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Molecular Pharmacology

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Research ArticleArticle

Chronic Exposure to μ-Opioid Agonists Produces Constitutive Activation of μ-Opioid Receptors in Direct Proportion to the Efficacy of the Agonist Used for Pretreatment

Jing-Gen Liu and Paul L. Prather
Molecular Pharmacology July 2001, 60 (1) 53-62; DOI: https://doi.org/10.1124/mol.60.1.53
Jing-Gen Liu
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Paul L. Prather
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Abstract

Chronic morphine treatment has been shown to produce constitutive activation of μ-opioid receptors, and this transition might contribute to the development of tolerance and dependence. The apparent ability of chronic morphine to increase the spontaneous, agonist-independent activation of μ-opioid receptors may be unique, due to its distinct partial agonist properties of possessing a relatively high intrinsic activity coupled with a poor ability to produce desensitization and down-regulation. Therefore, the present study tested the hypothesis that prolonged exposure to morphine would produce greater constitutive activity of μ-opioid receptors than exposure to the full agonist [d-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO). GH3 cells expressing μ-opioid receptors were exposed to chronic morphine, DAMGO, or no opioid under conditions determined to produce maximal desensitization, down-regulation, and cAMP rebound. After chronic treatment, the μ-opioid antagonists naloxone and β-chlornaltrexamine (β-CNA) were evaluated in two assays predictive of inverse agonist activity. Both antagonists produced a concentration-dependent inhibition of [35S]GTPγS binding only in membranes prepared from cells chronically exposed to opioids. This effect was reversed by the neutral μ-opioid antagonist CTAP. Additionally, conditions known to uncouple G protein-coupled receptors from G proteins produced a leftward shift in the competition curve of β-CNA for [3H]DAMGO binding only in membranes prepared from chronically treated cells. In contrast, these conditions produced no shift in the competition curve by the neutral antagonist CTAP in cells exposed to chronic DAMGO. Therefore, prolonged exposure of GH3MOR cells to opioids produced constitutive activation of μ-opioid receptors. Surprisingly, chronic treatment with the more efficacious agonist DAMGO produced greater increases in both measures of inverse agonist activity than did morphine. These observations may lend novel insight into the mechanisms of opioid tolerance and dependence.

  • Abbreviations

    DAMGO
    [d-Ala2,N-MePhe4,Gly-ol5]enkephalin
    CTAP
    d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2
    GppNHp
    5′-guanylylimidodiphosphate
    IBMX
    3-isobutyl-1-methylxanthine
    PTX
    pertussis toxin
    β-CNA
    β-chlornaltrexamine
    GTPγS
    guanosine 5′-O-(3-thio)triphosphate
    GPCR
    G protein-coupled receptor
    MOR
    μ-opioid receptor
    • Received January 9, 2001.
    • Accepted March 1, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Molecular Pharmacology: 60 (1)
    Molecular Pharmacology
    Vol. 60, Issue 1
    1 Jul 2001
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    Research ArticleArticle

    Chronic Exposure to μ-Opioid Agonists Produces Constitutive Activation of μ-Opioid Receptors in Direct Proportion to the Efficacy of the Agonist Used for Pretreatment

    Jing-Gen Liu and Paul L. Prather
    Molecular Pharmacology July 1, 2001, 60 (1) 53-62; DOI: https://doi.org/10.1124/mol.60.1.53

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    Research ArticleArticle

    Chronic Exposure to μ-Opioid Agonists Produces Constitutive Activation of μ-Opioid Receptors in Direct Proportion to the Efficacy of the Agonist Used for Pretreatment

    Jing-Gen Liu and Paul L. Prather
    Molecular Pharmacology July 1, 2001, 60 (1) 53-62; DOI: https://doi.org/10.1124/mol.60.1.53
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