title: Effects of the bradykinin B1 receptor antagonist des-Arg9[Leu8]bradykinin and genetic disruption of the B2 receptor on nociception in rats and mice.
abstract: 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.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: Rupniak
authors.forename: S
authors.initials: S
authors.lastname: Boyce
authors.forename: J K
authors.initials: JK
authors.lastname: Webb
authors.forename: A R
authors.initials: AR
authors.lastname: Williams
authors.forename: E J
authors.initials: EJ
authors.lastname: Carlson
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
authors.forename: J A
authors.initials: JA
authors.lastname: Borkowski
authors.forename: J F
authors.initials: JF
authors.lastname: Hess
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002351:Carrageenan; D004487:Edema / Q000139:chemically induced / Q000503:physiopathology; D005260:Female; D005557:Formaldehyde; D005620:Freund's Adjuvant; D006614:Hindlimb / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018002:Receptors, Bradykinin / Q000235:genetics*; D012018:Reflex / Q000187:drug effects
chemical_list: D065168:Bradykinin Receptor Antagonists; D018002:Receptors, Bradykinin; D005557:Formaldehyde; C051090:bradykinin, Leu(8)-des-Arg(9)-; D002351:Carrageenan; D005620:Freund's Adjuvant; D001920:Bradykinin