Molecular and cellular basis of mu-opioid receptor signaling: mechanisms underlying tolerance and dependence development
Opioids, while highly effective for pain management, are among the most addictive substances, contributing significantly to the global opioid crisis. Opioid use disorder (OUD) affects millions, with synthetic opioids like fentanyl exacerbating the epidemic due to their potency and widespread illicit...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2025.1597922/full |
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| author | Michael Swingler Martina Donadoni Ellen M. Unterwald Sanjay B. Maggirwar Ilker K. Sariyer |
| author_facet | Michael Swingler Martina Donadoni Ellen M. Unterwald Sanjay B. Maggirwar Ilker K. Sariyer |
| author_sort | Michael Swingler |
| collection | DOAJ |
| description | Opioids, while highly effective for pain management, are among the most addictive substances, contributing significantly to the global opioid crisis. Opioid use disorder (OUD) affects millions, with synthetic opioids like fentanyl exacerbating the epidemic due to their potency and widespread illicit availability. Opioids exert their effects through opioid receptors (ORs), primarily the mu opioid receptor (MOR), which mediates both therapeutic analgesia and adverse effects such as euphoria, dependence, and tolerance. Chronic opioid use leads to cellular adaptations, including receptor phosphorylation, desensitization, and recruitment of β-arrestin, which uncouple MOR from downstream signaling pathways. These changes, along with compensatory upregulation of adenylyl cyclase (AC) and cAMP signaling, underlie the development of tolerance, dependence, and withdrawal, however the exact signaling pathways responsible remain unknown. Emerging research highlights the role of neuroinflammation, genetic polymorphisms, and alternative splicing of MOR isoforms in modulating opioid responses and vulnerability to OUD. Current treatments for OUD, such as methadone, buprenorphine, and naltrexone, are limited by compliance, access, and relapse rates. Novel therapeutic strategies, including biased MOR agonists, opioid vaccines, and splice variant-specific agonists, offer promise for safer pain management and reduced abuse liability. However, a deeper understanding of opioid receptor signaling, neuroimmune interactions, and genetic factors is essential to develop more effective interventions. This review explores the molecular mechanisms of opioid tolerance, dependence, and withdrawal, emphasizing the need for innovative approaches to address the opioid crisis and improve treatment outcomes. |
| format | Article |
| id | doaj-art-e70b20cbf83043a9ac854299ed98f2bc |
| institution | Kabale University |
| issn | 1662-453X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neuroscience |
| spelling | doaj-art-e70b20cbf83043a9ac854299ed98f2bc2025-08-20T03:24:16ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2025-06-011910.3389/fnins.2025.15979221597922Molecular and cellular basis of mu-opioid receptor signaling: mechanisms underlying tolerance and dependence developmentMichael Swingler0Martina Donadoni1Ellen M. Unterwald2Sanjay B. Maggirwar3Ilker K. Sariyer4Department of Microbiology, Immunology and Inflammation, Center for Neurovirology and Gene Editing, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United StatesDepartment of Microbiology, Immunology and Inflammation, Center for Neurovirology and Gene Editing, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United StatesDepartment of Neural Sciences, Center for Substance Abuse Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United StatesDepartment of Microbiology, Immunology, and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, United StatesDepartment of Microbiology, Immunology and Inflammation, Center for Neurovirology and Gene Editing, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United StatesOpioids, while highly effective for pain management, are among the most addictive substances, contributing significantly to the global opioid crisis. Opioid use disorder (OUD) affects millions, with synthetic opioids like fentanyl exacerbating the epidemic due to their potency and widespread illicit availability. Opioids exert their effects through opioid receptors (ORs), primarily the mu opioid receptor (MOR), which mediates both therapeutic analgesia and adverse effects such as euphoria, dependence, and tolerance. Chronic opioid use leads to cellular adaptations, including receptor phosphorylation, desensitization, and recruitment of β-arrestin, which uncouple MOR from downstream signaling pathways. These changes, along with compensatory upregulation of adenylyl cyclase (AC) and cAMP signaling, underlie the development of tolerance, dependence, and withdrawal, however the exact signaling pathways responsible remain unknown. Emerging research highlights the role of neuroinflammation, genetic polymorphisms, and alternative splicing of MOR isoforms in modulating opioid responses and vulnerability to OUD. Current treatments for OUD, such as methadone, buprenorphine, and naltrexone, are limited by compliance, access, and relapse rates. Novel therapeutic strategies, including biased MOR agonists, opioid vaccines, and splice variant-specific agonists, offer promise for safer pain management and reduced abuse liability. However, a deeper understanding of opioid receptor signaling, neuroimmune interactions, and genetic factors is essential to develop more effective interventions. This review explores the molecular mechanisms of opioid tolerance, dependence, and withdrawal, emphasizing the need for innovative approaches to address the opioid crisis and improve treatment outcomes.https://www.frontiersin.org/articles/10.3389/fnins.2025.1597922/fullopioidstolerancedependenceopioid receptorssignalingalternative splicing |
| spellingShingle | Michael Swingler Martina Donadoni Ellen M. Unterwald Sanjay B. Maggirwar Ilker K. Sariyer Molecular and cellular basis of mu-opioid receptor signaling: mechanisms underlying tolerance and dependence development Frontiers in Neuroscience opioids tolerance dependence opioid receptors signaling alternative splicing |
| title | Molecular and cellular basis of mu-opioid receptor signaling: mechanisms underlying tolerance and dependence development |
| title_full | Molecular and cellular basis of mu-opioid receptor signaling: mechanisms underlying tolerance and dependence development |
| title_fullStr | Molecular and cellular basis of mu-opioid receptor signaling: mechanisms underlying tolerance and dependence development |
| title_full_unstemmed | Molecular and cellular basis of mu-opioid receptor signaling: mechanisms underlying tolerance and dependence development |
| title_short | Molecular and cellular basis of mu-opioid receptor signaling: mechanisms underlying tolerance and dependence development |
| title_sort | molecular and cellular basis of mu opioid receptor signaling mechanisms underlying tolerance and dependence development |
| topic | opioids tolerance dependence opioid receptors signaling alternative splicing |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2025.1597922/full |
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