title: Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice.
abstract: Morphine induces antinociception by activating mu opioid receptors (muORs) in spinal and supraspinal regions of the CNS. (Beta)arrestin-2 (beta)arr2), a G-protein-coupled receptor-regulating protein, regulates the muOR in vivo. We have shown previously that mice lacking (beta)arr2 experience enhanced morphine-induced analgesia and do not become tolerant to morphine as determined in the hot-plate test, a paradigm that primarily assesses supraspinal pain responsiveness. To determine the general applicability of the (beta)arr2-muOR interaction in other neuronal systems, we have, in the present study, tested (beta)arr2 knock-out ((beta)arr2-KO) mice using the warm water tail-immersion paradigm, which primarily assesses spinal reflexes to painful thermal stimuli. In this test, the (beta)arr2-KO mice have greater basal nociceptive thresholds and markedly enhanced sensitivity to morphine. Interestingly, however, after a delayed onset, they do ultimately develop morphine tolerance, although to a lesser degree than the wild-type (WT) controls. In the (beta)arr2-KO but not WT mice, morphine tolerance can be completely reversed with a low dose of the classical protein kinase C (PKC) inhibitor chelerythrine. These findings provide in vivo evidence that the muOR is differentially regulated in diverse regions of the CNS. Furthermore, although (beta)arr2 appears to be the most prominent and proximal determinant of muOR desensitization and morphine tolerance, in the absence of this mechanism, the contributions of a PKC-dependent regulatory system become readily apparent.
authors.affiliation: Howard Hughes Medical Institute Laboratories, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bohn
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
mesh_terms: D000470:Alkaloids; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000172:deficiency* / Q000235:genetics; D053119:Benzophenanthridines; D001667:Binding, Competitive / Q000187:drug effects; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004361:Drug Tolerance / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006358:Hot Temperature; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: D000470:Alkaloids; D000701:Analgesics, Opioid; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D010617:Phenanthridines; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine; C016299:chelerythrine; D011493:Protein Kinase C