Study of Activity Dependent Sympathetic Sprouting

 描述(由申请人提供)：临床上，许多慢性疼痛状况会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。交感神经阻滞剂常用于慢性疼痛的临床，但这种做法的临床和临床前证据是相互矛盾和不完整的。然而，最近的一项研究显示，在患有顽固性疼痛的患者中，使用导管方法提供比注射更持久的交感神经阻滞，取得了戏剧性的和有希望的结果。大多数临床前研究都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新发表的文献，我们认为某些病理性疼痛的开始和持续需要在感觉神经节水平上完整的交感神经支配，交感神经递质的释放加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，感觉神经节也会发生局部炎症反应，因此这一现象对于了解许多类型的慢性疼痛情况很重要。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的大幅、快速和持久的减少。这一过程包括将灰支(交感神经节后纤维)仅切断到腰部感觉神经节。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的许多效果，例如初级和次级免疫组织的交感神经去神经。由于其中一些组织的交感神经支配是抗炎的，全局交感神经切除可能掩盖了感觉神经节水平的促炎作用。由于患者经常接受局部交感神经阻滞，mSYMPX方法在临床上也更有意义。这一假设将在3个具体目标中得到验证：1)表征mSYMPX对疼痛的发展和持续以及对背根节局部炎症的影响。将测试mSYMPX在疼痛确立后的效果，并在显微镜下观察其对感觉神经节免疫细胞渗透的影响。2)探讨DRG内交感神经调节炎症反应的分子机制。基于我们的初步发现，由疼痛模型诱导的促炎细胞因子被mSYMPX正常化，将考察mSYMPX对局部细胞因子水平和免疫细胞极化的影响。3)探讨交感神经递质在交感神经介导的DRG炎症反应中的作用。使用我们实验室开发的局部灌流感觉神经节和局部击倒特定分子的新方法，我们将检查不同的去甲肾上腺素和ATP受体在交感纤维的促炎作用中的作用。拟议的实验将阐明交感神经维持疼痛的新机制，与几种带有炎症成分的慢性疼痛相关。

 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.