Effects of the bradykinin B-1 receptor antagonist des-Arg(9)[Leu(8)]bradykinin and genetic disruption of the B-2 receptor on nociception in rats and mice

The contributions of B-1 and B-2 bradykinin receptors to acute and chronic inflammatory hyperalgesia were examined using the peptide B-1 receptor antagonist des-Arg(9)[leu(8)]bradykinin and transgenic Bk2r(+) mice. In normal rats and mice, des-Arg(9)[Leu(8)]bradykinin (30 nmol/kg i.v. or s.c.) inhibited carrageenan-induced hyperalgesia and the late phase nociceptive response to formalin. The active dose range was narrow, suggesting partial agonist activity of this peptide. In rats with monoarthritis, des-Arg(9)[leu(8)]bradykinin (up to 30 nmol/kg i.v.) failed to reduce the number of vocalisations elicited by gentle flexion and extension of the inflamed limb; however, hyperalgesia was exacerbated by administration of the B-1 receptor agonist des-[Arg(9)]bradykinin (100 nmol/kg i.v.), consistent with other evidence for local induction of B-1 receptors during adjuvant-induced arthritis. The nociceptive response to intraplantar injection of bradykinin (10 nmol) and hyperalgesia induced by carrageenan (0.6 mg) were absent in Bk2r(+) mice, indicating that stimulation of B-2 receptors is an essential step in the initiation of some nociceptive and inflammatory reactions. However, the nociceptive response to formalin (2.5% intraplantar), including inhibition of the late phase by des-Arg(9)[Leu(8)]bradykinin (0.3 nmol), and induction of thermal hyperalgesia by Freund's adjuvant (0.1%) appeared intact in Bk2r(+) mice. These findings support other evidence for an involvement of B-1 receptors in inflammatory hyperalgesia and suggest that B-1 receptor antagonists may be clinically useful as anti-inflammatory and analgesic drugs. (C) 1997 International Association for the Study of Pain.