The aim of this study was to examine if the peripheral antinociceptive effects of diclofenac and indomethacin involve the sequential participation of NO and cGMP synthesis followed by potassium channel opening. The peripheral antinociceptive effects of diclofenac, indomethacin, pinacidil (a potassium channel opener) and atrial natriuretic peptide (ANP, which increases cGMP content in a NO-independent manner) were assayed using the formalin test in the rat. All compounds produced significant local antinociception. Diclofenac effect was reverted by N(G)-L-nitro-arginine methyl ester (L-NAME, an inhibitor of NO synthesis), by 1 H-(1,2,4)-oxadiazolo (4,2-a) quinoxalin-1-one (ODQ, an inhibitor soluble guanylyl cyclase), and by the potassium channel blockers glibenclamide, tolbutamide, charybdotoxin and apamin. Pinacidil effect was blocked by glibenclamide, tolbutamide, charybdotoxin and apamin, strongly suggesting that potassium channel opening results in antinociception. ANP effect was inhibited by the potassium channel blockers, but not by L-NAME, suggesting that potassium channel opening is a consequence of an increased cGMP content. Indomethacin was effective, but at doses higher than those of diclofenac, and could not be blocked by L-NAME nor by potassium channel blockers. The present results suggest that the L-arginine-NO-cGMP-potassium channel pathway is involved in the peripheral antinociceptive effect of diclofenac, but not of indomethacin, and thus provide evidence for differences in mechanisms of action among nonsteroidal antiinflammatory drugs (NSAIDs).