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This research investigates the effectiveness of a combined treatment using Cabergoline and Mdivi\u20101 to counteract the neuroadaptive changes caused by in vitro morphine treatment. The impact of Methadone, Cabergoline, and a combination of Cabergoline and Mdivi\u20101 on the cellular and molecular responses associated with Morphine\u2010induced changes was studied in human Neuroblastoma (SK\u2010N\u2010MC) and Glioblastoma (U87\u2010MG) cell lines that were exposed to prolong Morphine treatment. Cabergoline and Mdivi\u20101 combined treatment effectively influenced the molecular alterations associated with neuroadaptation in chronic morphine\u2010exposed neural cells. This combination therapy normalized autophagy and reduced oxidative stress by enhancing total\u2010antioxidant capacity, mitigating apoptosis, restoring BDNF expression, and balancing apoptotic elements. Our research outlines morphine's dual role in modulating mitochondrial dynamics via the dysregulation of the autophagy\u2013apoptosis axis. This emphasizes the significant involvement of DRP1 activity in neurological adaptation processes, as well as disturbances in the dopaminergic pathway during in vitro chronic exposure to morphine in neural cells. This study proposes a novel approach by recommending the potential effectiveness of combining Cabergoline and Mdivi\u20101 to modulate the neuroadaptations caused by morphine. Additionally, we identified BDNF and PCNA in neural cells as potential neuroprotective markers for assessing the effectiveness of drugs against opioid toxicity, emphasizing the need for further validation. The study uncovers diverse effects observed in pretreated morphine glioblastoma cells under treatment with Cabergoline and methadone. This highlights the potential for new treatments in the DRD2 pathway and underscores the importance of investigating the interplay between autophagy and apoptosis to advance research in managing cancer\u2010related pain. The study necessitates an in\u2010depth investigation into the relationship between autophagy and apoptosis, with a specific emphasis on protein interactions and the dynamics of cell signaling.<\/jats:p>","DOI":"10.1002\/jcb.30558","type":"journal-article","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T10:43:59Z","timestamp":1712313839000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Exploring neuroadaptive cellular pathways in chronic morphine exposure: An in\u2010vitro analysis of cabergoline and Mdivi\u20101 co\u2010treatment effects on the autophagy\u2013apoptosis axis"],"prefix":"10.1002","volume":"125","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7428-1106","authenticated-orcid":false,"given":"Mina","family":"Makvand","sequence":"first","affiliation":[{"name":"Department of Medical Genetics National Institute of Genetic Engineering and Biotechnology Tehran 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