Peripheral Receptor Mechanisms in Orofacial Muscle Pain

描述（由申请人提供）：本项目研究机械性痛觉过敏发展的外周神经机制;与持续性肌肉疼痛状况相关的突出临床特征。我们以前已经表明，外周定位的NMDA受体（NMDAR）和代谢型谷氨酸受体5（mGluR 5）是在引起急性肌肉伤害性感受以及机械痛觉过敏的重要组成部分。瞬时受体电位（TRP）家族的几个成员，特别是TRPV 1和TRPA 1，也在各种疼痛条件下的机械超敏反应的发展中发挥重要作用。由于外周谷氨酸受体的激活会引起各种细胞内信号级联反应，导致伤害感受器敏化，TRPV 1和TRPA 1都被认为是“炎症信号整合子”，因此我们提出NMDAR/mGluR 5和TRPV 1/TRPA 1在功能上相互作用，并且NMDAR/mGluR 5的激活通过多种细胞内信号通路导致TRPV 1/TRPA 1依赖性机械痛觉过敏。Aim 1通过行为药理学和体内RNAi研究评价了NMDAR/mGluR 5和TRPV 1/TRPA 1之间的功能相互作用，为三叉神经节（TG）两个受体系统之间的相互作用提供了形态学和生化基础。Aim 2中提出的实验研究了NMDAR/mGluR 5和TRPV 1相互作用的特定细胞内信号传导途径，Aim 3研究了NMDAR/mGluR 5和TRPA 1相互作用的独特细胞内信号传导机制。这里提出的综合研究将提供全面的信息外周介导的机械性痛觉过敏的新机制，并在临床肌肉疼痛条件，如颞下颌关节紊乱病的一个相对不足的领域有直接的翻译影响。 公共卫生相关性：这个项目研究了连接两个受体通道系统的细胞和分子机制，这两个受体通道系统独立地与肌肉疼痛和痛觉过敏有关。外周定位的谷氨酸受体如NMDA和I型代谢型谷氨酸受体正日益被认为是介导病理性疼痛状况发展的关键组分。我们有令人信服的初步证据表明，这些谷氨酸受体功能相互作用与TRPV 1和TRPA 1，瞬时受体电位家族的成员，这两种类型的受体系统之间的相互作用是机械性痛觉过敏所产生的颅面神经组织的重要元素。因此，该项目的结果可以提供重要的新的见解，病理性肌肉疼痛的条件和机制为基础的治疗策略，可以针对外周受体系统，以改善持续性口面肌肉疼痛的条件。

DESCRIPTION (provided by applicant): This project investigates peripheral neural mechanisms that underlie the development of mechanical hyperalgesia; a prominent clinical feature associated with persistent muscle pain conditions. We have previously shown that peripherally localized NMDA receptor (NMDAR) and metabotropic glutamate receptor 5 (mGluR5) are important components in evoking acute muscle nociception as well as mechanical hyperalgesia. Several members of the transient receptor potential (TRP) family, particularly TRPV1 and TRPA1, also play an essential role in the development of mechanical hypersensitivity under various pain conditions. Since activation of peripheral glutamate receptors invokes various intracellular signaling cascades leading to nociceptor sensitization, and both TRPV1 and TRPA1 are suggested to function as 'inflammatory signal integrators', we propose that NMDAR/mGluR5 and TRPV1/TRPA1 functionally interact and that activation of NMDAR/mGluR5 leads to TRPV1/TRPA1-dependent mechanical hyperalgesia via multiple intracellular signaling pathways. Aim1 evaluates functional interactions between NMDAR/mGluR5 and TRPV1/TRPA1 with behavioral pharmacology and in vivo RNAi studies, and provides the morphological and biochemical bases for the interactions between the two receptor systems in trigeminal ganglia (TG). Experiments proposed under Aim2 investigate specific intracellular signaling pathways underlying NMDAR/mGluR5 and TRPV1 interactions, and Aim3 examines intracellular signaling mechanisms unique for NMDAR/mGluR5 and TRPA1 interactions. The integrated studies proposed here will provide comprehensive information on novel mechanisms of peripherally mediated mechanical hyperalgesia, and have immediate translational implications in a relatively understudied area of clinical muscle pain conditions, such as temporomandibular disorders. PUBLIC HEALTH RELEVANCE: This project examines cellular and molecular mechaisms that link two receptor-channel systems that have been independently implicated in muscle pain and hyperalgesia. Peripherally localized glutamate receptors such as NMDA and type I metabotropic glutamate receptors are being increasingly recognized as critical components in mediating the development of pathological pain conditions. We have convincing preliminary evidence that these glutamate receptors functionally interact with TRPV1 and TRPA1, members of the transient receptor potential family, and that interactions between the two types of receptor systems are important elements for mechanical hyperalgesia arising from craniofacial msucle tissue. Therefore, outcomes of this project can offer important new insights in the development of pathologic muscle pain conditions and mechanism-based treatment strategies that can be directed at the peripheral receptor systems to ameliorate persistent orofacial muscle pain conditions.