Nitric oxide modulates spinal antinociceptive effect of clonidine but not that of baclofen in the formalin test in rats.

The aim of present study was to determine the influence of nitric oxide (NO) synthesis on intrathecal (i.t.) clonidine or baclofen antinociception in the formalin test. Formalin injection into the hindpaw of a rat induces a biphasic response in pain-related behaviours, such that C-fiber activation (acute pain) during phase 1 triggers a state of spinal sensitization characterized by longer lasting phase 2 (tonic pain). Intrathecal clonidine and baclofen, at doses without effect upon motor performance, produced a dose-dependent inhibition of both phases of the formalin test. Potency of both drugs, defined by ID50 for phase 2 of the formalin test, was 3.5 and 0.6 nmol, respectively. Intrathecal coadministration of L-arginine, substrate of NO synthase (NOS) or NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), dose-dependently reduced or potentiated, respectively, the antinociceptive effect of clonidine but not that of baclofen in the formalin test. The importance of NO formation in the antinociceptive effect of clonidine is further supported by the observation that neither D-arginine nor D-NAME were able to modify clonidine antinociception. These results suggest that the NO synthesis plays a modulatory role in the antinociceptive effect of clonidine, while the mechanism underlying the baclofen-induced antinociception seems to be different.