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

1 Interleukin-1 beta (IL-1 beta), IL-2 and IL-8 induced a mechanical hyperalgesia Following intra-articular (i.artic.) injection into rat knee joints, whereas IL-6 and tumour necrosis factor alpha (TNF-alpha) were without effect. 2 Co-administration of IL-1 receptor antagonist (0.1 mu g) with IL-1 beta (1 u), IL-2 (10 u) or IL-8 (0.1 u) prevented the subsequent development of the hyperalgesia. 3 Co-administration of desArg(9)Leu(8)BK (0.5-5 nmol) with IL-1 beta (1 u), IL-2 (10 u) or IL-8 (0.1 u) reduced the level of hyperalgesia at 1, 4 and 6 h post administration, whereas Hoe 140 (5 pmol) antagonized the hyperalgesia only at the 1 h time point. 4 Intravenous administration of desArg(9)Leu(8)BK (10 nmol kg(-1)) or Hoe 140 (100 pmol kg(-1)) following IL-1 beta (1 u), IL-2 (10 u), or IL-8 (0.1 u) reversed the subsequent hyperalgesia. 5 Administration of desArg(9)BK into joints 24 h after pre-treatment with IL-1 beta (1 u) produced analgesia at low doses (50 pmol) and hyperalgesia at a higher dose (0.5 nmol). Both these effects were blocked, by desArg(9)Leu(8)BK (0.5 nmol). 6 Administration of desArg(9)BK (0.5 nmol i.artic.) to animals 24 h after pre-treatment with IL-2 (1-100 u) or IL-8 (0.1-10 u) had no effect on the load tolerated by the treated joint. 7 Administration of indomethacin (1 mg kg(-1), s.c.) prior to IL-1 beta (1 u i.artic.) prevented the development of hyperalgesia. Administration of desArg(9)BK (5 pmol-0.5 nmol, i.artic.) to animals 24 h after indomethacin and IL-1 beta pretreatment had no effect on the load tolerated by the treated joint. 8 These data suggest that both bradykinin B-1 and B-2 receptors are involved in the induction and maintenance of cytokine-induced hyperalgesia. They also show that the induction of B-1 receptor-mediated hyperalgesia requires both cyclo-oxygenase products and IL-1 in vivo.