYKININ-INDUCED HYPERALGESIA IN THE RAT

While B-2 receptors mediate pain and hyperalgesia induced by bradykinin, in normal rats, recent reports indicate that, in the setting of inflammation, B-1 receptors also mediate pain and hyperalgesia. Since bradykinin-induced hyperalgesia in normal rats is mediated by prostaglandins released from the postganglionic sympathetic neurons, we have evaluated the; contribution of the sympathetic nervous system to the hyperalgesia induced by bradykinin, a preferential B-2-receptor agonist, and des-Arg(9)-bradykinin, a major metabolite of bradykinin and a selective B-1-receptor agonist. Mechanical hyperalgesia was quantified by the Randall-Selitto paw-withdrawal method. Inflammation was induced by injecting Complete Freund's Adjuvant into the left hindpaw of the rat and testing mechanical nociceptive threshold in the right hindpaw after injecting B-1 or B-2 agonists and/or antagonists. Sympathectomy was achieved by surgically removing sympathetic ganglia L(1)-L(4). Rats were used 48 h post-adjuvant injection. In the normal rat, intradermal injection of bradykinin but not des-Arg(9)-bradykinin, into the dorsal surface of the hindpaw, produced a dose-dependent decrease in mechanical nociceptive threshold. NPC 17731, a B-2-receptor antagonist, but not des-Arg(9)-[leu(8)]-bradykinin, a B-1-receptor antagonist, almost completely inhibited the decrease in mechanical threshold, suggesting that bradykinin hyperalgesia in the normal rat hindpaw was mediated by B-2 receptors. In rats whose left paws were treated, 48 h earlier, with adjuvant, intradermal injection of bradykinin or des-Arg(9)-bradykinin, into the right paw produced dose-dependent hyperalgesia. Bradykinin hyperalgesia was partially inhibited by NPC 17731, and the residual part by des-Arg(9),[Leu(8)]-bradykinin. des-Arg(9)-bradykinin hyperalgesia was inhibited by des-Arg(9),[Leu(8)]-bradykinin but not by NPC17731. These results suggest that in the setting of inflammation, bradykinin hyperalgesia was mediated by both B-1 and B-2 receptors, and that des-Arg(9)-bradykinin hyperalgesia was mediated by the B-1 receptor. Forty-eight hours after injection of complete Freund's adjuvant, in sympathectomized rats, bradykinin or des-Arg(9)-bradykinin failed to produce hyperalgesia, suggesting that intact sympathetic postganglionic neurons are required for the hyperalgesia produced by these agents in this model. These results are consistent with the suggestions that B-2 receptors mediate bradykinin-induced cutaneous hyperalgesia in the normal rat hindpaw. The hyperalgesia induced by bradykinin, 48 h post injection of complete Freund's adjuvant is mediated by both B-1 and B-2 receptors, that by des-Arg(9)-bradykinin is mediated by B-1 receptors. The hyperalgesia induced by both agents is dependent on the presence of intact sympathetic postganglionic neurons.