Study of Activity Dependent Sympathetic Sprouting

临床上，许多慢性疼痛状况因交感神经系统的活动而恶化或甚至依赖于交感神经系统的活动。 神经系统交感神经阻滞通常在临床上用于慢性疼痛病症，但临床和病理学研究表明， 这种做法的临床前证据是矛盾和不完整的。然而，最近的一项研究表明， 显示了使用导管方法提供更持久的交感神经的戏剧性和有希望的结果， 在顽固性疼痛患者中，大多数临床前研究都集中在 关于慢性疼痛模型中感觉和交感神经系统之间的异常相互作用。 根据我们的初步数据和最近的出版物，我们提出，某些疾病的发生和持续 病理性疼痛状况需要感觉神经系统的完整交感神经支配 交感神经递质的释放增强了感觉神经节的局部炎症， 神经节并导致疼痛。感觉神经节中的局部炎症反应甚至在远端神经损伤后也会发生。 因此，这种现象对于理解许多类型的慢性疼痛状况很重要。我们 初步数据显示，疼痛行为和炎症反应大幅、快速和持久减少， 在神经性和炎性疼痛模型中，在“微交感神经切除术”（mSYMPX）之后。这 手术包括仅切断腰部感觉神经的灰支（交感节后纤维 神经节mSYMPX避免了大多数先前研究中使用的化学或外科交感神经切除术的许多影响， 例如原发性和继发性免疫组织的交感神经去支配。由于交感神经支配 这些组织中的一些是抗炎的，全局交感神经切除术可能掩盖了促炎性 在感觉神经节水平的影响。mSYMPX方法也更具临床相关性，因为患者通常 局部交感神经阻滞该假设将在3个具体目标中进行测试：1）表征 mSYMPX对疼痛的发展和持续性以及对DRG中局部炎症的影响。的 将测试mSYMPX在疼痛后的作用，以及其对免疫细胞浸润的作用。 显微镜下观察感觉神经节。2)探讨交感神经系统的分子机制， 调节DRG中的炎症反应。mSYMPX对局部细胞因子水平和免疫功能的影响 基于我们的初步发现，促炎细胞因子诱导的细胞极化将被检查， 通过mSYMPX标准化。3)为了评估交感神经递质的功能作用， 交感神经介导的DRG炎症反应。使用我们开发的新方法， 实验室的局部灌注感觉神经节和局部击倒特定分子，我们将 检查不同的去甲肾上腺素能和ATP受体在介导促炎作用中的作用， 交感神经纤维拟议的实验将阐明一种新的机制， 与几种具有炎症成分的慢性疼痛状况相关的持续疼痛。

Clinically, many chronic pain conditions are worsened by or even dependent upon activity of the sympathetic nervous system. Sympathetic blockade is often used clinically in chronic pain conditions, but the clinical and preclinical evidence for this practice has been contradictory and incomplete. However, a very recent study showed dramatic and promising results using a catheter approach to provide longer lasting sympathetic blockade than is achieved by injection, in patients with intractable pain. Most preclinical research has focused on the abnormal interactions between the sensory and sympathetic nervous systems in models of chronic pain. Based on our preliminary data and recent publications, we propose that the initiation and persistence of certain pathological pain conditions requires intact sympathetic innervation of the sensory nervous system at the level of the sensory ganglion, and that release of sympathetic transmitters enhances local inflammation of the sensory ganglia and leads to pain. Local inflammatory responses in the sensory ganglia occur even after remote nerve injuries, so this phenomenon is important to understanding many types of chronic pain conditions. Our preliminary data show large, rapid, and long-lasting reduction of pain behaviors and inflammatory responses following a “microsympathectomy” (mSYMPX) in both neuropathic and inflammatory pain models. This procedure involves cutting the gray rami (sympathetic postganglionic fibers) to only the lumbar sensory ganglia. mSYMPX avoids many effects of chemical or surgical sympathectomy used in most previous studies, such as sympathetic denervation of primary and secondary immune tissues. Since sympathetic innervation of some of these tissues is anti-inflammatory, global sympathectomy may have obscured pro-inflammatory effects at the sensory ganglion level. The mSYMPX method is also more clinically relevant since patients often receive local sympathetic blocks. The hypothesis will be tested in 3 specific aims: 1) To characterize the effects of mSYMPX on the development and persistence of pain and on local inflammation in the DRG. The effects of mSYMPX after pain is well-established will be tested, and its effects on infiltration of immune cells in the sensory ganglia examined with microscopy. 2) To explore the molecular mechanisms for sympathetic regulation of inflammatory responses in the DRG. Effects of mSYMPX on local cytokine levels and immune cell polarization will be examined, based on our preliminary finding that the pro-inflammatory cytokines induced by a pain model are normalized by mSYMPX. 3) To assess the functional role of sympathetic transmitters in the sympathetically mediated inflammatory responses in the DRG. Using novel methods developed in our laboratory for locally perfusing the sensory ganglia and locally knocking down specific molecules, we will examine the roles of different noradrenergic and ATP receptors in mediating the pro-inflammatory role of the sympathetic fibers. The proposed experiments will elucidate a novel mechanism for sympathetically maintained pain with relevance to several chronic pain conditions with inflammatory component.