CaMKIIa regulates let‐7 microRNAs in opioid tolerance

We have previously reported that let‐7 miRNAs modulate opioid tolerance, through complex mechanisms that involve the μ opioid receptor and other signaling molecules. Chronic opioid treatment up‐regulated brain let‐7 miRNA expression, which was functionally correlated with the development of opioid tolerance. The aim of this study was to understand the mechanisms by which opioids regulate let‐7 miRNA. We determined the let‐7 transcript and found that the expression of primary let‐7 (pri‐let‐7) remained unchanged in human neuroblastoma SH‐SY5Y cells that were treated with morphine (1 mM, for 48 h). In agreement with the in vitro findings, chronic morphine treatment induced opioid tolerance, but did not alter the level of pri‐let‐7 in mouse brain. These data suggested that the robust elevation of let‐7 occurred at the post‐transcriptional level. In the presence of KN93, inhibitor of Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII), chronic morphine treatment failed to generate let‐7 up‐regulation in SH‐SY5Y cells. In CaMKIIa T286A point mutation mice lacking functional CaMKIIa, opioid tolerance was absent in −/− mice, but tolerance was full developed in littermate wildtype +/+ mice. Interestingly, let‐7 miRNA levels were much lower in CaMKIIa T286A mutant mice than those in wild‐type mice. Moreover, morphine failed to regulate let‐7 miRNA in CaMKIIa T286A mutant (−/−) mice. Taken together, these data suggested that CaMKIIa is required for the biogenesis and possibly regulation of let‐7 miRNA in opioid tolerance. Support or Funding Information R01 DA041809 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .