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 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 B(2) receptor antagonist Hoe 140. The i.t. injection of the kinin B(1) receptor agonists, des-Arg(9)-bradykinin (DABK) or des-Arg(10)-kallidin (DAKD) also caused dose-related thermal hyperalgesia. Different from the B(2) agonists, the i.t. injection of DABK or DAKD caused a weak, but prolonged hyperalgesia, an effect that was blocked by the B(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 B(1) receptor knockout mice (B(1)R KO), but not in the B(2) receptor knockout mice (B(2)R KO). Similarly, the i.t. injection of DABK elicited thermal hyperalgesia in WT mice, but not in B(1)R KO mice. However, DABK-induced hyperalgesia was more pronounced in the B(2)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.