The long-term goal of this project is to elucidate the mechanisms of sympathetically maintained pain (SMP). Three hypotheses are proposed regarding development and maintenance of SMP after spinal nerve ligation: 1) sympathetic sprouting in the dorsal root ganglion (DRG) is an important causal factor in SMP, 2) this ganglionic sympathetic sprouting is induced by increased levels of nerve growth factor (NGF) in the DRG, and 3) the susceptibility to SMP depends on amount of NGF production in the DRG.
Seven specific aims are formulated to test these hypotheses in the Chung model of neuropathic rat. Sympathetic sprouting in the DRG (Specific Aim 1) will be assayed by double immunofluorescent labeling of sympathetic fibers for tyrosine hydroxylase (TH) and growth associated protein GAP-43. Sympathetic synaptic varicosities and contacts, which are presumed sites of sympathetic effects on sensory neurons (Specific Aim 2), will be quantified by electron microscopic immunostaining and correlated with neuropathic pain behaviors. The types of DRG neurons with TH-baskets (Specific Aim 3) will be identified by double labeling for TH and DRG cell markers (RT97, SP, or CGRP). The NGF levels in the DRG of neuropathic rats (Specific Aim 4) will be measured by an enzyme linked immunosolvent assay (ELISA) method. The effects of anti-NGF on SMP (Specific Aim 5) will be tested by infusing anti-NGF into the DRG of neuropathic rats and then examining pain behaviors and sympathetic sprouting. The changes of NGF levels and sympathetic sprouting in the DRG of Brown Norway (BN) and Sasco Sprague-Dawley (SD) neuropathic rats, which are less susceptible to SMP, will be determined (Specific Aim 6) and correlated to pain behaviors. The effects of NGF on SMP in BN and Sasco SD neuropathic rats (Specific Aim 7) will be tested by infusing NGF into DRG of neuropathic rats and examining pain behaviors and sympathetic sprouting. Successful completion of the project should advance our understanding of the mechanisms of SMP and suggest treatments of neuropathic pain patients.
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