Regulation of opioid tolerance by let-7 family microRNA targeting the mu opioid receptor.
Regulation of opioid tolerance by let-7 family microRNA targeting the mu opioid receptor.
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DOI：
10.1523/jneurosci.2419-10.2010
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发表时间：
2010-07-28
期刊：
影响因子：
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通讯作者：
Wang ZJ
中科院分区：
文献类型：
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作者：
He Y;Yang C;Kirkmire CM;Wang ZJ
microRNA已成为神经元功能的关键调节因子。本研究旨在检测let-7 microRNA是否能够调节μ阿片受体（莫尔）和阿片耐受。利用生物信息学，我们在莫尔mRNA的3′-UTR中鉴定了一个let-7结合位点，实验证实该位点是let-7的直接靶点。在SH-SY 5 Y细胞中，使用LNA-let-7抑制剂敲低let-7揭示let-7对莫尔的抑制性调节。相反，吗啡显著上调SH-SY 5 Y细胞和阿片耐受小鼠模型中let-7的表达。LNA-let-7抑制剂降低小鼠脑let-7水平并部分减弱阿片类抗伤害耐受性。虽然慢性吗啡治疗没有改变整体莫尔转录，多核糖体相关的mRNA下降的let-7依赖的方式。Let-7被鉴定为转运和隔离莫尔mRNA至P体的介体，导致翻译抑制。这些结果表明let-7在阿片耐受中起着不可或缺的作用。
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′-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.