Evidence for the participation of kinins in Freund's adjuvant-induced inflammatory and nociceptive responses in kinin B1 and B2 receptor knockout mice.
Experiments were designed to investigate the role of kinin B(1) and B(2) receptors in Freund's adjuvant (CFA)-induced inflammation and nociception responses by the use of B(1) and B(2) null mutant mice. Intradermal (i.d.) injection of CFA produced time-dependent and marked hyperalgesic responses in both ipsilateral and contralateral paws of wild-type mice. Gene disruption of the kinin B(2) receptor did not interfere with CFA-induced hyperalgesia, but ablation of the gene of the B(1) receptor reduced the hyperalgesia in both ipsilateral (48+/-13%, at 12 h) and contralateral (91+/-22%, at 12 h) paws. Treatment of wild-type mice with the selective B(1) antagonist des-Arg(9)-[Leu(8)]-BK (150 nmol/kg, s.c.) reduced CFA-evoked thermal hyperalgesia, to an extent which was similar to that observed in mice lacking kinin B(1) receptor. I.d. injection of CFA produced a time-related and long-lasting (up to 72 h) increase in paw volume in wild-type mice. A similar effect was observed in B(1) knockout mice. In mice lacking B(2) receptor, the earlier stage of the CFA-induced paw oedema (6 h) was significantly greater compared with the wild-type animals, an effect which was almost completely reversed (76+/-5%) by des-Arg(9)-[Leu(8)]-BK. This data demonstrates that kinin B(1) receptor, but not B(2) receptor, exerts a critical role in controlling the persistent inflammatory hyperalgesia induced by CFA in mice, while B(2) receptor appears to have only a minor role in the amplification of the earlier stage of CFA-induced paw oedema formation. The results of the present study, taken together with those of previous studies, suggest that B(1) receptor antagonists represent a potential target for the development of new drugs to treat persistent inflammatory pain.
Ferreira
J
J
Department of Pharmacology, Centre of Biological Sciences, UFSC, SC, Florianópolis, Brazil.
Campos
M M
MM
Pesquero
J B
JB
Araújo
R C
RC
Bader
M
M
Calixto
J B
JB
D000818:Animals; D065168:Bradykinin Receptor Antagonists; D004487:Edema / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005620:Freund's Adjuvant; D006614:Hindlimb; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007705:Kinins / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000172:deficiency* / Q000235:genetics*
D065168:Bradykinin Receptor Antagonists; D007705:Kinins; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D005620:Freund's Adjuvant