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Disruption of endogenous descending pain control pathways may contribute to chronic pain after TBI. In prior work, we found that TBI induces a two-stage pain dysregulation involving acute mechanical hindpaw hypersensitivity that resolves by 28 days post-injury (DPI), followed by chronic failure of descending control of nociception (DCN) lasting up to 180 DPI. However, the impact of sex on the dysfunction of endogenous pain control systems after TBI has not been explored. Using a lateral fluid percussion model of TBI in male and female rats, we assessed mechanical nociceptive responses using von Frey fibers and tested pharmacological interventions targeting established descending pain modulatory systems. We employed the selective noradrenergic (NA) reuptake inhibitor, reboxetine, the selective serotonin reuptake inhibitor, escitalopram, adrenoceptor antagonists\u2019 prazosin (\u03b1\n                    <jats:sub>1<\/jats:sub>\n                    -adrenoceptors) and atipamezole (\u03b1\n                    <jats:sub>2<\/jats:sub>\n                    -adrenoceptors), and the serotonin 5-HT\n                    <jats:sub>3<\/jats:sub>\n                    receptor antagonist, ondansetron. Findings revealed that acute hindlimb hypersensitivity involved enhanced descending serotonergic pain facilitation via the 5-HT\n                    <jats:sub>3<\/jats:sub>\n                    receptor in both sexes. In uninjured rats, pain control relies on descending NA inhibitory signaling via spinal \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    -adrenoceptors. Boosting noradrenaline in the acute phase after TBI with reboxetine reduced acute mechanical pain, but studies with selective adrenoceptor antagonists revealed a persistent switch from an \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    - to an \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    -adrenoceptor-driven antinociceptive pathway after TBI in both males and females. Acute phase mechanical pain resolved by 28 DPI, exposing a chronic phase of DCN failure up to 180 DPI. Reboxetine treatment restored the DCN response in female TBI rat via \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    -adrenoceptor but failed in male TBI rats. Restoration of the DCN response in male TBI rats was restored by enhancing serotonin signaling with escitalopram. These results demonstrate key differences in the susceptibility of endogenous pain modulatory pathways and the adaptations of those pathways between male and female rats after TBI. These findings suggest that sex needs to be considered when designing mechanism-based therapies for pain after TBI.\n                  <\/jats:p>","DOI":"10.1177\/08977151251413263","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T13:08:46Z","timestamp":1770124126000},"page":"1158-1172","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["The Impact of Sex on the Dysfunction of Endogenous Pain Control after Traumatic Brain Injury"],"prefix":"10.1177","volume":"43","author":[{"given":"Karen-Amanda","family":"Irvine","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, California, USA."},{"name":"Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam R.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Brain and Spinal Injury Center, Department of Neurosurgery, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA."},{"name":"San Francisco Veterans Affairs Healthcare System, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. David","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, California, USA."},{"name":"Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3171\/2017.10.JNS17352"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature16035"},{"key":"e_1_3_2_4_2","unstructured":"(CDC) CfDCaP. Centers for Disease Control and Prevention (CDC) CDC; 2023. TBI data [Internet]. Available from: https:\/\/www.cdc.gov\/traumaticbraininjury\/data\/index.htm [Last accessed: September28 2023]."},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2009.03.011"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/pm\/pnx153"},{"key":"e_1_3_2_7_2","volume-title":"Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects","author":"Thomas TC","year":"2015","unstructured":"Thomas TC, , Colburn TA, , Korp K, et al. Translational considerations for behavioral impairment and rehabilitation strategies after diffuse traumatic brain injury. In: Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. (Kobeissy FH ed.) 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