Sildenafil produces antinociception and increases morphine antinociceptionin the formalin test

The antinociceptive activity of an inhibitor of phosphodiesterase 5 alone o r combined with morphine was assessed in the formalin test. Local administr ation of 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [3, 4-d]pyrimidin-5-yl)phenylsulfonyl]-4-methyl piperazine (sildenafil, inhibit or of phosphodiesterase 5) produced a dose-dependent antinociceptive effect in the second phase of the formalin test in female Wistar rats. In contras t, morphine produced antinociception in both phases. Sildenafil significant ly increased the morphine-induced antinociception. The antinociception prod uced by the drugs alone or combined was due to a local action, as its admin istration in the contralateral paw was ineffective. Pretreatment of the paw s with N-G-L-nitro-arginine methyl ester (L-NAME, nitric oxide (NO) synthes is inhibitor), 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor) or naloxone blocked the effect of the combination. Resul ts suggest that opioid receptors, NO and cyclic GMP are relevant in the com bination-induced antinociception. In conclusion, sildenafil produced antino ciception and increased that produced by morphine, probably through the inh ibition of cyclic GMP degradation. (C) 2000 Elsevier Science B.V. All right s reserved.