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NEUROPHARMACOLOGY

Opioid Partial Agonist Effects of 3-O-Methylnaltrexone in Rhesus Monkeys

Harvard Medical School (D.M.P., J.K.R., R.D.S.), New England Primate Research Center, Southborough, Massachusetts; and Department of Psychiatry and Behavioral Sciences (S.I.), University of Miami School of Medicine, Miami, Florida

3-O-Methylnaltrexone (3-MNTX), a putative antagonist of morphine-6--D-glucuronide (M6G) receptors, has been reported to block the behavioral effects of heroin at doses that do not block those of morphine, suggesting that M6G receptors may play a unique role in the addictive properties of heroin. This study investigated the effects of 3-MNTX in monkeys trained to discriminate i.v. heroin from vehicle or to self-administer i.v. heroin under a progressive-ratio schedule. Additional in vitro studies determined the effects of 3-MNTX and reference drugs on adenylyl cyclase activity in caudate-putamen membranes of monkeys and rats. In drug discrimination experiments, heroin, morphine, and M6G substituted for heroin in all subjects, whereas 3-MNTX substituted for heroin in one-half the monkeys tested. In these latter monkeys, the effects of 3-MNTX were antagonized by naltrexone, and pretreatment with 3-MNTX enhanced the effects of heroin, M6G, and morphine, indicative of µ-agonist activity. In monkeys showing no substitution of 3-MNTX for heroin, 3-MNTX antagonized the effects of heroin, M6G, and morphine. In self-administration experiments, heroin and 3-MNTX maintained injections per session significantly above those maintained by vehicle when the initial response requirement (IRR) was low; only heroin maintained significant self-administration when the IRR was high. In vitro, 3-MNTX inhibited adenylyl cyclase activity in both monkey and rat brain membranes. The degree of inhibition produced by 3-MNTX was less than that produced by the full agonist [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (DAMGO). The results suggest that 3-MNTX functions primarily as a partial agonist at µ-receptors in monkeys and do not support a singular role for M6G receptors in the abuse-related effects of heroin.

Address correspondence to: Dr. Donna M. Platt, Harvard Medical School, New England Primate Research Center, One Pine Hill Dr., Box 9102, Southborough, MA 01772-9102. E-mail: donna_platt{at}hms.harvard.edu