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 include 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 (GAD promoter-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. ? ? ?
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