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和衰弱的，并表现为 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 拟议研究的动机是脊髓或周围神经损伤引起的严重慢性疼痛 脊髓抑制突起的丧失和由此导致的背角疼痛的异常兴奋性 通过神经移植恢复脊髓抑制将缓解 神经性疼痛。为了实现这一点，损伤引起的疼痛的外周和中枢模型将 对神经病理学和干细胞移植策略进行评估。慢性压迫性损伤模型的建立 (CCI)将用于周围神经病理性疼痛，Quququic酸模型(QUIS)将用于兴奋性毒性脊髓 脐带损伤疼痛。目的1描述和比较脊髓背侧抑制性神经细胞丢失 喇叭和随之而来的CCI和QUIS后的夸大疼痛。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高兴奋性。研究项目： 这两个目标将包括深入评估脊柱的形态和神经化学变化。 可能导致抑制性丧失和异常兴奋性(GABA神经元丧失或 功能障碍)，感觉加工的改变(夸大的行为反应和c-fos激活 对有害和无害刺激的反应)和背角神经元兴奋性的生理性改变 建立模型和治疗干预措施之间的比较基础。AIMS 3-5将探索 应用神经前体细胞移植替代丢失或功能障碍的脊髓抑制性神经回路 周围神经或脊髓损伤后的背角。目标3将产生一个可靠和可重现的 外源性操作(营养因子)用于移植的GABA能神经前体细胞来源 休克)、基因操作(阻断HLH转录因子Hes1以促进GABA能分化) 和/或细胞选择(GAD启动子-GFP和FACS分选)。AIM 4将评估GABA能神经 祖细胞移植策略在恢复脊髓抑制和缓解慢性神经病变中的作用 中枢疼痛。Aim 5将评估嗜铬细胞和GABA能神经前体细胞共移植的策略，如 嗜铬细胞产生一种营养因子的混合物，这些营养因子可以改善神经干细胞的存活和 分化，并可减轻慢性神经病理性疼痛和脊髓损伤。这些研究的结果应该会导致 改进治疗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.