Temporomandibular joint disorders (TMD) include a family of conditions that present with pain in the temporomandibular joint (TMJ) and muscles of mastication. TMD is the most common non-dental orofacial pain, yet the underlying physiological and cellular mechanisms are poorly understood. Painful TMD is notable for a higher prevalence in women than men, and poor correlation between overt signs of injury and ratings of pain intensity. Reports of elevated levels of pro-inflammatory molecules in synovial fluid samples of non-osteoarthritic TMD patients suggest that low grade TMJ inflammation is a common feature of TMD, but likely goes undetected without direct synovial fluid sampling. The central hypothesis is that low grade TMJ inflammation primes trigeminal ganglion (TG) neurons and induces persistent hyperalgesia seen as altered response properties of spinomedullary (Vc/C1-2) neurons and jaw muscle activity. We propose that purinergic (P2) receptors and glial cell activation play key roles in TMJ priming and maintain hyperalgesia in a stimulus- and sex-dependent manner. The long-term goal of this project is to determine if interference with specific P2 receptors on neurons and glia are therapeutic targets for managing TMJ nociception and TMD pain in humans. A quantitative sensory testing (QST) protocol is developed to assess treatment effects on TMJ-responsive neurons. Converging lines of evidence using electrophysiological, behavioral, molecular, and anatomical approaches address three issues: 1) is transient low grade TMJ inflammation sufficient to cause persistent changes in the properties of TMJ-responsive TG and Vc/C1-2 neurons, jaw muscle activity and jaw movement; 2) what is the role of purinergic receptors in TMJ priming; and 3) what is the role of glial cells in maintenance of TMJ nociception? Unlike previous studies, this model uses a single exposure to a non-tissue damaging inflammatory agent to prime TMJ-responsive neuronal circuits in male and female rats and couples this insult to the responses of TMJ-responsive neurons with identified phenotypes.
Aim 1 establishes the QST protocol under TMJ primed conditions and determines the effects of priming on the properties of TG neurons, Vc/C1-2 neurons, on MMemg activity and jaw movement.
Aim 2 determines the expression and protein levels of P2 receptors closely associated with TG and Vc/C1-2 neurons and the role of those receptors on neural activity, jaw muscle activity and jaw movement.
Aim 3 determines the expression and protein levels of P2 receptors closely associated with satellite glia in TG and microglia at Vc/C1-2 neurons and the role of glial cell activation in TMJ hyperalgesia. Neuron-glia communication is a critical feature of persistent inflammatory hyperalgesia in other models, but remains poorly defined in TMJ nociception. When coupled with neural recording and jaw muscle reflexes, inhibition of P2 receptors closely associated with neurons or glia, inhibition of inflammasome formation by microglia and blockade of glia-specific secretory products by pharmacological and interference RNA approaches will enhance the understanding of neural mechanisms underlying persistent TMJ hyperalgesia.
Temporomandibular joint disorders are common craniofacial pain conditions of uncertain etiology. Low grade joint inflammation may prime pain pathways to over-react to subsequent insult. Understanding how pain pathways become sensitized may suggest new strategies to manage jaw pain.
