Regulation of opioid tolerance by let-7 family microRNA targeting the mu opioid receptor.
MicroRNA has emerged as a critical regulator of neuronal functions. This study aimed to test whether let-7 microRNAs can regulate the mu opioid receptor (MOR) and opioid tolerance. Employing bioinformatics, we identified a let-7 binding site in the 3'-untranslated region (UTR) of MOR mRNA, which was experimentally confirmed as a direct target of let-7. The repressive regulation of MOR by let-7 was revealed using a LNA-let-7 inhibitor to knockdown let-7 in SH-SY5Y cells. Conversely, morphine significantly upregulated let-7 expression in SH-SY5Y cells and in a mouse model of opioid tolerance. The LNA-let-7 inhibitor decreased brain let-7 levels and partially attenuated opioid antinociceptive tolerance in mice. Although chronic morphine treatment did not change overall MOR transcript, polysome-associated mRNA declined in a let-7-dependent manner. let-7 was identified as a mediator translocating and sequestering MOR mRNA to P-bodies, leading to translation repression. These results suggest that let-7 plays an integral role in opioid tolerance.
He
Ying
Y
Department of Biopharmaceutical Sciences, University of Illinois, 833 S. Wood Street, Chicago, IL 60612, USA.
Yang
Cheng
C
Kirkmire
Chelsea M
CM
Wang
Zaijie Jim
ZJ
D020413:3' Untranslated Regions / Q000187:drug effects / Q000235:genetics; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology; D016296:Mutagenesis / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011132:Polyribosomes / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment / Q000379:methods; D013997:Time Factors; D014162:Transfection / Q000379:methods
D020413:3' Untranslated Regions; D000701:Analgesics, Opioid; D035683:MicroRNAs; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; C487931:mirnlet7 microRNA, human; D009020:Morphine