Biomarkers of morphine tolerance and dependence are prevented by morphine-induced endocytosis of a mutant μ-opioid receptor

Growing evidence shows that trafficking of the μ-opioid receptor (MOR) is a critical process in functional recovery from desensitization following activation and plays important roles in morphine tolerance and dependence largely because of the failure of morphine to promote such trafficking. However...

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Bibliographic Details
Published in:The FASEB journal 2009-12, Vol.23 (12), p.4327-4334
Main Authors: He, Li, Kim, Joseph A, Whistler, Jennifer L
Format: Article
Language:English
Subjects:
adenylyl cyclase
Animals
Biomarkers
c-fos
Drug Tolerance
Endocytosis - drug effects
Endocytosis - physiology
Gene Knock-In Techniques
glucocorticoid receptor
Mice
Mice, Inbred C57BL
Morphine - metabolism
Morphine - pharmacology
Mutation
NMDA receptor
Pain Measurement
Receptors, Opioid, mu - genetics
Receptors, Opioid, mu - metabolism
Research Communications
trafficking
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Summary:Growing evidence shows that trafficking of the μ-opioid receptor (MOR) is a critical process in functional recovery from desensitization following activation and plays important roles in morphine tolerance and dependence largely because of the failure of morphine to promote such trafficking. However, morphine tolerance and dependence are believed to be mediated by multiple mechanisms, including well-documented biochemical changes in cAMP activity, N-methyl-D-aspartate receptors (NMDARs), glucocorticoid receptors (GRs), and c-fos. Here, we assess the consequences of promoting morphine-induced endocytosis on these biochemical changes utilizing a knock-in mouse model, RMOR, in which MORs undergo morphine-induced endocytosis. Chronic morphine treatment of wild-type (WT) mice promoted superactivation of adenylyl cyclase, alterations in NMDARs, and up-regulation of GR and c-fos in distinct brain regions. Notably, none of these biochemical changes occurred in the RMOR-knock-in mice. Together, these data demonstrate that morphine tolerance and dependence are mediated by multiple biochemical mechanisms and that MOR endocytosis plays a critical role in each of these mechanisms.--He, L., Kim, J. A., Whistler, J. L. Biomarkers of morphine tolerance and dependence are prevented by morphine-induced endocytosis of a mutant μ-opioid receptor.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.09-133223