INHIBITION OF MORPHINE ANTINOCICEPTION BY CENTRALLY ADMINISTERED HISTAMINE H-2-RECEPTOR ANTAGONISTS

The actions of zolantidine dimaleate and five other histamine H-2 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 H-2 receptor antagonist, tiotidine, also inhibited morphine responses in the hot plate test. Four other H-2 receptor antagonists of varying structure, brain-penetrating ability, and H-2 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 H-2 receptor antagonist potency (r = 0.98, P < 0.005, n = 5). Taken with previous studies showing the selectivity of these compounds for histamine H-2 receptors, and the antinociceptive properties of histamine, these results strongly suggest a role for brain histamine H-2 receptors in the expression of morphine antinociception.