Abstract
3-O-Methylnaltrexone (3-MNTX), a putative antagonist of morphine-6-β-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.
Footnotes
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This research was supported by U.S. Public Health Services Grants DA11928, DA11960, and RR00168. A preliminary report of these data was made at the 2001 Annual Meeting of the College on Problems of Drug Dependence.
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DOI: 10.1124/jpet.103.060962.
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ABBREVIATIONS: 6MAM, 6-monoacetylmorphine; M6G, morphine-6-β-d-glucuronide; M3G, morphine-3-β-d-glucuronide; 3-MNTX, 3-O-methylnaltrexone; DS, discriminative stimulus; PR, progressive-ratio; IRR, initial response requirement; FR, fixed-ratio; BP, break point; DAMGO, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin.
- Received October 6, 2003.
- Accepted November 20, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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