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Effects of the bradykinin B1 receptor antagonist des-Arg9[Leu8]bradykinin and genetic disruption of the B2 receptor on nociception in rats and mice

Rupniak, Nadia M.Ja,*; Boyce, Susana; Webb, Janine Ka; Williams, Angela Ra; Carlson, Emma Ja; Hill, Raymond Ga; Borkowski, Joseph Ab; Hess, Fred J.b

doi: 10.1016/S0304-3959(97)03343-5

The contributions of B1 and B2 bradykinin receptors to acute and chronic inflammatory hyperalgesia were examined using the peptide B1 receptor antagonist des-Arg9[Leu8]bradykinin and transgenic Bk2r-/- mice. In normal rats and mice, des-Arg9[Leu8]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-Arg9[Leu8]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 B1 receptor agonist des-[Arg9]bradykinin (100 nmol/kg i.v.), consistent with other evidence for local induction of B1 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 B2 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-Arg9[Leu8]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 B1 receptors in inflammatory hyperalgesia and suggest that B1 receptor antagonists may be clinically useful as anti-inflammatory and analgesic drugs.

aMerck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK

bMerck Research Laboratories, Rahway, NJ 07065, USA

*Corresponding author. Tel.: +44 01279 440484; fax: +44 01279 440390.

Received August 19, 1996; revised version received November 28, 1996; accepted January 15, 1997.

© Lippincott-Raven Publishers.
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