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dc.contributor.author Bohn, LM
dc.contributor.author Lefkowitz, RJ
dc.contributor.author Caron, MG
dc.coverage.spatial United States
dc.date.accessioned 2012-10-24T16:16:21Z
dc.date.issued 2002-12-01
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/12451149
dc.identifier 22/23/10494
dc.identifier.citation J Neurosci, 2002, 22 (23), pp. 10494 - 10500
dc.identifier.uri http://hdl.handle.net/10161/5920
dc.description.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.
dc.format.extent 10494 - 10500
dc.language ENG
dc.relation.ispartof J Neurosci
dc.subject Alkaloids
dc.subject Analgesics, Opioid
dc.subject Animals
dc.subject Arrestins
dc.subject Benzophenanthridines
dc.subject Binding, Competitive
dc.subject Cell Membrane
dc.subject Drug Tolerance
dc.subject Enzyme Inhibitors
dc.subject Guanosine 5'-O-(3-Thiotriphosphate)
dc.subject Hot Temperature
dc.subject Mice
dc.subject Mice, Inbred Strains
dc.subject Mice, Knockout
dc.subject Morphine
dc.subject Narcotic Antagonists
dc.subject Pain Measurement
dc.subject Pain Threshold
dc.subject Phenanthridines
dc.subject Protein Kinase C
dc.subject Receptors, Opioid, mu
dc.subject Reflex
dc.subject Spinal Cord
dc.title Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice.
dc.type Journal Article
duke.description.endpage 10500 en_US
duke.description.issue 23 en_US
duke.description.startpage 10494 en_US
duke.description.volume 22 en_US
dc.relation.journal Journal of Neuroscience en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/12451149
pubs.issue 23
pubs.organisational-group /Duke
pubs.organisational-group /Duke/Institutes and Provost's Academic Units
pubs.organisational-group /Duke/Institutes and Provost's Academic Units/University Institutes and Centers
pubs.organisational-group /Duke/Institutes and Provost's Academic Units/University Institutes and Centers/Duke Institute for Brain Sciences
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Biochemistry
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Cell Biology
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Neurobiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Cardiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.organisational-group /Duke/Trinity College of Arts & Sciences
pubs.organisational-group /Duke/Trinity College of Arts & Sciences/Chemistry
pubs.publication-status Published
pubs.volume 22
dc.identifier.eissn 1529-2401

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