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Temporomandibular disorder (TMD) is an oral dentofacial disease that is related to multiple factors such as disordered dental occlusion, emotional stress, and immune responses. In the past decades, tumor necrosis factor-alpha (TNF-α), a pleiotropic cytokine, has provided valuable insight into the pathogenesis of TMD, particularly in settings associated with inflammation. It is thought that TNF-α participates in the pathogenesis of TMD by triggering immune responses, deteriorating bone and cartilage, and mediating pain in the temporomandibular joint (TMJ). Initially, TNF-α plays the role of "master regulator" in the complex immune network by increasing or decreasing the production of other inflammatory cytokines. Then, the effects of TNF-α on cells, particularly on chondrocytes and synovial fibroblasts, result in pathologic cartilage degradation in TMD. Additionally, multiple downstream cytokines induced by TNF-α and neuropeptides can regulate central sensitization and inflammatory pain in TMD. Previous studies have also found some therapies target TMD by reducing the production of TNF-α or blocking TNF-α-induced pathways. All this evidence highlights the numerous associations between TNF-α and TMD; however, they are currently not fully understood and further investigations are still required for specific mechanisms and treatments targeting specific pathways. Therefore, in this review, we explored general mechanisms of TNF-α, with a focus on molecules in TNF-α-mediated pathways and their potential roles in TMD treatment. In view of the high clinical prevalence rate of TMD and damage to patients' QOL, this review provides adequate evidence for studying links between inflammation and TMD in further research and investigation.

Despite of many years of research, the data regarding interactions between the peripheral nervous system and the immune system remain incomplete. Most discoveries concern nociceptive signaling pathways. Among pain conditions with the utmost social implications, a large percentage exhibits the inflammatory process as an underlying cause. Here the most prominent are several disorders associated with the trigeminal nerve, including migraine, trigeminal neuralgia, and temporomandibular disorders. The molecular mechanisms of the trigeminal nociceptive transmission in general, and chronic trigeminal pain in particular, are almost completely unknown. Recent studies have shown that cytokines IL-1beta, IL-6 and TNF-alpha play a very important role in the pathogenesis of the immune response within the peripheral endings of trigeminal ganglion neurons. It has also been demonstrated that some proinflammatory cytokines (e.g., IL-1beta, TNF-alpha) are capable of sensitizing nociceptive neurons. Modulation of inflammatory response can thus influence pain reaction.

The pathophysiology of temporomandibular joint pain is not well understood. A significant amount of research has been conducted to evaluate synovial fluid in these patients and in healthy controls. Qualitative and quantitative analyses of the synovial fluid have shown a significant difference between these groups. A multitude of inflammatory mediators and degradation products have been identified. The concentration of these products has been shown to correlate with several clinical parameters including pain, chronicity, severity of degenerative change, and response to treatment. A common inflammatory pathway would appear to be involved in most patients. At the present time, synovial fluid analysis does not have the sensitivity or specificity to allow specific diagnoses and targeted treatment. Continued research with the specific aim of establishing more appropriate therapeutic modalities based on the biochemical pathways is warranted.

The present study was designed to test the hypothesis that estrogen exacerbates inflammation of the temporomandibular joint (TMJ). Evans blue dye was used to quantify plasma extravasation (PE) around the rat TMJ. In an initial set of experiments, TMJ PE was compared in naïve intact male and female rats, as well as in both groups after complete Freund's adjuvant (CFA)-induced inflammation of the TMJ. In contrast to our hypothesis, TMJ PE was significantly greater in both naïve and CFA-inflamed male rats than in females. To determine whether these differences were due to gonadal hormones, four additional groups of rats were studied: gonadectomized (Gx) males and females, Gx males with chronic testosterone (T) replacement, and Gx females with chronic estrogen (E) replacement. The sex difference in baseline TMJ PE appeared to reflect the actions of T. However, in the presence of TMJ inflammation, T augmented TMJ PE in males, while E attenuated TMJ PE in females. Changes in PE were also assessed in the contralateral TMJ. Results from this analysis indicated that there is a transient contralateral increase in TMJ PE in females but not males. Given that there is an inverse relationship between PE and joint damage, our results suggest that testosterone may mitigate, but estrogen may exacerbate, TMJ damage, particularly in the presence of overt inflammation. Importantly, our results may help explain both the higher prevalence and severity of temporomandibular disorder pain in females than males.