Remak bundle structure and function in neuropathic pain

Remak 束结构和神经病理性疼痛的功能

• 批准号: 6540395
• 负责人: JOHN W GRIFFIN
• 金额: $ 37.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-05 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540395
• 关键词: C fiber; Schwann cells; afferent nerve; capsaicin; confocal scanning microscopy; dorsal root; electron microscopy; electrophysiology; hyperalgesia; laboratory rat; neurogenesis; nociceptors; receptor sensitivity; sensory neuropathy; spinal nerves; statistics /biometry; sympathectomy; wallerian degeneration

DESCRIPTION: Neuropathic pain occurs in a variety of peripheral nerve diseases, including diabetic and HI V-associated neuropathies, as well as nerve injuries. The mechanisms underlying neuropathic pain remain incompletely understood. Animal models of neuropathic pain based on partial nerve injuries have provided important insights. Using a modification of the spinal nerve ligation (SNL) model of Chung in which the rat L5 mixed spinal root was ligated and transected, we have confirmed the development of mechanical and thermal hyperalgesia in the hindpaw. Three observations from our labs using this modified SNL lesion underlie the proposed studies: 1) The hyperalgesia is not reversed by an L5 dorsal rhizotomy. 2) Spontaneous activity develops in intact C fibers of the adjacent, uninjured L4 dorsal root. 3) There is prominent remodeling of the Remak bundles containing surviving C fibers in the sciatic nerve and its distal branches. These observations are most economically explained by the hypothesis that Wallerian degeneration in the distal nerve plays an important role in neuropathic pain. An attractive possibility is that the Remak bundles of the distal sciatic system frequently contain C fibers from more than one spinal root, so that when the L5 root is transected many Remak bundles are only partially denervated. The Schwann cells of these Remak bundles are postulated to respond as though they were wholly denervated, with production of excessive amounts of growth factors (e.g., NGF) and cytokines (e.g., TNF-alpha). The increased NGF is taken up by the surviving (L4) C fibers of that Remak bundle and transported back to the nerve cell bodies, where it induces expression of proteins (e.g., sodium channels) associated with increased excitability. This sequence could contribute to hyperalgesia as well as central sensitization. These processes could be especially relevant to slowly progressive degenerative neuropathies involving small nerve fibers, many of which have spontaneous pain and hyperalgesia. The proposed studies are centered around a three-way analysis of hyperalgesia, morphological changes in the distal nerve including Remak bundle remodeling, and spontaneous activity in C fibers of the adjacent, uninjured IA root. A set of lesions to the L5 spinal root system was chosen to dissect out the underlying mechanisms: 1) L5 dorsal root ganglionectomy to produce a selective lesion of primary afferents, 2) capsaicin application to the L5 mixed spinal root to produce a selective lesion of nociceptive afferents, 3) L5 ventral rhizotomy to produce a selective lesion of myelinated motor efferents, and 4) bilateral lumbar sympathectomy to produce a selective lesion of sympathetic efferents. We will also investigate if molecular changes in or relevant to the remodeled Remak bundles account for the spontaneous activity in the L4 C fibers. This research should provide additional insights into the mechanisms underlying neuropathic pain.

描述：神经性疼痛发生在多种周围神经疾病中， 包括糖尿病和HI V相关的神经病以及神经损伤。 神经性疼痛的基础机制尚未完全理解。 基于部分神经损伤的神经性疼痛的动物模型已提供 重要的见解。使用脊柱神经结扎（SNL）的修饰 Chung的模型，其中大鼠L5混合脊髓结扎并 转移，我们已经确认了机械和热的发展 后爪中的痛苦。我们实验室的三个观察 修改后的SNL病变是拟议的研究：1）Hypergeria不是 由L5背侧根茎逆转。 2）自发活动在完整中发展 相邻的，未受伤的L4背根的C纤维。 3）有突出 重塑装有坐骨神经中含有存储的C纤维的Remak捆绑包 神经及其远端分支。这些观察在经济上是最经济的 解释了远端神经中的沃勒利变性的假设 在神经性疼痛中起重要作用。有吸引力的可能性是 远端坐骨系统的Remak捆绑包经常包含来自的C纤维 一个以上的脊髓根，因此当L5 root转换时，许多remak 捆绑包仅部分取代。这些remak束的雪旺单元 假设回应好像他们完全被剥夺了， 产生过多的生长因子（例如NGF）和细胞因子 （例如，TNF-Alpha）。 NGF的增加是由幸存的（L4）C纤维所吸收的 那个remak捆绑包，然后将其运回神经细胞体 诱导与蛋白质（例如，钠通道）的表达 提高兴奋性。这个序列也可能导致痛风 作为中心敏化。这些过程可能与 涉及小神经纤维的缓慢进行性退化性神经病，许多 其中有自发的疼痛和痛觉过敏。拟议的研究是 围绕三向痛觉分析，形态学变化 远端神经，包括remak束重塑，并在 C相邻的，未受伤的IA根的纤维。 L5脊柱的一组病变 选择根系以剖定潜在机制：1）L5背侧 根神经节切除术以产生主要传入的选择性病变，2） 辣椒素施用到L5混合脊髓中以产生选择性病变 伤害性传入，3）L5腹侧根茎切开术，以产生选择性病变 骨髓运动发出和4）双侧腰椎交感神经切除术 交感神经的选择性病变。我们还将调查是否 分子变化或与重塑的Remak捆绑包有关 L4 C纤维中的自发活性。这项研究应提供 对神经性疼痛的基础机制的更多见解。