Ray Sudipta, Datta Souvik, Saha Arnab, Sil Susmita
Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Cells. 2025 Sep 17;14(18):1454. doi: 10.3390/cells14181454.
Opioid-use disorder (OUD) poses a growing global health crisis, with chronic opioid exposure linked not only to addiction but also to enduring neurological impairments. While traditional research has focused primarily on neuronal alterations, emerging evidence underscores the pivotal role of astrocytes, abundant glial cells in the central nervous system, and their secreted extracellular vesicles (EVs) in opioid-mediated neuropathology. This review delineates the mechanistic roles of astrocytes and astrocyte-derived EVs (ADEVs) across a spectrum of opioids, including morphine, heroin, fentanyl, codeine, tramadol, buprenorphine, and methadone. Opioids disrupt astrocytic homeostasis by impairing glutamate regulation, altering the redox balance, and activating pro-inflammatory signaling pathways. In response, astrocytes release EVs enriched with neurotoxic cargo, including amyloidogenic proteins, cytokines, microRNAs, and long non-coding RNAs, that propagate neuroinflammation, compromise blood-brain barrier (BBB) integrity, and exacerbate synaptic dysfunction. Preclinical models and in vitro studies reveal drug-specific astrocytic responses and ADEV profiles, implicating these vesicles in modulating microglial function, neuroimmune signaling, and neuronal viability. Notably, morphine-induced ADEVs promote amyloidosis and inflammatory signaling, while heroin and fentanyl affect glutamatergic and inflammasome pathways. Even opioids used in therapy, such as buprenorphine and methadone, alter astrocyte morphology and EV cargo, particularly during neurodevelopment. Collectively, these findings advance a neuro-glial paradigm for understanding opioid-induced brain injury and highlight ADEVs as both biomarkers and mediators of neuropathology. Targeting astrocyte-EV signaling pathways represents a promising therapeutic avenue to mitigate long-term neurological consequences of opioid exposure and improve outcomes in OUD.
阿片类药物使用障碍（OUD）构成了日益严重的全球健康危机，长期接触阿片类药物不仅与成瘾有关，还与持久的神经损伤有关。虽然传统研究主要集中在神经元改变上，但新出现的证据强调了星形胶质细胞（中枢神经系统中丰富的神经胶质细胞）及其分泌的细胞外囊泡（EVs）在阿片类药物介导的神经病理学中的关键作用。这篇综述阐述了星形胶质细胞和星形胶质细胞衍生的EVs（ADEVs）在一系列阿片类药物（包括吗啡、海洛因、芬太尼、可待因、曲马多、丁丙诺啡和美沙酮）中的作用机制。阿片类药物通过损害谷氨酸调节、改变氧化还原平衡和激活促炎信号通路来破坏星形胶质细胞的体内平衡。作为响应，星形胶质细胞释放富含神经毒性物质的EVs，包括淀粉样蛋白生成蛋白、细胞因子、微小RNA和长链非编码RNA，这些物质会引发神经炎症、损害血脑屏障（BBB）完整性并加剧突触功能障碍。临床前模型和体外研究揭示了药物特异性的星形胶质细胞反应和ADEVs特征，表明这些囊泡在调节小胶质细胞功能、神经免疫信号和神经元活力方面发挥作用。值得注意的是，吗啡诱导的ADEVs促进淀粉样变性和炎症信号传导，而海洛因和芬太尼影响谷氨酸能和炎性小体途径。即使是用于治疗的阿片类药物，如丁丙诺啡和美沙酮，也会改变星形胶质细胞形态和EVs成分，尤其是在神经发育过程中。总体而言，这些发现推进了一种神经胶质范式来理解阿片类药物引起的脑损伤，并强调ADEVs作为神经病理学的生物标志物和介质。靶向星形胶质细胞-EV信号通路是减轻阿片类药物暴露的长期神经后果并改善OUD治疗结果的一个有前景的治疗途径。
