Functional Interactions Between Peripheral P2X3 and TRP Channels

描述（由申请人提供）：肌筋膜疼痛的条件，包括那些与颞下颌关节和肌肉疾病（TMD）影响数百万人。这些疾病极难治疗，往往使患者的生活质量很差。本申请的长期目标是双重的：1）阐明机械性痛觉过敏（与肌筋膜疼痛病症（例如TMD）相关的主要症状）发展的基础的新的细胞信号传导机制，和2）使用这种科学奋进作为获得成为成功的独立疼痛科学家所需的知识和技能的训练工具。P2 X3受体是非选择性阳离子通道，参与伤害性处理，包括介导机械性痛觉过敏。TRPV 1和TRPA 1（TRPV 1/A1）通道以前也参与肌肉中机械性痛觉过敏的发展。它们被认为是促炎受体激活后的炎症信号整合剂。初步数据表明，P2 X3的直接激活诱导机械性痛觉过敏，并且用TRPV 1/A1拮抗剂预处理相同的肌肉抑制这种痛觉过敏。钙渗透性P2 X3通道激活可导致信号级联的启动，这导致激酶如CaMKII和PKC的激活，已知这些激酶使TRP通道敏感。本研究拟采用行为学分析、钙离子成像和生化手段来表征P2 X3和TRPV 1/A1之间的功能性相互作用。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。在肌炎条件下的机械痛觉过敏的新机制的识别可能有助于替代治疗策略的管理TMD和其他肌肉疼痛的条件。 公共卫生相关性：口面部肌肉疼痛，特别是与颞下颌关节和肌肉疾病影响约12%的人口。目前可用的治疗是不够的，因为周围的模糊的基础病理条件。根据NIDCR和FOA：PA-10-108的任务，本研究提出：1）确定连接嘌呤能和TRP通道的新细胞机制，这些机制可作为未来的治疗靶点; 2）为新兴疼痛科学家的发展和培训提供工具。

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.