TY - JOUR T1 - Regulation of Opioid Tolerance by let-7 Family MicroRNA Targeting the μ Opioid Receptor JF - The Journal of Neuroscience JO - J. Neurosci. SP - 10251 LP - 10258 DO - 10.1523/JNEUROSCI.2419-10.2010 VL - 30 IS - 30 AU - Ying He AU - Cheng Yang AU - Chelsea M. Kirkmire AU - Zaijie Jim Wang Y1 - 2010/07/28 UR - http://www.jneurosci.org/content/30/30/10251.abstract N2 - 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. ER -