Functional Interactions Between Peripheral P2X3 and TRP Channels

描述(由申请人提供)：肌筋膜疼痛状况，包括那些与颞下颌关节和肌肉紊乱(TMD)相关的情况，影响着数百万人。这些疾病极难治疗，往往会让患者的生活质量变差。这项应用的长期目标有两个：1)阐明机械性痛敏发生的新的细胞信号机制，机械性痛觉过敏是与TMD等肌筋膜疼痛相关的主要症状；2)将这一科学努力用作培训工具，以获得成为一名成功的独立疼痛科学家所需的知识和技能。P2X3受体是一种非选择性阳离子通道，参与了包括机械性痛觉过敏在内的伤害性反应。TRPV1和TRPA1(TRPV1/A1)通道也与肌肉机械性痛敏的发生有关。它们被认为是促炎受体激活后的炎症信号整合因子。初步数据表明，直接激活P2X3可引起机械性痛觉过敏，而用TRPV1/A1拮抗剂对同一肌肉进行预处理可抑制这种痛觉过敏。钙通透性的P2X3通道的激活可以导致信号级联的启动，从而导致CaMKII和PKC等已知的使Trp通道敏感的激酶的激活。这项研究建议使用行为分析、钙成像和生化方法来表征P2X3和TRPV1/A1之间的功能相互作用。这些同样的技术也将被用来阐明介导这些相互作用的信号通路。肌炎条件下机械性痛敏的新机制的识别有助于替代治疗TMD和其他肌肉疼痛情况的治疗策略。 公共卫生相关性：口腔面部肌肉疼痛，特别是与颞下颌关节和肌肉疾病相关的疼痛，影响着大约12%的人口。目前可用的治疗方法是不充分的，因为围绕这种疾病的基本病理的模棱两可。根据NIDCR和FOA：PA-10-108的使命，这项研究建议：1)确定连接嘌呤能和色氨酸通道的新的细胞机制，这些机制可以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.