BRADYKININ INITIATES CYTOKINE-MEDIATED INFLAMMATORY HYPERALGESIA

1 The hyperalgesic activities in rats of bradykinin, carrageenin and lipopolysaccharide (LPS) were investigated in a model of mechanical hyperalgesia. 2 Bradykinin and carrageenin evoked dose-dependent hyperalgesia with maximum responses of similar magnitude to responses to LPS (1 and 5 mug). 3 Hoe 140, an antagonist of BK2 receptors, inhibited in a dose-dependent manner hyperalgesic responses to bradykinin, carrageenin and LPS (1 mug) but not responses to LPS (5 mug), prostaglandin E2, dopamine, tumour necrosis factor alpha (TNFalpha), IL-1, IL-6 and IL-8. 4 Responses to bradykinin and LPS (I and 5 mug) were inhibited by the cyclo-oxygenase inhibitor, indomethacin and by the beta-adrenoceptor antagonist, atenolol. The effects of indomethacin and atenolol were additive: their combination abolished responses to bradykinin and LPS (1 mug) and markedly attenuated the response to LPS (5 mug). 5 Antiserum neutralizing endogenous TNFalpha abolished the response to bradykinin whereas antisera neutralizing endogenous IL-1beta, IL-6 and IL-8 each partially inhibited the response. The combination of antisera neutralizing endogenous IL-1beta + IL-8 or IL-6 + IL-8 abolished the response to bradykinin. 6 Antisera neutralizing endogenous TNFalpha, IL-1beta, IL-6 and IL-8 each partially inhibited responses to LPS (I and 5 mug). Increasing the dose of antiserum to TNFalpha or giving a combination of antisera to IL-1beta + IL-8 or IL-6 + IL-8 further inhibited responses to LPS (1 and 5 mug). 7 These data show that bradykinin can initiate the cascade of cytokine release that mediates hyperalgesic responses to carrageenin and endotoxin (1 mug). The lack of effect of Hoe 140 on hyperalgesic responses to LPS (5 mug) suggests that the release of hyperalgesic cytokines can be initiated independently of bradykinin BK2 receptors.