{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:14:13Z","timestamp":1788480853067,"version":"build-2803163510"},"reference-count":239,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R21AG069541"],"award-info":[{"award-number":["R21AG069541"]}]},{"name":"NIH","award":["RO1DA060755"],"award-info":[{"award-number":["RO1DA060755"]}]},{"name":"NIH","award":["RO1DA060753"],"award-info":[{"award-number":["RO1DA060753"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2013brain 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.<\/jats:p>","DOI":"10.3390\/cells14181454","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T11:00:00Z","timestamp":1758106800000},"page":"1454","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Astrocytes and Astrocyte-Derived Extracellular Conduits in Opiate-Mediated Neurological Disorders"],"prefix":"10.3390","volume":"14","author":[{"given":"Sudipta","family":"Ray","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8274-2435","authenticated-orcid":false,"given":"Souvik","family":"Datta","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8206-7470","authenticated-orcid":false,"given":"Arnab","family":"Saha","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susmita","family":"Sil","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1177\/2049463712438493","article-title":"Basic opioid pharmacology: An update","volume":"6","author":"Pathan","year":"2012","journal-title":"Br. 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