Sustained and repeated mouth opening leads to development of painful temporomandibular disorders involving macrophage/microglia activation in mice

Temporomandibular disorder (TMD) is a set of heterogeneous musculoskeletal conditions involving the temporomandibular joint (TMJ) and/or the masticatory muscles. Up to 33% of the population has had at least 1 symptom of TMD with 5% to 10% of them requiring treatment. Common symptoms include limited jaw movement, joint sound, and pain in the orofacial area. Once TMD becomes chronic, it can be debilitating with comorbidities that greatly reduce one's overall quality of life. However, the underlying mechanism of TMD is unclear because of the multicausative nature of the disease. Here, we report a novel mouse model of TMD where a bite block was placed in between the upper and lower incisors such that the mouth was kept maximally open for 1.5 hours per day for 5 days. After sustained mouth opening, mice developed persistent orofacial mechanical allodynia and TMJ dysfunction. At the cellular level, we found masseter muscle dystrophy, and increased proteoglycan deposition and hypertrophic chondrocytes in the mandibular condyle. Increased F4/80 macrophages were also observed in the masseter muscles and the TMJ posterior synovium. We also found ATF3 neuronal injury and increased F4/80 macrophages in the trigeminal ganglia. Microglia activation was observed in the trigeminal subnucleus caudalis. Inhibiting macrophage and microglia activation with a colony stimulating factor-1 receptor inhibitor prevented the development of orofacial mechanical allodynia, but not TMJ dysfunction. This study suggests that mouth opening for an extended period during dental treatments or oral intubations may risk the development of chronic TMD and inflammation associated with macrophage and microglia in the tissue and trigeminal system contributes to the development of TMD pain.