The role of nitric oxide (NO) in the antinociceptive effect of indomethacin was assessed in the pain-induced functional impairment model in the rat (PIFIR model), a model of inflammatory and chronic pain similar to that observed in clinical gout. Oral administration of indomethacin (5.6 mg/kg), a nonselective cyclooxygenase inhibitor, significantly decreased the nociceptive response elicited by uric acid injected into the knee joint of the right hind limb (2.0±3.0 and 149.7±18.0 area units [au], in the absence and the presence of indomethacin, respectively). This effect of indomethacin was reduced in nearly 50% by local pretreatment with the nonselective inhibitor of NO synthase, N^G-l-nitro-arginine methyl ester (l-NAME) (72.9±10.7 vs. 149.7±18.0 au, P<0.05). On the other hand, local administration of l-arginine (a NO synthase substrate) or sodium nitroprusside (a non-enzymatic NO donor) each increased in almost 40% the antinociceptive effect of indomethacin (230.9±12.6 and 226.6±9.7 vs. 149.7±18.0 au, P<0.05), whereas d-arginine (the inactive isomer of arginine) had no effect on the indomethacin antinociceptive response (208.0±34.9 vs. 149.7±18.0 au). These results suggest that, the antinociceptive effect of indomethacin involves, at least in part, the NO–cyclic GMP pathway at peripheral level.