The peripheral antinociceptive effect of resveratrol is associated with activation of potassium channels.

The possible participation of K(+) channels in the antinociceptive action induced by resveratrol was assessed in the 1% formalin test. Local administration of resveratrol produced a dose-dependent antinociception in the second phase of the test. The antinociception produced by resveratrol was due to a local action as its administration in the contralateral paw was not active. Local pretreatment of the injured paw with glibenclamide, tolbutamide or glipizide (ATP-sensitive K(+) channel inhibitors) did not modify resveratrol-induced antinociception. In contrast, charybdotoxin and apamin (large and small conductance Ca(2+) activated-K(+) channel blockers, respectively), 4-aminopyridine or tetraethylammonium (voltage-dependent K(+) channel inhibitors) dose-dependently prevented resveratrol-induced antinociception. Local peripheral administration of glibenclamide, but not charybdotoxin or apamin, significantly reduced the antinociceptive effect produced by peripheral morphine (positive control). At the highest effective doses, none of the drugs used induced behavioral side effects as revealed by the evaluation of stepping, righting, corneal and pinna reflexes. In addition, when given alone, none of the inhibitors modified the nociceptive behavior induced by 1% formalin. The results suggest that resveratrol opens large and small conductance Ca(2+)-activated K(+) channels, but not ATP-sensitive K(+) channels, in order to produce its peripheral antinociceptive effect in the formalin test. The participation of voltage-dependent K(+) channels was also suggested, but since non-selective inhibitors were used the data awaits further confirmation.