{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T13:59:58Z","timestamp":1777039198893,"version":"3.51.4"},"reference-count":74,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2017,3,20]],"date-time":"2017-03-20T00:00:00Z","timestamp":1489968000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS039041"],"award-info":[{"award-number":["R01 NS039041"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Patients with temporomandibular joint disorders (<jats:styled-content style=\"fixed-case\">TMD<\/jats:styled-content>), reactive arthritis and rheumatoid arthritis often have combined etiology of hereditary and microenvironmental factors contributing to joint pain. Multiple clinical and animal studies indicate \u2018double\u2010hit\u2019 inflammatory insults can cause chronic inflammation. The first inflammatory insult primes the immune system and subsequent insults elicit amplified responses. The present \u2018double hit\u2019 study produced a chronic orofacial pain model in mice with genetic deletion of both <jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content>\u03b1 receptors (<jats:styled-content style=\"fixed-case\">TNFR<\/jats:styled-content>1\/R2\u2212\/\u2212), investigating the main nociceptive signalling pathways in comparisons to wild type mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An initial inflammatory insult was given unilaterally into the temporomandibular joint (<jats:styled-content style=\"fixed-case\">TMJ<\/jats:styled-content>). Secondary hypersensitivity was tested on the skin over the TMJ throughout the experiment. Three weeks later after complete reversal of hypersensitivity, a second inflammatory insult was imposed on the colon. Pharmacological interventions were tested for efficacy after week 10 when hypersensitivity was chronic in <jats:styled-content style=\"fixed-case\">TNFR<\/jats:styled-content>1\/R2\u2212\/\u2212 mice. Serum cytokines were analysed at Days 1, 14, and Week 18.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The double hit insult produced chronic hypersensitivity continuing through the 4\u2010month experimental timeline in the absence of <jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content>\u03b1 signalling. P2X7 and <jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content> receptor antagonists temporarily attenuated chronic hypersensitivity. Serum cytokine\/chemokine analysis on Day 14 when <jats:styled-content style=\"fixed-case\">CFA<\/jats:styled-content> induced hypersensitivity was resolved identified increased levels of pro\u2010inflammatory cytokines <jats:styled-content style=\"fixed-case\">CCL<\/jats:styled-content>2, <jats:styled-content style=\"fixed-case\">CXCL<\/jats:styled-content>9, <jats:styled-content style=\"fixed-case\">CXCL<\/jats:styled-content>10, <jats:styled-content style=\"fixed-case\">RANTES<\/jats:styled-content> and decreased levels of anti\u2010inflammatory cytokines <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101ra and <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20104 in <jats:styled-content style=\"fixed-case\">TNFR<\/jats:styled-content>1\/R2\u2212\/\u2212 compared to <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These data suggest a causal feed\u2010forward signalling cascade of these little studied cytokines have the potential to cause recrudescence in this orofacial inflammatory pain model in the absence of <jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content>\u03b1 signalling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Using a mouse model of chronic inflammatory temporomandibular joint disorder, we determined that absence of functional <jats:styled-content style=\"fixed-case\">TNFR<\/jats:styled-content>1\/R2 induces aberrant inflammatory signalling caused by other increased pro\u2010inflammatory and decreased anti\u2010inflammatory cytokines that could serve as blood biomarkers and may predict disease 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