Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA; Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901- 8525, USA.
Mol Ther. 2023 May 3;31(5):1332-1345. doi: 10.1016/j.ymthe.2023.03.030. Epub 2023 Apr 3.
Repeated use of opioids such as morphine causes changes in the shape and signal transduction pathways of various brain cells, including astrocytes and neurons, resulting in alterations in brain functioning and ultimately leading to opioid use disorder. We previously demonstrated that extracellular vesicle (EV)-induced primary ciliogenesis contributes to the development of morphine tolerance. Herein, we aimed to investigate the underlying mechanisms and potential EV-mediated therapeutic approach to inhibit morphine-mediated primary ciliogenesis. We demonstrated that miRNA cargo in morphine-stimulated-astrocyte-derived EVs (morphine-ADEVs) mediated morphine-induced primary ciliogenesis in astrocytes. CEP97 is a target of miR-106b and is a negative regulator of primary ciliogenesis. Intranasal delivery of ADEVs loaded with anti-miR-106b decreased the expression of miR-106b in astrocytes, inhibited primary ciliogenesis, and prevented the development of tolerance in morphine-administered mice. Furthermore, we confirmed primary ciliogenesis in the astrocytes of opioid abusers. miR-106b-5p in morphine-ADEVs induces primary ciliogenesis via targeting CEP97. Intranasal delivery of ADEVs loaded with anti-miR-106b ameliorates morphine-mediated primary ciliogenesis and prevents morphine tolerance. Our findings bring new insights into the mechanisms underlying primary cilium-mediated morphine tolerance and pave the way for developing ADEV-mediated small RNA delivery strategies for preventing substance use disorders.
阿片类药物（如吗啡）的重复使用会导致包括星形胶质细胞和神经元在内的各种脑细胞的形态和信号转导途径发生变化，导致大脑功能发生改变，并最终导致阿片类药物使用障碍。我们之前的研究表明，细胞外囊泡（EV）诱导的初级纤毛发生有助于吗啡耐受的发展。在此，我们旨在研究潜在的机制和 EV 介导的治疗方法，以抑制吗啡介导的初级纤毛发生。我们证明了吗啡刺激星形胶质细胞衍生的细胞外囊泡（吗啡-ADEV）中的 miRNA 货物介导了星形胶质细胞中的吗啡诱导的初级纤毛发生。CEP97 是 miR-106b 的靶标，是初级纤毛发生的负调节剂。载有抗 miR-106b 的 ADEV 的鼻内递送降低了星形胶质细胞中 miR-106b 的表达，抑制了初级纤毛发生，并防止了吗啡给药小鼠耐受的发展。此外，我们还在阿片类药物滥用者的星形胶质细胞中证实了初级纤毛发生。吗啡-ADEV 中的 miR-106b-5p 通过靶向 CEP97 诱导初级纤毛发生。载有抗 miR-106b 的 ADEV 的鼻内递送可改善吗啡介导的初级纤毛发生并预防吗啡耐受。我们的研究结果为初级纤毛介导的吗啡耐受的机制提供了新的见解，并为开发用于预防物质使用障碍的 ADEV 介导的小 RNA 传递策略铺平了道路。
