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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051667-03
Application #
7354812
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2006-07-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
3
Fiscal Year
2008
Total Cost
$334,267
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Jergova, Stanislava; Gajavelli, Shyam; Pathak, Nirmal et al. (2016) Recombinant neural progenitor transplants in the spinal dorsal horn alleviate chronic central neuropathic pain. Pain 157:977-89
Jergova, Stanislava; Gajavelli, Shyam; Varghese, Mathew S et al. (2016) Analgesic Effect of Recombinant GABAergic Cells in a Model of Peripheral Neuropathic Pain. Cell Transplant 25:629-43
Nasirinezhad, Farinaz; Jergova, Stanislava; Pearson, James P et al. (2015) Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy. Neuropharmacology 95:100-9
Jergova, Stanislava; Hentall, Ian D; Gajavelli, Shyam et al. (2012) Intraspinal transplantation of GABAergic neural progenitors attenuates neuropathic pain in rats: a pharmacologic and neurophysiological evaluation. Exp Neurol 234:39-49
Hama, Aldric; Sagen, Jacqueline (2012) Combinations of intrathecal gamma-amino-butyrate receptor agonists and N-methyl-d-aspartate receptor antagonists in rats with neuropathic spinal cord injury pain. Eur J Pharmacol 683:101-8
Hama, Aldric; Sagen, Jacqueline (2009) Antinociceptive effects of the marine snail peptides conantokin-G and conotoxin MVIIA alone and in combination in rat models of pain. Neuropharmacology 56:556-63
Furmanski, Orion; Gajavelli, Shyam; Lee, Jeung Woon et al. (2009) Combined extrinsic and intrinsic manipulations exert complementary neuronal enrichment in embryonic rat neural precursor cultures: an in vitro and in vivo analysis. J Comp Neurol 515:56-71
Hentall, Ian D; Burns, Scott B (2009) Restorative effects of stimulating medullary raphe after spinal cord injury. J Rehabil Res Dev 46:109-22
Lee, Jeung Woon; Furmanski, Orion; Castellanos, Daniel A et al. (2008) Prolonged nociceptive responses to hind paw formalin injection in rats with a spinal cord injury. Neurosci Lett 439:212-5
Herzberg, Uri; Hama, Aldric; Sagen, Jacqueline (2008) Spinal subarachnoid adrenal medullary transplants reduce hind paw swelling and peripheral nerve transport following formalin injection in rats. Brain Res 1198:85-92

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