INTERACTIONS OF TRPV1 AND TRPA1 AND INFLAMMATORY PAIN

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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.