Title | Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Xu 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 |
Journal | J Clin Invest |
Volume | 127 |
Issue | 4 |
Pagination | 1561-1573 |
Date Published | 2017 Apr 03 |
ISSN | 1558-8238 |
Keywords | Alternative 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 |
Abstract | 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. |
DOI | 10.1172/JCI88760 |
Alternate Journal | J. Clin. Invest. |
PubMed ID | 28319053 |
PubMed Central ID | PMC5373896 |
Grant List | T32 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 |