Peripheral Receptor Mechanisms in Orofacial Muscle Pain

描述(由申请人提供)：这个项目调查了机械性痛觉过敏发展的外周神经机制；这是与持续性肌肉疼痛条件相关的一个显著的临床特征。我们以前已经证明，外周定位的NMDAR和代谢型谷氨酸受体5(MGluR5)是诱发急性肌肉伤害性感觉和机械性痛敏的重要成分。瞬时受体电位(TRP)家族的几个成员，特别是TRPV1和TRPA1，在各种疼痛条件下的机械超敏反应的发展中也发挥着重要作用。由于外周谷氨酸受体的激活启动了多种细胞内信号转导通路，导致伤害性感受器敏化，TRPV1和TRPA1被认为是“炎性信号整合因子”，我们认为NMDAR/mGluR5和TRPV1/TRPA1在功能上相互作用，NMDAR/mGluR5的激活通过多条细胞内信号通路导致依赖TRPV1/TRPA1的机械性痛敏。AIM1通过行为药理学和体内RNAi研究评价NMDAR/mGluR5和TRPV1/TRPA1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形态和生化基础。在AIM2下提出的实验研究了NMDAR/mGluR5和TRPV1相互作用下特定的细胞内信号通路，而Aim3研究了NMDAR/mGluR5和TRPA1相互作用特有的细胞内信号机制。这里提出的综合研究将提供关于外周介导的机械性痛敏的新机制的全面信息，并对临床肌肉疼痛状况相对较少研究的领域，如颞下颌关节紊乱病，具有直接的翻译意义。 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已经独立地牵涉到肌肉疼痛和痛觉过敏。外周定位的谷氨酸受体，如NMDA和I型代谢型谷氨酸受体，越来越被认为是介导病理性疼痛发生发展的关键成分。我们有令人信服的初步证据表明，这些谷氨酸受体与瞬时受体潜力家族成员TRPV1和TRPA1在功能上相互作用，并且这两种类型的受体系统之间的相互作用是头面部粘膜组织产生机械性痛敏的重要因素。因此，该项目的成果可以为病理性肌肉疼痛状况的发展和基于机制的治疗策略的发展提供重要的新见解，这些策略可以针对外周受体系统来改善持续性口面部肌肉疼痛状况。

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.