TY - JOUR AU - Xu, Jin AU - Lu, Zhigang AU - Narayan, Ankita AU - Le Rouzic, Valerie P. AU - Xu, Mingming AU - Hunkele, Amanda AU - Brown, Taylor G. AU - Hoefer, William F. AU - Rossi, Grace C. AU - Rice, Richard C. AU - Martínez-Rivera, Arlene AU - Rajadhyaksha, Anjali M. AU - Cartegni, Luca AU - Bassoni, Daniel L. AU - Pasternak, Gavril W. AU - Pan, Ying-Xian T1 - Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine PY - 2017/04/03/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI88760 VL - 127 IS - 4 UR - https://doi.org/10.1172/JCI88760 SP - 1561 EP - 1573 PB - The American Society for Clinical Investigation ER -