Neural Transplants and Spinal Neuropathic Pain Processes

Project: Research project

Project Details

Description

Pain from injury to the peripheral or central nervous system is often persistent and debilitating, and presents
a significant clinical challenge as it does not respond well to traditional therapies. The underlying hypothesis
and motivation for the proposed studies is that severe chronic pain from spinal cord or peripheral nerve injury
results from loss of spinal inhibitory processes and consequent abnormal hyperexcitability in dorsal horn pain
transmission neurons, and that restoration of spinal inhibition by neural transplantation will alleviate
neuropathic pain. In order to accomplish this, peripheral and central models of injury-induced pain will be
evaluated for neuropathology and stem cell transplantation strategies. The chronic constriction injury model
(CCI) will be used for peripheral neuropathic pain and the quisqualic acid model (QUIS) for excitotoxic spinal
cord injury pain. Aim 1 will characterize and compare the inhibitory neuronal cell loss in the spinal dorsal
horn and consequent exaggerated pain following CCI and QUIS. Aim 2 will characterize and compare the
abnormal activation and hyperexcitability of spinal dorsal horn neurons following CCI and QUIS. Studies in
these 2 aims will includes in depth evaluation of morphological and neurochemical changes in the spinal
dorsal horn that likely contribute to inhibitory loss and abnormal hyperexcitability (GABA neuronal loss or
dysfunction), alterations in sensory processing (exaggerated behavioral responses and c-fos activation in
response to noxious and innocuous stimuli), and physiological alterations in dorsal horn neuronal excitability
to establish a comparative basis between the models and treatment interventions. Aims 3-5 will explore the
use of neural progenitor transplants to replace lost or dysfunctional inhibitory neurocircuitry in the spinal
dorsal horn following peripheral nerve or spinal cord injury. Aim 3 will generate a reliable and reproducible
source of GABAergic neural progenitor cells for transplantation using extrinsic manipulation (trophic factor
shock), genetic manipulation (blocking HLH transcription factor Hes1 to promote GABAergic differentiation)
and/or cell selection (GADpromoter-GFP and FACS sorting). Aim 4 will evaluate GABAergic neural
progenitor transplantation strategies in restoring spinal inhibition and alleviating chronic neuropathic and
central pain. Aim 5 will evaluate chromaffin cell and GABAergic neural progenitor co-grafting strategies, as
chromaffin cells produce a cocktail of trophic factors which improve neural stem cell survival and
differentiation, and can reduce chronic neuropathic and SCI pain. Findings from these studies should lead to
improved interventive strategies in the management of intractable neuropathic pain.
StatusFinished
Effective start/end date7/1/061/31/11

Funding

  • National Institute of Neurological Disorders and Stroke: $334,267.00
  • National Institute of Neurological Disorders and Stroke: $334,267.00
  • National Institute of Neurological Disorders and Stroke: $334,267.00
  • National Institute of Neurological Disorders and Stroke: $343,313.00
  • National Institute of Neurological Disorders and Stroke: $100,980.00

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