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Chronic pain is prevalent and interferes with post-injury functioning and quality of life, whereas substance use disorder (SUD) is the third most common neuropsychiatric diagnosis after TBI. Neither of these conditions has a clear mechanistic explanation based on the known pathophysiology of TBI. Dynorphin is an endogenous opioid neuropeptide that is significantly dysregulated after TBI. Both dynorphin and its primary receptor, the \u0138-opioid receptor (KOR), are implicated in the neuropathology of chronic pain and SUD. Here, we review the known roles of dynorphin and KORs in chronic pain and SUDs. We synthesize this information with our current understanding of TBI and highlight potential mechanistic parallels between and across conditions that suggest a role for dynorphin in long-term sequelae after TBI. In pain studies, dynorphin\/KOR activation has either antinociceptive or pro-nociceptive effects, and there are similarities between the signaling pathways influenced by dynorphin and those underlying development of chronic pain. Moreover, the dynorphin\/KOR system is considered a key regulator of the negative affective state that characterizes drug withdrawal and protracted abstinence in SUD, and molecular and neurochemical changes observed during the development of SUD are mirrored by the pathophysiology of TBI. We conclude by proposing hypotheses and directions for future research aimed at elucidating the potential role of dynorphin\/KOR in chronic pain and\/or SUD after TBI.<\/jats:p>","DOI":"10.1089\/neu.2021.0063","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T12:53:29Z","timestamp":1636462409000},"page":"1-19","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":14,"title":["Endogenous Opioid Dynorphin Is a Potential Link between Traumatic Brain Injury, Chronic Pain, and Substance Use Disorder"],"prefix":"10.1177","volume":"39","author":[{"given":"Kaitlin M.","family":"Best","sequence":"first","affiliation":[{"name":"Department of Nursing and Clinical Care Services, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."},{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa M.","family":"Mojena","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon A.","family":"Barr","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."},{"name":"Department of Anesthesiology and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."},{"name":"Department of Psychology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heath D.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health Sciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."},{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiva S.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."},{"name":"Department of Anesthesiology and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"e_1_3_4_2_2","first-page":"Services","article-title":"Surveillance Report of Traumatic Brain Injury-related Emergency Department Visits, Hospitalizations, and Deaths: United States 2006-2014","author":"Peterson A.B.","year":"2019","unstructured":"Peterson A.B., , Xu L., , Daugherty J., , and Breiding M.J. 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