RT Journal Article
SR Electronic
T1 Regulation of Opioid Tolerance by let-7 Family MicroRNA Targeting the μ Opioid Receptor
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 10251
OP 10258
DO 10.1523/JNEUROSCI.2419-10.2010
VO 30
IS 30
A1 He, Ying
A1 Yang, Cheng
A1 Kirkmire, Chelsea M.
A1 Wang, Zaijie Jim
YR 2010
UL http://www.jneurosci.org/content/30/30/10251.abstract
AB MicroRNA has emerged as a critical regulator of neuronal functions. This study aimed to test whether let-7 microRNAs can regulate the μ 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.