The modulation by K + channel-acting drugs of the antinociceptive effect of several 5-HT 1 A receptor agonists was examined with the hot plate test in mice. All the 5-HT 1 A receptor agonist tested induced dose-dependent antinociception, the order of potency being (±)-8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) > buspirone lesopitron tandospirone. The blockers of ATP-sensitive K + channels (K A T P ) gliquidone and glipizide (1-4 and 16-64 μg/mouse i.c.v., respectively) reduced the antinociceptive effect of 8-OH-DPAT, whereas cromakalim (32-64 μg/mouse i.c.v.), an opener of K A T P channels, enhanced the effect. In contrast, 4-aminopyridine (25-250 ng/mouse i.c.v.) and tetraethylammonium (10-20 μg/mouse i.c.v.), which antagonize several non-ATP-dependent K + conductances, were inactive. The same results were found with other agonists of 5-HT 1 A receptors (lesopitron, buspirone and tandospirone): gliquidone inhibited whereas cromakalim increased their antinociceptive effects. None of the K + channel-acting drugs modified the binding of [ 3 H]8-OH-DPAT to hippocampal membranes, whereas all the 5-HT 1 A receptor agonists displaced the ligand. These results suggest that ATP-sensitive K + conductances are involved in the antinociception induced by agonists of 5-HT 1 A receptors.