The antinociceptive effect of rofecoxib, a preferential inhibitor of cyclooxygenase-2, was assessed in the pain-induced functional impairment model in the rat. Systemic administration of rofecoxib generated a dose-dependent antinociceptive effect in rats injected with uric acid into the knee joint of the right hindlimb in order to produce nociception. Ipsilateral intra-articular pretreatment with N^G-l-nitro-arginine methyl ester (l-NAME, an inhibitor of nitric oxide (NO) synthesis), 1H-(1,2,4)-oxadiazolo (4,2-a)quinoxalin-1-one (ODQ, an inhibitor soluble guanylyl cyclase), and the ATP-sensitive potassium channel blocker glibenclamide reversed the antinociceptive effect of rofecoxib p.o. However, ipsilateral intra-articular pretreatment with l-arginine (a NO substrate), or 3-morpholino-sydnonimine-HCl (SIN-1, a non-enzymatic donor of NO), potentiated the antinociceptive effect induced by rofecoxib. The present results suggest that, in addition to cyclooxygenase-2 inhibition, the antinociceptive effect of rofecoxib could also involve activation of the l-arginine–NO–cyclic GMP (cGMP) pathway, followed by opening of ATP-sensitive K⁺ channels at the peripheral level.