Regulation of masticatory myalgia development by distinct trigeminal neuron subtypes innervating masseter muscle

点击翻译按钮获取中文摘要

Project Summary/Abstract Temporomandibular disorders affecting the muscles of mastication (TMDM) are the most prevalent group of chronic orofacial pain conditions. TMDM chronic pain arising from the masseter muscle (MM) is common. My long-term goals are to elucidate the underlying mechanisms controlling the development of TMDM chronicity and to understand the function and TMDM-induced plasticity of neurons innervating the MM. I recently demonstrated that the MM of mice and primates is predominantly innervated by myelinated A-fibers with unique electrophysiological characteristics and receptor compositions. To further unravel the identity of these neurons we performed single-cell RNA sequencing and have identified unique types of neurons that innervate the MM. Selective markers can be used for specific manipulation of activities for these neuronal clusters. The main objective of this proposal is to define the contribution of MM innervating TG neuronal groups in the progress of TMDM chronicity. The central hypothesis of this proposal is that neurons innervating the MM have specialized neuron type-dependent distinct contributions in the development of TMDM chronicity and undergo unique plasticity of mechano-gated responses during TMDM. To test this hypothesis, our newly developed clinically relevant model of chronic masseteric muscle pain (myalgia) in mice will be employed. Aim 1 will define the contribution of different types of neurons innervating the MM in the development of TMDM by measuring mechanical hypersensitivity using grimace scores, von Frey, conditioned place avoidance, and bite force. To do this, we will exploit the availability of transgenic mouse lines and our single-cell data for manipulation of neuronal activities for specific groups of TG neurons innervating MM. Designer Receptors Exclusively Activated by Designer Drugs (DREADD) will be used to inhibit neuronal activities. Aim 2 will examine the impact of TMDM on mechano-gated responses in neuronal groups innervating the MM. Our single-cell RNA sequencing data indicates that neuronal groups innervating MM all express the mechanically gated PIEZO-2 channel but at considerably different levels. We hypothesize that neurons innervating the MM have distinct neuron type- dependent responses to mechanical stimuli, and TMDM-driven plasticity. Whole-cell patch-clamp electrophysiology will be used to investigate mechano-gated current properties in different TG neuronal groups innervating MM in naïve and TMDM mice at the initiation of pain. Finally, using in vivo imaging, regulation of different mechanical modalities by TMDM condition will be assessed. The results from this proposal will have a positive impact by outlining novel therapeutic strategies and candidate targets for the prevention and treatment of debilitating masticatory myalgia.