Clear Search sequence regions


  • behaviors (1)
  • brain (1)
  • brain stem (1)
  • dependence (3)
  • exon (10)
  • G protein (1)
  • hypothalamus (1)
  • male (1)
  • mice (9)
  • mu opioid receptor (4)
  • opioids (3)
  • OPRM1 (4)
  • protein isoforms (2)
  • receptor (3)
  • strain (1)
  • transit (1)
  • β arrestin 2 (2)
  • Sizes of these terms reflect their relevance to your search.

    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.

    Citation

    Jin Xu, Zhigang Lu, Ankita Narayan, Valerie P Le Rouzic, Mingming Xu, Amanda Hunkele, Taylor G Brown, William F Hoefer, Grace C Rossi, Richard C Rice, Arlene Martínez-Rivera, Anjali M Rajadhyaksha, Luca Cartegni, Daniel L Bassoni, Gavril W Pasternak, Ying-Xian Pan. Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine. The Journal of clinical investigation. 2017 Apr 03;127(4):1561-1573

    Expand section icon Mesh Tags

    Expand section icon Substances


    PMID: 28319053

    View Full Text