The actions of zolantidine dimaleate and five other histamine H2 receptor antagonists, given into the lateral ventricle of rats, were assessed on nociceptive responses in the presence and absence of systemically administered morphine. On the tail flick response, zolantidine induced a time- and dose-dependent inhibition of morphine antinociception, with no effect on responses in the absence of morphine. Zolantidine and another H2 receptor antagonist, tiotidine, also inhibited morphine responses in the hot plate test. Four other H2 receptor antagonists of varying structure, brain-penetrating ability, and H2 potency also induced dose-related inhibition of morphine tail flick responses. Over three orders of magnitude, the potency of these compounds as inhibitors of morphine antinociception was highly correlated with H2 receptor antagonist potency (r = 0.98, P less than 0.005, n = 5). Taken with previous studies showing the selectivity of these compounds for histamine H2 receptors, and the antinociceptive properties of histamine, these results strongly suggest a role for brain histamine H2 receptors in the expression of morphine antinociception.