INTERACTIONS OF TRPV1 AND TRPA1 AND INFLAMMATORY PAIN

炎性疼痛的管理代表了一个主要的科学和卫生保健挑战，目前使用的许多镇痛药提供的疼痛缓解不足。基于机制的疼痛管理方法可能有助于有效和新颖的假设的发展，并改善目标选择，协助动物疼痛模型的开发和分析，并最终为临床试验的设计提供信息。炎症性疼痛有外周和中枢两种成分。对炎性疼痛的外周机制的研究特别令人感兴趣，因为它提供了开发具有最小CNS副作用的镇痛剂的潜力。这是一个在过去十年中取得快速进展的领域，尽管我们对炎症性疼痛的外周机制的理解仍然不完整。 在本申请中，我们提出测试的主要假设，TRPA1和TRPV1通道之间的功能相互作用在炎症诱导的刺激的感觉神经元的整合中起着关键作用。根据这一假设，炎症介质对TRPA1通道的激活和致敏作用由复合物内的TRPV1通道直接控制，该复合物通过充当TRPA1通道的调节剂来实现这些作用。我们的具体目标是： 具体目标1：确定TRPA1和TRPV1通道是否是感觉神经元中受体复合物的一部分，以及该复合物是否表现出新的表型。 具体目标#2：确定TRPV1是否通过蛋白激酶C（PKC）和感觉神经元中的炎症介质缓激肽控制TRPA1介导的反应的敏化。 具体目标#3：确定在感觉神经元中炎症诱导的由TRPA 1介导并由TRPV 1控制的二酰基甘油和2-花生四烯酸甘油反应是否 这一概念上的创新假说提出了感觉神经元整合炎症刺激的独特机制，具有很强的科学和医学意义。

The management of inflammatory pain represents a major scientific and health care challenge and many currently used analgesics provide inadequate pain relief. A mechanistic-based approach to pain management might contribute to the development of valid and novel hypotheses and improve target selection, assist the development and analysis of animal pain models, and eventually inform the design of clinical trials. Inflammatory pain has peripheral and central components. Research into peripheral mechanisms of inflammatory pain is of particular interest since it offers the potential for developing analgesics with minimal CNS side effects. This is an area in which there have been rapid advances over the past decade, although our understanding of peripheral mechanisms of inflammatory pain still remains incomplete. In this application, we propose to test the primary hypothesis that a functional interaction between TRPA1 and TRPV1 channels plays a key role in the integration of inflammation-induced stimuli by sensory neurons. According to this hypothesis, activation and sensitization of the TRPA1 channel by inflammatory mediators are directly controlled by the TRPV1 channel within a complex that fulfills these actions by serving as a modulator to the TRPA1 channel. Our specific aims will: Specific Aim #1: Determine whether TRPA1 and TRPV1 channels are a part of a receptor complex in sensory neurons and whether this complex exhibits a novel phenotype. Specific Aim #2: Determine whether TRPV1 controls the sensitization of the TRPA1-mediated responses by protein kinase C (PKC) and an inflammatory mediator bradykinin in sensory neurons. Specific Aim #3: Determine whether inflammation-induced diacylglycerol and 2-arachydonic glycerol responses mediated by TRPA1 and controlled by TRPV1 in sensory neurons This conceptually innovative hypothesis which proposes distinct mechanisms of integration of inflammatory stimuli by sensory neurons has strong potential for scientific and medical implications.