Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center Omaha Nebraska USA.
J Extracell Vesicles. 2020 Oct;10(1):e12027. doi: 10.1002/jev2.12027. Epub 2020 Nov 19.
Opioids, such as morphine, are the mainstay for the management of postsurgical pain. Over the last decade there has been a dramatic increase in deaths related to opioid overdose. While opioid abuse has been shown to result in increased neuroinflammation, mechanism(s) underlying this process, remain less understood. In recent years, microRNAs have emerged as key mediators of gene expression regulating both paracrine signaling and cellular crosstalk. MiRNAs constitute the extracellular vesicle (EV) cargo and can shuttle from the donor to the recipient cells. Exposure of human primary astrocytes to morphine resulted in induction and release of miR-138 in the EVs isolated from conditioned media of cultured astrocytes. Released EVs were, in turn, taken up by the microglia, leading to activation of these latter cells. Interestingly, activation of microglia involved binding of the GUUGUGU motif of miR138 to the endosomal toll like receptor (TLR)7, leading, in turn, to cellular activation. These findings were further corroborated in vivo in wildtype mice wherein morphine administration resulted in increased microglial activation in the thalamus. In TLR7 mice on the other hand, morphine failed to induce microglial activation. These findings have ramifications for the development of EV-loaded anti-miRNAs as therapeutics for alleviating neuroinflammation in opioids abusers.
阿片类药物，如吗啡，是治疗术后疼痛的主要药物。在过去的十年中，与阿片类药物过量相关的死亡人数急剧增加。虽然阿片类药物滥用已被证明会导致神经炎症增加，但这一过程的机制仍不太清楚。近年来，microRNAs 已成为调节旁分泌信号和细胞串扰的基因表达的关键介质。miRNAs 构成细胞外囊泡（EV）的货物，并可以从供体转移到受体细胞。将吗啡暴露于人原代星形胶质细胞中，导致培养的星形胶质细胞条件培养基中分离的 EV 中的 miR-138 诱导和释放。释放的 EV 反过来被小胶质细胞摄取，导致这些细胞的激活。有趣的是，小胶质细胞的激活涉及 miR138 的 GUUGUGU 基序与内体 toll 样受体（TLR）7 的结合，进而导致细胞激活。这些发现进一步在野生型小鼠中得到证实，其中吗啡给药导致丘脑中小胶质细胞的激活增加。另一方面，在 TLR7 小鼠中，吗啡未能诱导小胶质细胞的激活。这些发现对于开发负载 EV 的抗 miRNAs 作为治疗阿片类药物滥用者神经炎症的疗法具有重要意义。
