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Research ArticleNEUROPHARMACOLOGY

Methocinnamox Is a Potent, Long-Lasting, and Selective Antagonist of Morphine-Mediated Antinociception in the Mouse: Comparison with Clocinnamox, β-Funaltrexamine, and β-Chlornaltrexamine

Jillian H. Broadbear, Tina L. Sumpter, Timothy F. Burke, Stephen M Husbands, John W. Lewis, James H. Woods and John R. Traynor
Journal of Pharmacology and Experimental Therapeutics September 2000, 294 (3) 933-940;
Jillian H. Broadbear
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Tina L. Sumpter
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Timothy F. Burke
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Stephen M Husbands
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John W. Lewis
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James H. Woods
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John R. Traynor
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Abstract

The irreversible μ-opioid antagonists β-funaltrexamine (β-FNA) and β-chlornaltrexamine (β-CNA) are important pharmacological tools but have a κ-agonist activity and, in the latter case, low selectivity. This work examines whether clocinnamox (C-CAM) and the newer analog, methocinnamox (M-CAM), represent improved long-lasting antagonists for examining μ-opioid-mediated effects in vivo. β-FNA, β-CNA, C-CAM, and M-CAM were compared after systemic administration in mice and in vitro. β-FNA and β-CNA were effective agonists in the writhing assay, reversible by the κ-antagonist norbinaltorphimine. Neither C-CAM nor M-CAM had agonist activity in vivo. M-CAM was devoid of agonist action at cloned opioid receptors. All four compounds depressed the dose-effect curve for the μ-agonist morphine in the warm-water tail-withdrawal test 1 h after administration; at 48 h, recovery was evident. In the writhing assay, the dose-effect curve for morphine was shifted in a parallel fashion in the order M-CAM ≫ C-CAM > β-CNA ≥ β-FNA. In comparison with their ability to shift the dose-effect curve for bremazocine (κ) and BW373U86 (δ), β-CNA was the least μ-selective, followed by C-CAM < β-FNA < M-CAM. M-CAM (1.8 mg/kg) produced a 74-fold increase in the ED50 of morphine while showing no effect on bremazocine or BW373U86 dose-response curves. In binding assays, C-CAM and M-CAM were 8-fold selective for μ- over κ-receptors, whereas β-FNA and β-CNA were μ/δ-, but not μ/κ, selective. However, ex vivo binding assays confirmed the μ-receptor selectivity of M-CAM. M-CAM is thus a potent, long-lasting, and specific antagonist at μ-receptors in vivo that lacks confounding agonist actions.

Footnotes

  • Send reprint requests to: Dr. J. R. Traynor, Department of Pharmacology, University of Michigan Medical School, 1301, MSRBIII, Ann Arbor, MI 48109-0632. E-mail:jtraynor{at}umich.edu

  • ↵1 This work was supported by United States Public Health Service Grant DA-00254.

  • ↵2 Present address: Astra Merck, 3838 N. Causeway Blvd., Lakeway III, Ste. 2400, Metairie, LA 70002.

  • ↵3 Present address: Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.

  • Abbreviations:
    β-CNA
    β-chlornaltrexamine
    β-FNA
    β-funaltrexamine
    C-CAM
    clocinnamox
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
    DPDPE
    [d-Pen2,d-Pen5]-enkephalin
    M-CAM
    methocinnamox
    MM-CAM
    3-methoxymethocinnamox
    nor-BNI
    norbinaltorphimine
    NTI
    naltrindole
    • Received February 21, 2000.
    • Accepted May 8, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 3
1 Sep 2000
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Research ArticleNEUROPHARMACOLOGY

Methocinnamox Is a Potent, Long-Lasting, and Selective Antagonist of Morphine-Mediated Antinociception in the Mouse: Comparison with Clocinnamox, β-Funaltrexamine, and β-Chlornaltrexamine

Jillian H. Broadbear, Tina L. Sumpter, Timothy F. Burke, Stephen M Husbands, John W. Lewis, James H. Woods and John R. Traynor
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 933-940;

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Research ArticleNEUROPHARMACOLOGY

Methocinnamox Is a Potent, Long-Lasting, and Selective Antagonist of Morphine-Mediated Antinociception in the Mouse: Comparison with Clocinnamox, β-Funaltrexamine, and β-Chlornaltrexamine

Jillian H. Broadbear, Tina L. Sumpter, Timothy F. Burke, Stephen M Husbands, John W. Lewis, James H. Woods and John R. Traynor
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 933-940;
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