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

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‐aspartale, 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.