We will explore the signals that regulate the excitability of the peripheral terminals of nociceptor neurons and the synaptic contacts they make with dorsal horn neurons following peripheral inflammation. We propose that peripheral and central sensitization are both driven by the inflammatory mediators PGE2, bradykinin and IL1 beta. We propose that the transient receptor potential channel TRPA1 is a receptor-operated channel for PGE2, BK and IL1 on sensory neurons, and that the TTX-resistant Nav1.9 sodium channel is an effector of increased nociceptor sensitivity. We hypothesize that IL1 contributes to the acute and delayed phases of peripheral and central sensitization by acting directly on nociceptors to increase excitability and transmitter release, as well as by inducing COX-2 in the periphery and CMS. We will examine the effects of IL1 on pain-related behavior and its downstream requirement for Nav1.9, and TRPA1. How IL1 increases the excitability of nociceptor neurons will be investigated electrophysiologically and by calcium imaging in DRG cultures and IL1's effect on transmitter release will be studied in adult spinal cord slices. We propose that BK contributes to central sensitization by acting presynaptically on A-delta and C-fiber afferent central terminals to increase glutamate release, and postsynaptically on dorsal horn neurons to increase glutamate responsiveness. We will test if the presynaptic action of BK in the dorsal horn involves Nav1.9 or TRPA1 and acts after peripheral inflammation via it B1 receptor. We will study if PGE2's actions on DRG neurons are dependent on TRPA1 and Nav1.9. The particular role of COX-2 expressed in immune cells or neurons to peripheral and central sensitization will be studied using cell-specific conditional knockouts of COX-2 and the extent to which bradykinin and IL1 act via COX-2 in the periphery and dorsal horn to produce their sensitizing actions, will be determined. The overall aim is to understand the immediate and delayed mechanisms that contribute in the periphery and spinal cord to the development of inflammatory pain. Understanding the molecular mechanisms involved will help reveal targets for developing novel analgesics. ? ?
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