Evidence for the participation of kinins in Freund's adjuvant-induced inflammatory and nociceptive responses in kinin B-1 and B-2 receptor knockout mice

Abstract

Experiments were designed to investigate the rule 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 ss-as 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 tire development of new drugs to treat persistent inflammatory pain. (C) 2001 Published by Elsevier B.V.