The use of kinin B1 and B2 receptor knockout mice and selective antagonists to characterize the nociceptive responses caused by kinins at the spinal level

The mechanisms by which kinins induce hyperalgesia in the spinal cord were investigated by using B1 or B2 knockout mice in conjunction with kinin selective agonists and antagonists. The i.t. administration of the kinin B2 receptor agonists, bradykinin (BK) or Tyr8-BK produced dose-related thermal hyperalgesia evaluated in the hot-plate test. BK-induced hyperalgesia was abolished by the B2 receptor antagonist Hoe 140. The i.t. injection of the kinin B1 receptor agonists, des-Arg9-bradykinin (DABK) or des-Arg10-kallidin (DAKD) also caused dose-related thermal hyperalgesia. Different from the B2 agonists, the i.t. injection of DABK or DAKD caused a weak, but prolonged hyperalgesia, an effect that was blocked by the B1 receptor antagonist des-Arg9-[Leu8]-bradykinin (DALBK). The i.t. injection of BK caused thermal hyperalgesia in wild-type mice (WT) and in the B1 receptor knockout mice (B1R KO), but not in the B2 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 B2R 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 B1 and B2 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