Interaction between the antinociceptive effect of ketoprofen and adrenergic modulatory systems.

The interaction between the antinociceptive activity of ketoprofen and adrenergic agents was evaluated in the writhing test of mice. Dose-response curves were obtained for systemic and intrathecal antinociceptive effects of ketoprofen, phenylephrine, clonidine, desipramine, and prazosin; and ED50 were calculated. The interactions were evaluated by isobolographic analysis of the systemic or intrathecal co-administration of fixed-ratio combinations of ketoprofen with each adrenergic agent. The intraperitoneal combinations of ketoprofen with phenylephrine, clonidine, and prazosin showed supra-additivity, indicating that activation of alpha1 and alpha2 adrenoceptors play a role in nociceptive transmission at supraspinal levels. The same combinations given intrathecal were only additive. Desipramine intraperitoneal was also supra-additive: however, when ketoprofen was administered intrathecally with desipramine, only an additive interaction was obtained. The supra-additive interactions suggest that complementary mechanisms of antinociception have been activated, related with interference with the multiplicity of receptors and systems involved in the transmission of the nociceptive information. Racemic ketoprofen has an antinociceptive activity which is probably not only due to COX inhibition but also involves noradrenergic systems at spinal and supraspinal levels.