RT Journal Article SR Electronic T1 A role for histamine and H2-receptors in opioid antinociception. JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 476 OP 484 VO 250 IS 2 A1 K R Gogas A1 L B Hough A1 N B Eberle A1 R A Lyon A1 S D Glick A1 S J Ward A1 R C Young A1 M E Parsons YR 1989 UL http://jpet.aspetjournals.org/content/250/2/476.abstract AB To investigate the role of brain H2-receptors in opioid antinociceptive mechanisms, the effects of several antagonists of histamine H2-receptors were determined on morphine (MOR)-induced antinociception, opioid-mediated footshock-induced antinociception (FSIA) and on other opiate effects in rats. Zolantidine dimaleate (ZOL), the first brain-penetrating H2 antagonist (0.03-1.6 mumol/kg s.c.) caused a dose-related inhibition of MOR antinociception in both the tail-flick and hot-plate tests, with no effect on base-line responding. ZOL also inhibited opioid FISA with a similar potency. MOR-induced locomotor activity was also reduced by ZOL, but no effect was seen on MOR-induced hyperthermia, catalepsy or lethality. ZOL (10(-5) M) was inactive at mu, delta or kappa opioid receptors and showed at least 35-fold higher affinity at the H2-receptor than at receptors for serotonin, dopamine, norepinephrine or acetylcholine in brain. To clarify further the role of H2-receptors in ZOL's antiopiate activity, the potencies of seven structural congeners of ZOL were determined on the H2-receptor and on MOR antinociception. Over 3 orders of magnitude, the rank order of potencies of the compounds for inhibiting MOR antinociception was highly correlated with their potencies as H2 antagonists. Cimetidine, unlike other H2 antagonists, potentiated MOR antinociception, potentiated opioid FSIA and increased brain MOR levels, actions that are not likely to be due to blockade of H2-receptors. These findings strongly suggest that stimulation of opioid receptors leads to antinociception by mechanisms that include activation of brain H2-receptors.