Nitric oxide (NO), a second messenger produced by the enzyme NO synthase (NOS), is involved in peripheral and central pain mechanisms. The effect of NO on pain is controversial. There is evidence to support a pronociceptive activity of NO. Thus, intradermal injection of L-arginine or NO donors, but not D-arginine, produced mechanical hyperalgesia. In addition, local administration of NOS inhibitors is able to block bradykinin- and formalin –induced pain, acetic-acid-induced abdominal writhing, PGE₂- induced mechanical hyperalgesia and carrageenin-induced thermal hyperalgesia. In other cases, there is evidence to support an antinociceptive action for NO. L- arginine caused antinociception in carrageenan-induced  hyperalgesia. This antinociception was blocked by either NOS or guanylyl cyclase inhibitors and potentiated by inhibitors of cyclic GMP phosphodiesterase. In addition, the antinociceptive activity of several antinociceptive drugs (morphine, metamizol, diclofenac, ketorolac and meloxicam) is dose-dependently reduced by NOS and soluble guanylyl cylase inhibitors. These data suggest that NO-cyclic GMP pathway at the periphery play an important role in antinociception. Recent pharmacological data suggest that opening of K⁺ channels is also an important step in the mechanism of action that leads to antinociception by some drugs that activate the NO-cyclic GMP pathway. The participation of different systems, such as the NO- cyclic GMP-K⁺ channel pathway, would allow development of new therapies to relief inflammatory or neruopathic pain.