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Research ArticleNEUROPHARMACOLOGY

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

Donna M. Platt, James K. Rowlett, Sari Izenwasser and Roger D. Spealman
Journal of Pharmacology and Experimental Therapeutics March 2004, 308 (3) 1030-1039; DOI: https://doi.org/10.1124/jpet.103.060962
Donna M. Platt
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James K. Rowlett
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Sari Izenwasser
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Roger D. Spealman
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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

  • 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.

  • DOI: 10.1124/jpet.103.060962.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 308 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 3
1 Mar 2004
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Research ArticleNEUROPHARMACOLOGY

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

Donna M. Platt, James K. Rowlett, Sari Izenwasser and Roger D. Spealman
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 1030-1039; DOI: https://doi.org/10.1124/jpet.103.060962

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Research ArticleNEUROPHARMACOLOGY

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

Donna M. Platt, James K. Rowlett, Sari Izenwasser and Roger D. Spealman
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 1030-1039; DOI: https://doi.org/10.1124/jpet.103.060962
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