Nonsteroidal Antiinflammatory Drug Modulation of Behavioral Responses to Intrathecal N-Methyl-D-Aspartate, but Not to Substance P and Amino-Methyl-Isoxazole-Propionic Acid in the Rat

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Antinociception by nonsteroidal antiinflammatory drugs, notably diclofenac and S(+)-ibuprofen, has traditionally been attributed to peripheral tissue cyclooxygenase inhibition. This study investigates the potential role of the nitric oxide system for the central antinociceptive effects of diclofenac, S(+)-, and R(-)-ibuprofen. Diclofenac and S(+) but not R(-)-ibuprofen inhibited the behavioral response dose dependently, "biting, scratching, and licking (BSL)," induced by the spinal application of N-methyl-D-aspartate, but not that of amino-methylisoxazole-propionic acid or substance P. Diclofenac and S(+)-ibuprofen induced a parallel shift in the number of BSL responses and in the duration of the response in the behavioral model at their approximate median effective doses (diclofenac 1 µmol and S(+)-ibuprofen 5 µmol). Pretreatment with L-arginine, the natural substrate for the nitric oxide synthetase, antagonized diclofenac, and S(+)-ibuprofen-induced suppression of the biting, scratching, and licking response evoked by intrathecal N-methyl-D-aspartate. D-arginine did not antagonize the diclofenac- and S(+)-ibuprofen-induced antinociception. The study results indicate that analgesia after diclofenac and S(+)-ibuprofen involves a central mechanism which may add to the peripheral antinociceptive effect of these agents. The central action of diclofenac and S(+)-ibuprofen is partly mediated by an interaction with the N-methyl-D-aspartate receptor and nitric oxide-generating mechanisms.

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