TitleAlternatively spliced mu opioid receptor C termini impact the diverse actions of morphine.
Publication TypeJournal Article
Year of Publication2017
AuthorsXu J, Lu Z, Narayan A, Le Rouzic VP, Xu M, Hunkele A, Brown TG, Hoefer WF, Rossi GC, Rice RC, Martinez-Rivera A, Rajadhyaksha AM, Cartegni L, Bassoni DL, Pasternak GW, Pan Y-X
JournalJ Clin Invest
Date Published2017 Apr 03
KeywordsAlternative Splicing, Analgesics, Opioid, Animals, Brain, Codon, Nonsense, Dose-Response Relationship, Drug, Drug Tolerance, Exons, Gastrointestinal Transit, Guanosine 5'-O-(3-Thiotriphosphate), Locomotion, Male, Mice, 129 Strain, Mice, Inbred C57BL, Morphine, Morphine Dependence, Protein Binding, Protein Isoforms, Receptors, Opioid, mu

Extensive 3' alternative splicing of the mu opioid receptor gene OPRM1 creates multiple C-terminal splice variants. However, their behavioral relevance remains unknown. The present study generated 3 mutant mouse models with truncated C termini in 2 different mouse strains, C57BL/6J (B6) and 129/SvEv (129). One mouse truncated all C termini downstream of Oprm1 exon 3 (mE3M mice), while the other two selectively truncated C-terminal tails encoded by either exon 4 (mE4M mice) or exon 7 (mE7M mice). Studies of these mice revealed divergent roles for the C termini in morphine-induced behaviors, highlighting the importance of C-terminal variants in complex morphine actions. In mE7M-B6 mice, the exon 7-associated truncation diminished morphine tolerance and reward without altering physical dependence, whereas the exon 4-associated truncation in mE4M-B6 mice facilitated morphine tolerance and reduced morphine dependence without affecting morphine reward. mE7M-B6 mutant mice lost morphine-induced receptor desensitization in the brain stem and hypothalamus, consistent with exon 7 involvement in morphine tolerance. In cell-based studies, exon 7-associated variants shifted the bias of several mu opioids toward β-arrestin 2 over G protein activation compared with the exon 4-associated variant, suggesting an interaction of exon 7-associated C-terminal tails with β-arrestin 2 in morphine-induced desensitization and tolerance. Together, the differential effects of C-terminal truncation illustrate the pharmacological importance of OPRM1 3' alternative splicing.

Alternate JournalJ. Clin. Invest.
PubMed ID28319053
PubMed Central IDPMC5373896
Grant ListT32 DA007242 / DA / NIDA NIH HHS / United States
R01 DA029122 / DA / NIDA NIH HHS / United States
R01 DA013997 / DA / NIDA NIH HHS / United States
R01 DA006241 / DA / NIDA NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R21 DA029244 / DA / NIDA NIH HHS / United States
R37 DA007242 / DA / NIDA NIH HHS / United States
R01 DA007242 / DA / NIDA NIH HHS / United States
R21 DA040858 / DA / NIDA NIH HHS / United States