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. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Pan, Baohan; Grunewald, Benedikt; Nguyen, Thien et al. (2012) The lateral thoracic nerve and the cutaneous maximus muscle--a novel in vivo model system for nerve degeneration and regeneration studies. Exp Neurol 236:6-18
Farah, Mohamed H; Pan, Bao Han; Hoffman, Paul N et al. (2011) Reduced BACE1 activity enhances clearance of myelin debris and regeneration of axons in the injured peripheral nervous system. J Neurosci 31:5744-54
Shim, Beom; Ringkamp, Matthias; Lambrinos, George L et al. (2007) Activity-dependent slowing of conduction velocity in uninjured L4 C fibers increases after an L5 spinal nerve injury in the rat. Pain 128:40-51
Campbell, James N; Meyer, Richard A (2006) Mechanisms of neuropathic pain. Neuron 52:77-92
Guan, Yun; Borzan, Jasenka; Meyer, Richard A et al. (2006) Windup in dorsal horn neurons is modulated by endogenous spinal mu-opioid mechanisms. J Neurosci 26:4298-307
Ringkamp, Matthias; Meyer, Richard A (2005) Injured versus uninjured afferents: Who is to blame for neuropathic pain? Anesthesiology 103:221-3
Murinson, Beth B; Archer, David R; Li, Yongbo et al. (2005) Degeneration of myelinated efferent fibers prompts mitosis in Remak Schwann cells of uninjured C-fiber afferents. J Neurosci 25:1179-87
Murinson, Beth Brianna; Hoffman, Paul Ned; Banihashemi, Michael Reza et al. (2005) C-fiber (Remak) bundles contain both isolectin B4-binding and calcitonin gene-related peptide-positive axons. J Comp Neurol 484:392-402
Sheth, Rishi N; Dorsi, Michael J; Li, Yongbo et al. (2002) Mechanical hyperalgesia after an L5 ventral rhizotomy or an L5 ganglionectomy in the rat. Pain 96:63-72
Wu, Gang; Ringkamp, Matthias; Murinson, Beth B et al. (2002) Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents. J Neurosci 22:7746-53