Functional Interactions Between Peripheral P2X3 and TRP Channels

外设 P2X3 和 TRP 通道之间的功能交互

• 批准号: 8060323
• 负责人: Jami Lynn Saloman
• 金额: $ 3.2万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060323
• 关键词: Affect; Arthralgia; Behavioral; Behavioral Assay; Biochemical; Biological Assay; Calcium; Cations; Chronic; Coupling; Cytoplasm; Data; Development; Etiology; Event; Exhibits; Family; Functional disorder; Future; G-Protein-Coupled Receptors; Human; Hyperalgesia; Image; Image Analysis; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Knowledge; Lead; Left; Link; Masseter Muscle; Mechanics; Mediating; Mediation; Mission; Molecular; Muscle; Myalgia; Myofascial Pain Syndromes; Myopathy; Myositis; National Institute of Dental and Craniofacial Research; Neurons; Nociception; Nociceptors; Outcomes Research; Pain; Pathology; Patients; Peripheral; Phosphorylation; Phosphotransferases; Population; Preparation; Process; Purinoceptor; Quality of life; Rattus; Reporting; Scientist; Signal Pathway; Signal Transduction; Spinal Ganglia; Stimulus; Structure of trigeminal ganglion; Symptoms; TRPV1 gene; Techniques; Temporomandibular Joint; Temporomandibular Joint Disorders; Time; Training; Transducers; Work; alternative treatment; analog; base; calmodulin-dependent protein kinase II; cost; craniofacial; design; in vivo; inhibitor/antagonist; member; novel; orofacial; receptor; relating to nervous system; research study; skills; therapeutic target; treatment strategy

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.

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障碍（TMD）相关的疾病。这些疾病极难治疗，通常使患者的生活质量差。该应用的长期目标是两倍：1）阐明机械性痛觉过敏发展的新型细胞信号传导机制，这是与肌筋膜疼痛状况（例如TMD和2）相关的主要症状，例如使用这项科学的努力作为获得成功独立疼痛科学家所需的知识和技能的训练工具。 P2X3受体是与伤害性处理有关的非选择性阳离子通道，包括机械性痛觉过敏的介导。 TRPV1和TRPA1（TRPV1/A1）通道先前还与肌肉机械性痛觉过敏的发展有关。促炎受体激活后，建议它们为炎症信号积分器。初步数据表明，P2X3的直接激活会诱导机械性痛觉过敏，并用TRPV1/A1拮抗剂对同一肌肉进行预处理，抑制了这种痛觉过敏。钙可渗透的P2X3通道激活可能导致信号级联反应的启动，这导致激活CAMKII和PKC等激活，这些激活已知会使TRP通道敏感。这项研究建议使用行为测定，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。鉴定在肌炎条件下机械性痛觉过敏的新机制可能有助于治疗TMD和其他肌肉疼痛状况的替代治疗策略。 公共卫生相关性：口面肌肉疼痛，特别是与颞下颌关节和肌肉疾病有关的肌肉疼痛会影响大约12％的人群。当前可用的治疗方法不足，因为围绕该病情的潜在病理的歧义。根据NIDCR和FOA的任务：PA-10-108，本研究提出了1）确定连接嘌呤能和TRP通道的新型细胞机制，这些机制可以用作未来的治疗靶标和2）为疼痛科学家的开发和培训提供了一种工具。