Functional peripheral and central vagal neural circuits of interoception inhibiting pain

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TMDs are conditions that cause pain and dysfunction in the jaw, the masticatory muscles, and associated head and neck musculoskeletal structures. The prevalence among U.S. adults is 24%, and more than 15 million patients are affected by severe pain and limited mandibular motion, resulting in reduced quality of life and a high economic burden. Despite these costs, the exact mechanisms by which biomarkers or biomarker signatures occur in TMD patients are not well known, nor is it clear what specific molecules at the level of the primary sensory neuron or peripheral TMJ region mediate the transition to chronic, persistent jaw joint and muscle pain. As a result, treatment options for these patients are severely limited. In this proposal, we will perform single cell and tissue RNA sequence analysis and shotgun lipidomic analysis of temporomandibular joint (TMJ) relevant to the transduction, transmission, and regulation of TMD pain. Our objective is to delineate biomarkers and biomarker signatures and to identify novel targets of non-opioid therapeutics to improve the management of patients with TMD pain. In our analysis of biomarkers and/biomarker signatures in TMD pain, we will consider the unique neurobiology of TMJ and orofacial regions. First, different orofacial tissues and regions, including TMJ, likely contribute differentially to TMD pain. Since the retrodiscal tissues are highly innervated by peripheral nerves and are highly vascularized compared to other regions, such malpositioning increases direct mechanical irritation of the retrodiscal tissues during joint functions, which leads to inflammatory changes and further pathologies. In addition, the orofacial region, especially masseter muscle, which connects the mandible to the cheekbone may also be damaged and/or inflamed by TMJ injury. The masseter muscle is used for chewing and jaw clenching. Muscle overuse from tooth-grinding and jaw-clenching cause the muscle to become tense, inflamed, and painful. Thus, retrodiscal tissues and masseter muscle might provide ideal targets for non-opioid therapeutics for pain therapy. Second, sex is an important biological variable. Since TMD pain is highly prevalent in females, we will have a primary focus on this population and on the role of sex hormone regulation and receptors in pain regulation. We presume that injury induces substantial changes in TMJ neurobiology and molecular signature particularly in young females. Third, in addition to nociceptive sensory afferents localized in trigeminal ganglia (TG), TMJ is also innervated by vagal afferents. Our preliminary data suggest that TMJ vagal afferents can inhibit hyperalgesia induced by TMJ injury suggesting they can modulate severity of TMD pain. Therefore, we will undertake genetic and lipidomic assays of vagal ganglia projecting to TMJ. In Aim 1, we will delineate biomarkers and/or biomarker signatures of TMD pain in peripheral TMJ tissues and TG and vagal ganglia (VG) neurons projecting to TMJ (RNA sequencing and lipidomics) in mice. Biomarkers and/or biomarker signatures from TMD pain will be screened by RNA sequencing and lipidomics assays using TMJ tissue and orofacial tissue. We will determine the landscape of lipids by identification and quantification of individual lipid species (potentially thousands) and polyphosphoinositide classes and will identify altered metabolic pathways in TMJ afferents and TG and VG from injured and control mice using multi-dimensional mass spectrometry-based shotgun lipidomics (MDMS-SL). In Aim 2, we will Identify targets for non-opioid therapeutics in inflamed TMJ and orofacial regions in humans. Our RNA sequencing and lipidomics analysis promise to provide genetic and lipidomic information and insight into the dynamics of the TMJ and orofacial tissue in healthy and inflamed TMJ from mice and humans. We expect the findings will facilitate identification of novel targets for development of non-opioid therapeutics for TMD pain.