• S L McIlwrath, R Nesemeier, F Ma, H S Oz, L Zhang, and K N Westlund.
• Department of Physiology, College of Medicine, University of Kentucky, Lexington, USA.
• Eur J Pain. 2017 Aug 1; 21 (7): 1209-1223.

BackgroundPatients with temporomandibular joint disorders (TMD), reactive arthritis and rheumatoid arthritis often have combined etiology of hereditary and microenvironmental factors contributing to joint pain. Multiple clinical and animal studies indicate 'double-hit' inflammatory insults can cause chronic inflammation. The first inflammatory insult primes the immune system and subsequent insults elicit amplified responses. The present 'double hit' study produced a chronic orofacial pain model in mice with genetic deletion of both TNFα receptors (TNFR1/R2-/-), investigating the main nociceptive signalling pathways in comparisons to wild type mice.MethodsAn initial inflammatory insult was given unilaterally into the temporomandibular joint (TMJ). 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 TNFR1/R2-/- mice. Serum cytokines were analysed at Days 1, 14, and Week 18.ResultsThe double hit insult produced chronic hypersensitivity continuing through the 4-month experimental timeline in the absence of TNFα signalling. P2X7 and NMDA receptor antagonists temporarily attenuated chronic hypersensitivity. Serum cytokine/chemokine analysis on Day 14 when CFA induced hypersensitivity was resolved identified increased levels of pro-inflammatory cytokines CCL2, CXCL9, CXCL10, RANTES and decreased levels of anti-inflammatory cytokines IL-1ra and IL-4 in TNFR1/R2-/- compared to WT mice.ConclusionsThese data suggest a causal feed-forward signalling cascade of these little studied cytokines have the potential to cause recrudescence in this orofacial inflammatory pain model in the absence of TNFα signalling.SignificanceUsing a mouse model of chronic inflammatory temporomandibular joint disorder, we determined that absence of functional TNFR1/R2 induces aberrant inflammatory signalling caused by other increased pro-inflammatory and decreased anti-inflammatory cytokines that could serve as blood biomarkers and may predict disease progression.© 2017 European Pain Federation - EFIC®.

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