Study of Activity-Dependent Sympathetic Sprouting

交感神经系统（SNS）在调节疼痛和炎症中的作用已经很好地- 在动物模型中建立。在临床上，交感神经阻滞常用于治疗神经病理性疼痛 例如CRPS。最近的一项临床研究证明了其疗效，显示出戏剧性和有希望的结果 使用导管方法来提供比通过注射实现的更持久的交感神经阻滞， 顽固性神经性疼痛患者。我们的小组揭示了SNS介导的疼痛的潜在机制 我们在过去20年的合作者包括：活动相关SNS萌芽; 自发活动;免疫和炎症反应;感觉神经元簇放电。我们报道 最近，持续的神经性疼痛是由活跃的神经再生驱动的。我们的初步数据还 显示交感神经介导的巨噬细胞活化可能在神经再生中很重要， 神经损伤后的神经元存活。最有趣的是，我们发现交感神经介导的免疫/炎症 当邻近坐骨淋巴结转移时，反应，神经再生和疼痛行为可以逆转， (LN)被删除，这表明SNS-淋巴结相互作用可能对发展至关重要， 神经性疼痛的管理。我们假设交感神经萌芽及其与感觉神经的相互作用 神经损伤后的神经元是神经保护性的，交感神经激活促进细胞存活， 由于增加神经/轴突再生而增强疼痛。我们进一步假设SNS介导了 免疫反应，神经再生，和细胞存活的操纵巨噬细胞活化，并在 至少部分地通过与相邻淋巴结的相互作用。这一假设将在三个具体目标中得到检验 (SA)SA 1：确定周围神经损伤后交感神经支配是否具有神经保护作用。SA2： 在小鼠模型中研究细胞死亡、再生和巨噬细胞亚型之间的关系， 神经性疼痛SA 3：确定邻近淋巴结（LN）在交感神经系统中的作用和功能 调节免疫反应、神经再生和细胞存活。我们的假设提出了一些新的 概念，并代表了交感神经对疼痛和炎症的影响的研究的新方向。的 拟议的研究将首次调查和表征交感神经对神经元的影响， 存活，感觉神经节水平的轴突再生，及其与淋巴结的相互作用， 神经性疼痛病症，其具有高发病率、高成本和高发病率，并且对于其有效治疗 通常是不可用的或不令人满意的。

The role of the sympathetic nervous system (SNS) in regulating pain and inflammation has been well- established in animal models. In the clinic, sympathetic blockade is often used for managing neuropathic pain such as CRPS. The efficacy was evidenced by a recent clinical study showing dramatic and promising results using a catheter approach to provide longer lasting sympathetic blockade than is achieved by injection, in patients with intractable neuropathic pain. Mechanisms underlying SNS-mediated pain revealed by our group and our collaborators in the past 20 years include: activity associated SNS sprouting; generation of spontaneous activity; immune and inflammatory response; clustered firing of sensory neurons. We reported recently that persistent neuropathic pain is driven by active nerve regeneration. Our preliminary data also showed that sympathetic-mediated macrophage activation may be important in nerve regeneration as well as neuronal survival after nerve injury. Most interestingly, we found sympathetic-mediated immune/inflammatory responses, nerve regeneration, and pain behaviors could be reversed when the adjacent sciatic lymph node (LN) was removed, suggesting SNS-lymph node interactions may be critical for the development and possibly management of neuropathic pain. We hypothesize that sympathetic sprouting and its interactions with sensory neurons after nerve injury are neuroprotective and that sympathetic activation promotes cell survival but enhances pain due to increased nerve/axonal regeneration. We further hypothesize that SNS mediates immune responses, nerve regeneration, and cell survival by manipulation of macrophage activation, and, at least, partially, by interactions with adjacent lymph nodes. The hypothesis will be tested in three specific aims (SA): SA1: To determine whether sympathetic innervation is neuroprotective after peripheral nerve injury. SA2: To examine the relationships between cell death, regeneration, and macrophage subtypes in mouse models of neuropathic pain. SA3: To determine the role and function of adjacent lymph nodes (LN) in sympathetic regulation of immune response, nerve regeneration and cell survival. Our hypothesis proposes some novel concepts and represents a new direction for the study of sympathetic influences on pain and inflammation. The proposed studies will investigate and characterize, for the first-time, the sympathetic influences on neuronal survival, axonal regeneration at the level of sensory ganglia, and its interactions with lymph nodes in neuropathic pain conditions, which have high incidence, cost, and morbidity and for which effective treatments are often unavailable or unsatisfactory.