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生的外周神经机制；与持续性肌肉疼痛状况相关的突出临床特征。我们之前已经表明，外周定位的NMDA受体（NMDAR）和代谢性谷氨酸受体5 （mGluR5）是引起急性肌肉伤害感觉和机械性痛觉过敏的重要成分。瞬时受体电位（TRP）家族的一些成员，特别是TRPV1和TRPA1，也在各种疼痛条件下机械性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可调用多种细胞内信号级联，导致伤害感受器致敏，并且TRPV1和TRPA1都被认为是“炎症信号整合者”，我们认为NMDAR/mGluR5和TRPV1/TRPA1在功能上相互作用，NMDAR/mGluR5的激活通过多种细胞内信号通路导致TRPV1/TRPA1依赖性的机械痛觉过敏。Aim1通过行为药理学和体内RNAi研究评估NMDAR/mGluR5和TRPV1/TRPA1之间的功能相互作用，为三叉神经节（TG）中两个受体系统之间的相互作用提供形态学和生化基础。Aim2研究了NMDAR/mGluR5和TRPV1相互作用的细胞内信号通路，Aim3研究了NMDAR/mGluR5和TRPA1相互作用的细胞内信号机制。本文提出的综合研究将提供有关外周介导的机械性痛觉过敏新机制的全面信息，并对临床肌肉疼痛状况（如颞下颌疾病）的研究相对不足的领域具有直接的转化意义。

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.