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Biomarkers of morphine tolerance and dependence are prevented by morphine‐induced endocytosis of a mutant μ‐opioid receptor
Author(s) -
He Li,
Kim Joseph A.,
Whistler Jennifer L.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-133223
Subject(s) - morphine , endocytosis , adenylyl cyclase , opioid , receptor , μ opioid receptor , chemistry , physical dependence , pharmacology , microbiology and biotechnology , biology , biochemistry
Growing evidence shows that trafficking of the μ‐opioid receptor (MOR) is a critical process in functional recovery from desensitization following ac‐ tivation and plays important roles in morphine toler‐ ance and dependence largely because of the failure of morphine to promote such trafficking. However, mor‐ phine tolerance and dependence are believed to be mediated by multiple mechanisms, including well‐doc‐ umented biochemical changes in cAMP activity, N‐ methyl‐D‐aspartate receptors (NMDARs), glucocorti‐ coid receptors (GRs), and c‐fos. Here, we assess the consequences of promoting morphine‐induced endocy‐ tosis on these biochemical changes utilizing a knock‐in mouse model, RMOR, in which MORs undergo mor‐ phine‐induced endocytosis. Chronic morphine treat‐ ment 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 mu‐ tant μ‐opioid receptor. FASEBJ. 23, 4327‐4334 (2009). www.fasebj.org