Effects of the bradykinin B1 receptor antagonist des-Arg9[Leu8]bradykinin and genetic disruption of the B2 receptor on nociception in rats and mice.
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.
Rupniak
N M
NM
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, UK.
Boyce
S
S
Webb
J K
JK
Williams
A R
AR
Carlson
E J
EJ
Hill
R G
RG
Borkowski
J A
JA
Hess
J F
JF
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
D065168:Bradykinin Receptor Antagonists; D018002:Receptors, Bradykinin; D005557:Formaldehyde; C051090:bradykinin, Leu(8)-des-Arg(9)-; D002351:Carrageenan; D005620:Freund's Adjuvant; D001920:Bradykinin