INTERACTIONS OF TRPV1 AND TRPA1 AND INFLAMMATORY PAIN

炎症性疼痛的管理是一项重大的科学和卫生保健挑战，许多目前使用的镇痛药不能充分缓解疼痛。以机械为基础的疼痛管理方法可能有助于提出有效和新颖的假设，改善靶点选择，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。炎症性疼痛有外周性和中枢性成分。研究炎性疼痛的外周机制是特别感兴趣的，因为它提供了开发具有最小中枢神经系统副作用的镇痛药的潜力。这是一个在过去十年中有快速进展的领域，尽管我们对炎症性疼痛的外周机制的理解仍然不完整。

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.