A comparison of noninternalizing (herkinorin) and internalizing (DAMGO) μ-opioid agonists on cellular markers related to opioid tolerance and dependence

Authors

  • Heng Xu,

    1. Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, Maryland
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  • John S. Partilla,

    1. Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, Maryland
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  • Xiaoying Wang,

    1. Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, Maryland
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  • John M. Rutherford,

    1. Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, Maryland
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  • Kevin Tidgewell,

    1. Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, Iowa
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  • Thomas E. Prisinzano,

    1. Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, Iowa
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  • Laura M. Bohn,

    1. Department of Pharmacology, Ohio State University College of Medicine and Public Health, Columbus, Ohio
    2. Department of Psychiatry, Ohio State University College of Medicine and Public Health, Columbus, Ohio
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  • Richard B. Rothman

    Corresponding author
    1. Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, Maryland
    • Clinical Psychopharmacology Section, IRP, NIDA, NIH, P.O. Box 5180, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA
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  • This article is a US government work and, as such, is in the public domain in the United States of America.

Abstract

Previous studies established that Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) and (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(Benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester (herkinorin) are fully efficacious μ-agonists. Herkinorin (HERK), unlike DAMGO, does not recruit β-arrestin and promote μ-receptor internalization, even in cells that over express β-arrestin. We hypothesized that chronic HERK and DAMGO treatment will differentially affect cellular markers of tolerance and dependence. CHO cells expressing the cloned human μ-receptor were treated for 20 h with 10 μM DAMGO, HERK, morphine, or medium. Both DAMGO and HERK acted as full agonists in the [35S]GTP-γ-S binding assay with EMAX values of 230% and EC50 values of 12.8 and 92.5 nM, respectively. In the cAMP assay, DAMGO and HERK had similar EMAX values of ∼80% and EC50 values of 3.23 and 48.7 nM, respectively. Chronic exposure to both drugs produced moderate tolerance to both drugs (∼2 to 5 fold) in the [35S]GTP-γ-S binding assay. In the cAMP assay, chronic DAMGO produced tolerance to both drugs (∼3 to 4 fold). Chronic HERK eliminated the ability of either drug to inhibit forskolin-stimulated cAMP accumulation. Chronic DAMGO increased, and chronic HERK decreased, forskolin-stimulated cAMP accumulation. Naloxone, after chronic HERK (but not DAMGO) induced a large increase in forskolin-stimulated cAMP accumulation. Viewed collectively with published data, the current data indicate that both internalizing and noninternalizing μ-agonists produce cellular signs of tolerance and dependence. Synapse 61:166–175, 2007. Published 2006 Wiley-Liss, Inc.

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