BRADYKININ B-1 AND B-2 RECEPTOR MECHANISMS AND CYTOKINE-INDUCED HYPERALGESIA IN THE RAT

The involvement of bradykinin (BK) B-1 and B-2 receptors in cytokine-i nduced hyperalgesia has been studied in the rat. Intraplantar injectio ns of interleukin (IL) 1 beta and tumor necrosis factor alpha (TNF alp ha) induced thermal hyperalgesia, with in the the case of IL-1 beta, c ontralateral hyperalgesia also present. Subsequent to administration o f IL-1 beta, but not after TNF alpha, des-Arg(9)-BK reduced the withdr awal latency in both ipsi- and contra-lateral paws. Mechanical hyperal gesia was also induced by IL-1 beta, IL-2, and IL-8 when injected into rat knee joints, whereas IL-6 and TNF alpha were without effect. Coad ministration of des-Arg(9),Leu(8)-BK prevented the development of the cytokine-induced hyperalgesia for the duration of the experiment (6 h) , but HOE-140 only reversed the hyperalgesia for the Ist h. At 3.5 h a fter IL-1 beta, IL-2, or IL-8, administration of des-Arg(9), Leu(8)-BK or HOE-140 (iv) completely reversed the hyperalgesia. Twenty-four hou rs after pretreatment with IL-1 beta, injection of des-Arg(9)-BK into the joint produced opposite effects, depending on the dose: at 50 pmol the hyperalgesia was reversed, but at 0.5 nmol there was further hype ralgesia. Both responses were blocked by B-1 but not B-2 receptor anta gonists. These data suggest that both B-1 and B-2 receptors are involv ed in the induction and maintenance of cytokine-induced hyperalgesia. B-1 receptors appear to play a more important role than B-2 receptors in the development of mechanical hyperalgesia.