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

支配咬肌的不同三叉神经元亚型对咀嚼肌痛发展的调节

• 批准号: 10678376
• 负责人: Karen Lindquist
• 金额: $ 4.14万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678376
• 关键词: Acceleration; Affect; Afferent Neurons; Anatomy; Basic Science; Behavioral Assay; Bite; Bite Force; Cardiovascular system; Cells; Cessation of life; Characteristics; Chronic; Clinical; Complex; Data; Deglutition; Development; Devices; Disease; Electrophysiology (science); Epidemic; Fiber; Foundations; Functional disorder; Gene Expression Profile; Genetic; Goals; Grant; Health; Hypersensitivity; Injury; Investigation; Kidney; Knowledge; Learning; Machine Learning; Masseter Muscle; Mastication; Masticatory muscles; Measures; Mechanics; Mechanoreceptors; Mediating; Modality; Modeling; Mus; Muscle Development; Musculoskeletal Pain; Myalgia; Neurites; Neuroglia; Neurologic; Neuronal Plasticity; Neurons; Opioid; Orofacial Pain; Overdose; Pain; Pain management; Peripheral; Persons; Piezo 2 ion channel; Prevention; Primates; Property; Published Comment; Regulation; Research; Risk Factors; Role; Scientist; Smiling; Substance abuse problem; Temporomandibular Joint Disorders; Testing; Time; Training; Transgenic Mice; Translational Research; Trigeminal System; Work; base; behavioral phenotyping; burden of illness; candidate marker; career; chronic pain; clinically relevant; collagenase; defined contribution; designer receptors exclusively activated by designer drugs; disability; genetic signature; in vivo imaging; masticatory myalgia; mechanical stimulus; mouse model; multidisciplinary; muscular structure; novel therapeutic intervention; opioid overuse; orofacial; pain relief; patch clamp; prevent; receptor; response; single cell analysis; single cell sequencing; single-cell RNA sequencing; social; therapeutic target

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.

项目摘要/摘要 影响咀嚼肌的颞下颌关节紊乱病(TMDM)是最常见的 慢性口腔面部疼痛状况。由咬肌(MM)引起的TMDM慢性疼痛是常见的。我的 长期目标是阐明控制TMDM慢性化发展的潜在机制 最近，为了了解支配MM的神经元的功能和TMDM诱导的可塑性 结果表明，小鼠和灵长类动物的多发性骨髓瘤主要由有髓A纤维支配，具有独特的 电生理特性和受体组成。为了进一步解开这些神经元的身份 我们进行了单细胞RNA测序，并确定了支配MM的独特类型的神经元。 选择性标记物可用于对这些神经元簇的活动进行特定操作。主 本研究的目的是明确MM支配三叉神经节神经元群在大鼠脑缺血再灌注损伤过程中的作用。 TMDM慢性化。这一提议的中心假设是，支配MM的神经元具有专门的 神经元类型依赖在TMDM慢性化和TMDM发生中的不同作用 TMDM过程中机械门控反应的独特可塑性。为了验证这一假设，我们新开发的 将采用临床相关的小鼠慢性咀嚼肌痛(肌痛)模型。目标1将定义 不同类型神经元支配MM在TMDM形成中的作用 使用鬼脸评分、冯·弗雷、条件性位置回避和咬合力的机械过敏。去做 因此，我们将利用转基因小鼠品系和我们的单细胞数据来操纵神经元 特异组TG神经元对MM-Designer受体的激活作用 特制药物(DREADD)将被用来抑制神经元活动。目标2将研究TMDM的影响 支配MM的神经元群的机械门控反应。我们的单细胞RNA测序数据 提示支配MM的神经元群均表达机械门控的PIZO-2通道，但在 有相当不同的水平。我们假设支配MM的神经元有不同的神经元类型- 对机械刺激的依赖反应，以及TMDM驱动的可塑性。全细胞膜片钳 电生理学将被用来研究不同TG神经元群的机械门控电流特性 幼稚小鼠和TMDM小鼠在疼痛开始时对MM的神经支配。最后，利用活体成像，调节 将根据TMDM条件评估不同的机械形式。这项提案的结果将会有一个 通过概述新的治疗策略和预防和治疗的候选目标产生积极影响 令人衰弱的咀嚼肌痛。