The effect of the administration of pertussis toxin as well as modulators of different subtypes of K + channels on the antinociception induced by the H 1 -antihistamines pyrilamine, diphenhydramine and promethazine was evaluated in the mouse hot plate test. Pretreatment with pertussis toxin (0.25 mg/mouse i.c.v.) prevented pyrilamine, diphenhydramine and promethazine antinociception. The K ATP channel openers minoxidil and pinacidil potentiated the antinociception produced by the H 1 -antihistamines whereas the K ATP channel blocker gliquidone prevented the anti H 1 -induced analgesia. The Ca 2 + -gated K + channel blocker apamin antagonized pyrilamine, diphenhydramine and promethazine analgesia. Pretreatment with an antisense oligonucleotide (aODN) to mKv1.1, a voltage-gated K + channel, at the dose of 3.0 nmol/single i.c.v. injection, never modified the antinociception induced by the H 1 -antihistamines in comparison with degenerate oligonucleotide (dODN)-treated mice. At the highest effective doses, none of the drugs used modified animals' gross behaviour nor impaired motor coordination, as revealed by the rota rod test. The present data demonstrate that both K ATP and Ca 2 + -gated K + channels, contrary to voltage-gated K + channel Kv1.1, represent an important step in the transduction mechanism underlying central antinociception induced by H 1 -antihistamines.