The effects of thioperamide, an H3 antagonist, and histamine H1 and H2 antagonists (s.c.) on morphine (s.c. or i.c.v.)- and U-50,488H (i.c.v.)-induced antinociception in male ddY mice were examined using the hot-plate (55 degrees C) test. Thioperamide significantly inhibited morphine-induced antinociception, but not U-50,488H-induced antinociception. The suppressive effect of thioperamide on morphine-induced antinociception was reversed by the H1 antagonist pyrilamine, but not by the H2 antagonist zolantidine. On the other hand, pyrilamine significantly potentiated the antinociception induced by morphine, but not that induced by U-50,488H. Zolantidine significantly inhibited morphine-induced antinociception in a dose-dependent manner, but not U-50,488H-induced antinociception. Both astemizole, an H1 antagonist, and ranitidine, an H2 antagonist, which are known to barely cross the blood brain barrier, did not affect morphine-induced antinociception. These results suggest that morphine-induced antinociception may be potentiated by activation of H2 receptors and suppressed by activation of H1 receptors in the brain. Furthermore, neuronal histamine release induced by thioperamide may suppress morphine-induced antinociception through H1 receptors.