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*Compound via MeSH
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*MORPHINE
*PENTOBARBITAL
*PHENOXYBENZAMINE
*PHENTOLAMINE
*PROPRANOLOL HYDROCHLORIDE
Journal of Pharmacology And Experimental Therapeutics, Vol. 189, Issue 1, 72-82, 1974
Copyright © 1974 by American Society for Pharmacology and Experimental Therapeutics

ALPHA ADRENERGIC BLOCKING AGENTS: ANTINOCICEPTIVE ACTIVITY AND ENHANCEMENT OF MORPHINE-INDUCED ANALGESIA

Theodore J. Cicero 1, Edward R. Meyer 1, and Ben R. Smithloff 1

1 Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri

The effects of reducing the activity of norepinephrine in the nervous system, either by depleting endogenous levels via dopamine-beta-hydroxylase inhibition or blocking its effects at the receptor level, on hot-plate reaction time and morphine's analgesic activity were determined in rats. Inhibition of dopamine-beta-hydroxylase resulted in a significant prolongation of morphine's antinociceptive activity on the hot-plate. The alpha adrenergic blocker, phenoxybenzamine, alone produced a nearly 2-fold increase an reaction time on the hot-plate when a dose of 10 mg/kg was administered 22 hours prior to testing. Higher doses of phenoxybenzamine (20 and 30 mg/kg) caused no further elevation in reaction time. In rats pretreated with phenoxybeimzamine, the effect of a minimally effective dose of morphine (5 mg/kg) on hot-plate reaction time was significantly enhanced, both in terms of the initial increase in reaction time after the administration of the narcotic and the duration of its antinociceptive activity. The combined effect of phenyxybenzamine and morphine on hot-plate reaction time was substantially greater than that which would be predicted simply on the basis of an addition of the two drugs' effects. Another alpha blocker, phentolaimine, also produced a slight degree of antinociceptive activity by itself and an enhancement of morphine-induced analgesia, whereas two beta adrenergic blockers, propranolol and practolol, were ineffective in this regard. The observed interaction between phmenoxybenzamine and morphine was not related to an altered distribution of the narcotic in the brain. The results of these studies suggest that the actions of morphine and related narcoties may be associated with a reduction in norepinephrine's activity in the nervous system particularly at alpha adrenergic receptor sites.

Submitted on August 11, 1973
Accepted on December 18, 1973




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