{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T03:25:03Z","timestamp":1788837903481,"version":"build-2803163510"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-11-2-0077"],"award-info":[{"award-number":["W81XWH-11-2-0077"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008569","name":"Oklahoma Center for the Advancement of Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008569","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001298","name":"Presbyterian Health Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001298","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:p>Post-Traumatic Stress Disorder (PTSD) is a debilitating mental health disorder that occurs after exposure to a traumatic event. Patients with comorbid chronic pain experience affective distress, worse quality of life, and poorer responses to treatments for pain or PTSD than those with either condition alone. FDA-approved PTSD treatments are often ineffective analgesics, requiring additional drugs to treat co-morbid symptoms. Therefore, development of new treatment strategies necessitate a better understanding of the pathophysiology of PTSD and comorbid pain. The single prolonged stress (SPS) model of PTSD induces the development of persistent mechanical allodynia and thermal hyperalgesia. Increased Nociceptin\/Orphanin FQ (N\/OFQ) levels in serum and CSF accompany these exaggerated nociceptive responses, as well as increased serum levels of the pro-inflammatory cytokine tumor necrosis factor (TNF-\u03b1). Therefore, the primary goal was to determine the role of TNF-\u03b1 in the development of SPS-induced allodynia\/hyperalgesia and elevated serum and CNS N\/OFQ using two approaches: TNF-\u03b1 synthesis inhibition, and blockade with anti-TNF-\u03b1 antibody that acts primarily in the periphery. Administration of TNF-\u03b1 synthesis blocker, thalidomide (THL), immediately after SPS prevented increased TNF-\u03b1 and development of allodynia and hyperalgesia. The THL effect lasted at least 21 days, well after thalidomide treatment ended (day 5). THL also prevented SPS-induced increases in serum N\/OFQ and reversed regional N\/OFQ mRNA expression changes in the CNS. Serum TNF-\u03b1 increases detected at 4 and 24 h post SPS were not accompanied by blood brain barrier disruption. A single injection of anti-TNF-\u03b1 antibody to male and female rats during the SPS procedure prevented the development of allodynia, hyperalgesia, and elevated serum N\/OFQ, and reduced SPS-induced anxiety-like behaviors in males. Anti-TNF\u03b1 treatment also blocked development of SPS-induced allodynia in females, and blocked increased hypothalamic N\/OFQ in males and females. This suggests that a peripheral TNF-\u03b1 surge is necessary for the initiation of allodynia associated with SPS, as well as the altered central and peripheral N\/OFQ that maintains nociceptive sensitivity. Therefore, early alleviation of TNF-\u03b1 provides new therapeutic options for investigation as future PTSD and co-morbid pain treatments.<\/jats:p>","DOI":"10.3389\/fpsyt.2021.721999","type":"journal-article","created":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T02:02:51Z","timestamp":1629856971000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":28,"title":["TNF-Alpha as an Initiator of Allodynia and Anxiety-Like Behaviors in a Preclinical Model of PTSD and Comorbid Pain"],"prefix":"10.3389","volume":"12","author":[{"given":"Patrick","family":"Dib","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Ihnat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randle 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