title: Analgesic tone conferred by constitutively active mu opioid receptors in mice lacking β-arrestin 2.
abstract: Hedonic reward, dependence and addiction are unwanted effects of opioid analgesics, linked to the phasic cycle of μ 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 μ receptors, often necessitating mutagenesis or pharmacological manipulation to enhance basal signaling. We previously demonstrated that the absence of β-arrestin 2 (β-arr2) augments the constitutive coupling of μ receptors to voltage-activated Ca²+ channels in primary afferent dorsal root ganglion neurons from β-arr2⁻/⁻ mice. We used this in vitro approach to characterize neutral competitive antagonists and inverse agonists of the constitutively active wild type μ receptors in neurons. We administered these agents to β-arr2⁻/⁻ mice to explore the role of constitutive μ receptor activity in nociception and hedonic tone. This study demonstrates that the induction of constitutive μ receptor activity in vivo in β-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 β-arr2⁻/⁻ and β-arr2+/+ mice, suggesting that hedonic tone was unaffected.
authors.affiliation: Institute of Academic Anaesthesia, Centre for Neuroscience, University of Dundee, Dundee DD19SY, UK.
authors.forename: Hoa
authors.initials: H
authors.lastname: Lam
authors.forename: Matthew
authors.initials: M
authors.lastname: Maga
authors.forename: Amynah
authors.initials: A
authors.lastname: Pradhan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Evans
authors.forename: Nigel T
authors.initials: NT
authors.lastname: Maidment
authors.forename: Tim G
authors.initials: TG
authors.lastname: Hales
authors.forename: Wendy
authors.initials: W
authors.lastname: Walwyn
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics*; D004594:Electrophysiology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D010147:Pain Measurement; D010446:Peptide Fragments / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013004:Somatostatin / Q000494:pharmacology; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605258:Arrb2 protein, mouse; D019390:Arrestins; C529311:CTAP octapeptide; D010446:Peptide Fragments; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D009270:Naloxone; D013004:Somatostatin; D009271:Naltrexone