Neural Transplants and Spinal Neuropathic Pain Processes

外周或中枢神经系统损伤引起的疼痛通常是持续性的和使人衰弱的， 这是一个重大的临床挑战，因为它对传统疗法没有很好的反应。潜在的假设 提出这项研究的动机是脊髓或周围神经损伤引起的严重慢性疼痛 脊髓抑制过程的丧失和随之而来的背角疼痛的异常兴奋性 传递神经元，并且通过神经移植恢复脊髓抑制将减轻 神经性疼痛为了实现这一点，外周和中枢模型的损伤引起的疼痛将 评估神经病理学和干细胞移植策略。慢性压迫性损伤模型 (CCI)将用于外周神经性疼痛，使君子酸模型（QUIS）用于兴奋性毒性脊髓损伤。 脊髓损伤疼痛。目的1将描述和比较脊髓背侧抑制性神经元细胞丢失 角和随之而来的夸大疼痛后CCI和QUIS。目标2将描述和比较 CCI和QUIS后脊髓背角神经元的异常激活和过度兴奋。研究 这两个目标将包括深入评价脊髓的形态学和神经化学变化， 可能导致抑制性丧失和异常过度兴奋（GABA神经元丧失或 功能障碍），感觉处理的改变（夸大的行为反应和c-fos激活， 对有害和无害刺激的反应），以及背角神经元兴奋性的生理变化 建立模型和治疗干预措施之间的比较基础。目标3-5将探讨 神经祖细胞移植物替代脊髓中丧失或功能障碍的抑制性神经回路的用途 背角周围神经或脊髓损伤。目标3将产生一个可靠的和可重复的 外源性GABA能神经前体细胞移植（营养因子 休克）、遗传操作（阻断HLH转录因子Hes 1以促进GABA能分化） 和/或细胞选择（GAD启动子-GFP和FACS分选）。目的4将评价GABA能神经元 祖细胞移植策略在恢复脊髓抑制和减轻慢性神经病和 中枢性疼痛目的5将评估嗜铬细胞和GABA能神经前体细胞共移植策略， 嗜铬细胞产生营养因子的混合物，其改善神经干细胞存活， 分化，并且可以减少慢性神经性和SCI疼痛。这些研究的结果应该会导致 改善顽固性神经病理性疼痛的干预策略。

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.