The present proposals are based on three unifying postulates: that spontaneous activity in a population of C fiber nociceptors is capable of driving neuropathic pain;that the nociceptors responsible for driving neuropathic pain include TrkA-positive nociceptors that have received excessive amounts of nerve growth factor (NGF);and that this excessive NGF can be derived either from collateral sprouting of uninjured nociceptors into denervated regions of the skin. Thus degeneration and loss of neighboring nerve fibers will be sufficient to result in this excessive NGF signaling in the intact nerve fibers. The proposed studies represent a multidisciplinary collaborative effort, with new measures of electrophysiological changes, new models of selective nociceptor injury, and a new genetically engineered mouse in which a TrkA receptor kinase mutation is """"""""knocked-in"""""""" so that the TrkA is blocked in its signaling by a small molecule inhibitor, 1NMPP1 that has no effect on wild-type TrkA. We find that administration of the inhibitor eliminates CGRP+ nociceptors from the skin of the hindfoot within 8 days, leaving only the Ret+ positive nociceptors. This preparation will allow assessment of the physiology and behavior produced by the Ret+ in isolation. We also find that these mice have markedly blunted pain behaviors in models on inflammatory pain (CFA) and neuropathic pain (L5 spinal nerve ligation). These studies will define the role of TrkA-positive neurons in the generation of neuropathic pain. We have established the methodologic requirements to carry out all aspects of this research in mice, including physiologic measures of activity- dependent changes in C fiber conduction and behavioral testing for mechanical and thermal hyperalgesia. We have also developed a new system for examining collateral sprouting in the mouse hindfoot, using sparing of the saphenous nerve. The proposed data will have implications for understanding and treating not just pain in partial nerve injuries, but painful neuropathies such as diabetes, causalgia, and postherpetic neuralgia.
