Functional Interactions Between Peripheral P2X3 and TRP Channels

描述（由申请人提供）：肌筋膜疼痛状况，包括与颞下颌关节和肌肉疾病（TMD）相关的疼痛，影响了数百万人。这些情况极难治疗，往往使患者的生活质量很差。这项应用的长期目标有两个方面：1)阐明机械性痛觉过敏（与肌筋膜疼痛状况（如TMD）相关的主要症状）发展的新细胞信号机制；2)利用这一科学努力作为获得知识和技能的培训工具，成为一名成功的独立疼痛科学家。P2X3受体是一种非选择性阳离子通道，与伤害性加工有关，包括介导机械性痛觉过敏。TRPV1和TRPA1 （TRPV1/A1）通道先前也与肌肉中机械性痛觉过敏的发生有关。它们被认为是促炎受体激活后的炎症信号整合者。初步数据表明，直接激活P2X3可诱导机械性痛觉过敏，而用TRPV1/A1拮抗剂预处理同一块肌肉可抑制这种痛觉过敏。钙渗透性P2X3通道激活可能导致信号级联反应的启动，从而导致CaMKII和PKC等激酶的激活，这些激酶已知对TRP通道敏感。本研究建议使用行为分析、钙成像和生化手段来表征P2X3和TRPV1/A1之间的功能相互作用。这些相同的技术也将用于阐明介导这些相互作用的信号通路。在肌炎条件下机械性痛觉过敏的新机制的确定可能有助于TMD和其他肌肉疼痛条件管理的替代治疗策略。

DESCRIPTION (provided by applicant): Myofascial pain conditions, including those associated with temporomandibular joint and muscle disorder (TMD) affect millions of people. These conditions are extremely difficult to treat, often leaving patients with a poor quality of life. The long-term objective of this application is two-fold: 1) to elucidate novel cellular signaling mechanisms underlying the development of mechanical hyperalgesia, a major symptom associated with myofascial pain conditions such as TMD and 2) to use this scientific endeavor as a training vehicle for acquiring the knowledge and skills needed to become a successful independent pain scientist. P2X3 receptors are nonselective cation channels that have been implicated in nociceptive processing, including the mediation of mechanical hyperalgesia. TRPV1 and TRPA1 (TRPV1/A1) channels have also previously been implicated in the development of mechanical hyperalgesia in muscle. They are suggested to be inflammatory signal integrators following the activation of pro-inflammatory receptors. Preliminary data suggests direct activation of P2X3 induces mechanical hyperalgesia and pretreatment of the same muscle with TRPV1/A1 antagonists inhibits this hyperalgesia. Calcium permeable P2X3 channel activation could lead to the initiation of signaling cascades which results in the activation of kinases such as CaMKII and PKC, which are known to sensitize TRP channels. This study proposes to use behavioral assays, calcium imaging, and biochemical means to characterize the functional interactions between P2X3 and TRPV1/A1. These same techniques will also be used to elucidate the signaling pathways mediating these interactions. The identification of new mechanisms underlying mechanical hyperalgesia during myositis conditions could contribute to alternative treatment strategies for the management of TMD and other muscle pain conditions. PUBLIC HEALTH RELEVANCE: Orofacial muscle pain particularly that associated with temporomandibular joint and muscle disorder affects approximately 12% of the population. The currently available treatments are inadequate because of the ambiguity surrounding the underlying pathology of the condition. In accordance with the missions of the NIDCR and the FOA: PA-10-108 this study proposes to 1) determine novel cellular mechanisms linking purinergic and TRP channels which could serve as future therapeutic targets and 2) provide a vehicle for the development and training of a rising pain scientist.