Study of Activity Dependent Sympathetic Sprouting

 描述（由申请人提供）：临床上，许多慢性疼痛状况因交感神经系统的活动而恶化，甚至依赖于交感神经系统的活动。交感神经阻滞常用于慢性疼痛的临床治疗，但临床和临床前的证据是矛盾和不完整的。然而，最近的一项研究显示，在顽固性疼痛患者中，使用导管方法提供比注射更持久的交感神经阻滞的效果显著且有希望。大多数临床前研究集中在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，我们提出某些病理性疼痛状况的发生和持续需要感觉神经系统在感觉神经节水平上的完整交感神经支配，并且交感神经递质的释放增强了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，因此这种现象对于理解许多类型的慢性疼痛状况很重要。我们的初步数据显示，在神经性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均大幅、快速和持久减少。该手术涉及仅切断腰感觉神经节的灰支（交感节后纤维）。mSYMPX避免了大多数先前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。由于这些组织中的一些的交感神经支配是抗炎性的，因此全局交感神经切除术可能在感觉神经节水平上掩盖了促炎作用。mSYMPX方法也更具有临床相关性，因为患者经常接受局部交感神经阻滞。将在3个特定目的中检验该假设：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。将测试mSYMPX在疼痛后的作用，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)探讨交感神经对背根节炎性反应调控的分子机制。基于我们的初步发现，即疼痛模型诱导的促炎细胞因子通过mSYMPX正常化，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交感神经介导的DRG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低特定分子的新方法，我们将研究不同的去甲肾上腺素能和ATP受体在介导交感神经纤维的促炎作用中的作用。拟议的实验将阐明一种新的机制，交感神经维持疼痛与相关的几个慢性疼痛条件与炎症成分。

 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.