Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine.
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.
Jin
J
Xu
Zhigang
Z
Lu
Ankita
A
Narayan
Valerie P
VP
Le Rouzic
Mingming
M
Xu
Amanda
A
Hunkele
Taylor G
TG
Brown
William F
WF
Hoefer
Grace C
GC
Rossi
Richard C
RC
Rice
Arlene
A
Martínez-Rivera
Anjali M
AM
Rajadhyaksha
Luca
L
Cartegni
Daniel L
DL
Bassoni
Gavril W
GW
Pasternak
Ying-Xian
YX
Pan
D017398:Alternative Splicing; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D018389:Codon, Nonsense; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005091:Exons; D005772:Gastrointestinal Transit / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000235:genetics; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*
D000701:Analgesics, Opioid; D018389:Codon, Nonsense; C404943:Oprm protein, mouse; D020033:Protein Isoforms; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine