Study of Activity Dependent Sympathetic Sprouting

 描述（由申请人提供）：临床上，许多慢性疼痛病症因交感神经系统的活动而恶化，甚至取决于交感神经系统的活动。交感神经阻滞在临床上经常用于治疗慢性疼痛，但这种做法的临床和临床前证据是矛盾且不完整的。然而，最近的一项研究显示，对于顽固性疼痛患者，使用导管方法提供比注射更持久的交感神经阻滞效果，效果显着且有希望。大多数临床前研究都集中在慢性疼痛模型中感觉神经系统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发表的文章，我们提出，某些病理性疼痛状况的发生和持续需要感觉神经节水平的感觉神经系统完整的交感神经支配，并且交感神经递质的释放会增强感觉神经节的局部炎症并导致疼痛。即使在远端神经损伤后，感觉神经节中的局部炎症反应也会发生，因此这种现象对于了解多种类型的慢性疼痛状况非常重要。我们的初步数据显示，在神经病理性疼痛和炎症性疼痛模型中，“微交感神经切除术”（mSYMPX）后，疼痛行为和炎症反应大幅、快速且持久地减少。该手术涉及仅将灰支（交感神经节后纤维）切割至腰部感觉神经节。 mSYMPX 避免了先前大多数研究中使用的化学或手术交感神经切除术的许多影响，例如初级和次级免疫组织的交感神经去神经支配。由于其中一些组织的交感神经支配具有抗炎作用，因此整体交感神经切除术可能掩盖了感觉神经节水平的促炎作用。 mSYMPX 方法也更具临床相关性，因为患者经常接受局部交感神经阻滞。该假设将在 3 个具体目标中得到检验： 1) 表征 mSYMPX 对疼痛的发生和持续以及对 DRG 局部炎症的影响。将测试疼痛确定后 mSYMPX 的效果，并用显微镜检查其对感觉神经节中免疫细胞浸润的影响。 2）探讨交感神经调节背根神经节炎症反应的分子机制。基于我们的初步发现，mSYMPX 使疼痛模型诱导的促炎细胞因子正常化，我们将检查 mSYMPX 对局部细胞因子水平和免疫细胞极化的影响。 3) 评估交感神经递质在背根神经节交感神经介导的炎症反应中的功能作用。使用我们实验室开发的局部灌注感觉神经节和局部敲除特定分子的新方法，我们将检查不同去甲肾上腺素能和 ATP 受体在介导交感纤维促炎作用中的作用。拟议的实验将阐明一种与几种具有炎症成分的慢性疼痛相关的交感神经维持疼痛的新机制。

 DESCRIPTION (provided by applicant): 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 thi 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.