Peripheral Receptor Mechanisms in Orofacial Muscle Pain

口面部肌肉疼痛的外周受体机制

• 批准号: 8250277
• 负责人: JIN Y Ro
• 金额: $ 35.27万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250277
• 关键词: Acute; Area; Behavioral; Behavioral Assay; Biochemical; Clinical; Co-Immunoprecipitations; Data; Development; Elements; Etiology; Family; Glutamate Receptor; Hyperalgesia; Hypersensitivity; Image Analysis; Immunohistochemistry; Inflammatory; Investigation; Label; Lead; Link; Mechanics; Mediating; Metabotropic Glutamate Receptors; Molecular; Muscle; Muscle Development; Myalgia; Myofascial Pain Syndromes; Myopathy; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Nociception; Nociceptors; Outcome; Pain; Pathologic; Pathology; Peripheral; Phosphorylation; Play; RNA Interference; Rattus; Receptor Activation; Recruitment Activity; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Stimulus; Structure of trigeminal ganglion; System; TRPV1 gene; Temporomandibular Joint Disorders; Tissues; Transducers; base; behavioral pharmacology; clinically significant; craniofacial; in vivo; insight; interdisciplinary approach; knock-down; member; metabotropic glutamate receptor 5; neuromechanism; novel; novel therapeutic intervention; orofacial; protein complex; public health relevance; receptor; research study; treatment strategy

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.

描述（由申请人提供）：该项目研究机械痛觉过敏发生的周围神经机制；与持续性肌肉疼痛相关的一个突出的临床特征。我们之前已经表明，外周定位的 NMDA 受体 (NMDAR) 和代谢型谷氨酸受体 5 (mGluR5) 是诱发急性肌肉伤害感受和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 TRPV1 和 TRPA1，在各种疼痛条件下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会引发各种细胞内信号级联反应，导致伤害感受器敏化，并且 TRPV1 和 TRPA1 都被认为充当“炎症信号整合器”，因此我们提出 NMDAR/mGluR5 和 TRPV1/TRPA1 功能上相互作用，并且 NMDAR/TRPA1 的激活mGluR5 通过多种细胞内信号通路导致 TRPV1/TRPA1 依赖性机械痛觉过敏。 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，并为三叉神经节（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 提出的实验研究了 NMDAR/mGluR5 和 TRPV1 相互作用背后的特定细胞内信号传导途径，而 Aim3 则研究了 NMDAR/mGluR5 和 TRPA1 相互作用独特的细胞内信号传导机制。这里提出的综合研究将提供关于外周介导的机械痛觉过敏的新机制的全面信息，并且对临床肌肉疼痛病症（例如颞下颌疾病）的研究相对较少的领域具有直接的转化意义。 公共健康相关性：该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涉及肌肉疼痛和痛觉过敏。外周定位的谷氨酸受体（例如 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病症发展的关键成分。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电位家族成员 TRPV1 和 TRPA1 存在功能性相互作用，并且两种类型受体系统之间的相互作用是颅面肌组织引起机械痛觉过敏的重要因素。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提供重要的新见解，这些策略可以针对外周受体系统以改善持续性口面部肌肉疼痛状况。