The use of kinin B-1 and B-2 receptor knockout mice and selective antagonists to characterize the nociceptive responses caused by kinins at the spinal level

Abstract

The mechanisms by which kinins induce hyperalgesia in the spinal cord were investigated by using B-1 or B-2 knockout mice in conjunction with kinin selective agonists and antagonists. the i.t. administration of the kinin B-2 receptor agonists bradykinin (BK) or Tyr(8)-BK produced dose-related thermal hyperalgesia evaluated in the hot-plate test. BK-induced hyperalgesia was abolished by the beta(2) receptor antagonist Hoe 140. the i.t. injection of the kinin beta(1) receptor agonists, des-Arg(9)-bradykinin (DABK) or des-Arg(10)-okallidin (DAKD) also caused dose-related thermal hyperalgesia. Different from the beta(2) agonists, the i.t. injection of DABK or DAKD caused a weak, but prolonged hyperalgesia, an effect that was blocked by the beta(1) receptor antagonist des-Arg(9)-[Leu(8)]-bradykinin (DALBK). the i.t. injection of BK caused thermal hyperalgesia in wild-type mice (WT) and in the beta(1) receptor knockout mice (B1R KO), but not in the beta(2) receptor knockout mice (B2R KO). Similarly, the i.t. injection of DABK elicited thermal hyperalgesia in WT mice, but not in B1R KO mice. However, DABK-induced hyperalgesia was more pronounced in the B,R KO mice when compared with the WT mice. the i.t. injection of Hoe 140 or DALBK inhibited the second phase of formalin (F)-induced nociception. Furthermore, i.t. Hoe 140, but not DALBK, also inhibits the first phase of F response. Finally, the i.t. injection of DALBK, but not of Hoe 140, inhibits the long-term thermal hyperalgesia observed in the ipsilateral and in contralateral paws after intraplantar injection with complete Freund's adjuvant. These findings provide evidence that kinins acting at both B-1 and B-2 receptors at the spinal level exert a critical role in controlling the nociceptive processing mechanisms. Therefore, selective kinin antagonists against both receptors are of potential interest drugs to treat some pain states. (C) 2002 Elsevier B.V. All rights reserved.