Analgesic tone conferred by constitutively active mu opioid receptors in mice lacking beta-arrestin 2

Hoa Lam, Matthew Maga, Amynah Pradhan, Christopher J. Evans, Nigel T. Maidment, Tim G. Hales, Wendy Walwyn

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    19 Citations (Scopus)

    Abstract

    Hedonic reward, dependence and addiction are unwanted effects of opioid analgesics, linked to the phasic cycle of mu opioid receptor activation, tolerance and withdrawal. In vitro studies of recombinant G protein coupled receptors (GPCRs) over expressed in cell lines reveal an alternative tonic signaling mechanism that is independent of agonist. Such studies demonstrate that constitutive GPCR signaling can be inhibited by inverse agonists but not by neutral antagonists. However, ligand-independent activity has been difficult to examine in vivo, at the systems level, due to relatively low levels of constitutive activity of most GPCRs including mu receptors, often necessitating mutagenesis or pharmacological manipulation to enhance basal signaling. We previously demonstrated that the absence of beta-arrestin 2 (beta-arr2) augments the constitutive coupling of mu receptors to voltage-activated Ca2+ channels in primary afferent dorsal root ganglion neurons from beta-arr2-/- mice. We used this in vitro approach to characterize neutral competitive antagonists and inverse agonists of the constitutively active wild type mu receptors in neurons. We administered these agents to beta-arr2-/- mice to explore the role of constitutive mu receptor activity in nociception and hedonic tone. This study demonstrates that the induction of constitutive mu receptor activity in vivo in beta-arr2-/- mice prolongs tail withdrawal from noxious heat, a phenomenon that was reversed by inverse agonists, but not by antagonists that lack negative efficacy. By contrast, the aversive effects of inverse agonists were similar in beta-arr2-/- and beta-arr2+/+ mice, suggesting that hedonic tone was unaffected.

    Original languageEnglish
    Article number24
    Pages (from-to)-
    Number of pages10
    JournalMolecular Pain
    Volume7
    DOIs
    Publication statusPublished - 12 Apr 2011

    Keywords

    • BASAL SIGNALING ACTIVITY
    • MORPHINE-DEPENDENT MICE
    • KNOCK-OUT MICE
    • CALCIUM-CHANNELS
    • NARCOTIC DEPENDENCE
    • AGONIST
    • ANTAGONISTS
    • 6-BETA-NALTREXOL
    • MODULATION
    • WITHDRAWAL

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