STUDY OF ACTIVITY-DEPENDENT SYMPATHETIC SPROUTING

活动依赖性交感神经萌芽的研究

• 批准号: 8243574
• 负责人: Jun-Ming Zhang
• 金额: $ 33.66万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-04 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243574
• 关键词: ATP Receptors; Accounting; Action Potentials; Adrenergic Fibers; Affect; Afferent Neurons; Animals; Axotomy; Behavioral Mechanisms; Biological Models; Cells; Chronic; Clinical; Complex Regional Pain Syndromes; Conflict (Psychology); Economic Burden; Fiber; Frequencies; In Vitro; Inflammation; Inflammatory Response; Knowledge; Mediating; Methods; Microelectrodes; Modeling; Morbidity - disease rate; Neuroglia; Neurons; Norepinephrine; Operative Surgical Procedures; Pain; Patients; Peripheral; Peripheral nerve injury; Phase; Play; Preparation; Publishing; Rattus; Reagent; Reporting; Research; Role; Sensory; Sensory Ganglia; Societies; Source; Spinal Ganglia; Staging; Sympathectomy; System; Testing; Time; Work; chronic pain; extracellular; in vivo; mouse model; neuronal excitability; novel strategies; pain behavior; painful neuropathy; public health relevance; research study; therapeutic target; tool

DESCRIPTION (provided by applicant): Many chronic pain conditions remain difficult to treat, presenting a high burden to society. Conditions such as complex regional pain syndrome may be maintained or exacerbated by sympathetic activity. The discovery of abnormal connections between sympathetic and sensory neurons, e.g. the sprouting of sympathetic fibers into the sensory ganglia (DRG) after peripheral nerve injury, offered a possible explanation, but studies of this effect yielded conflicting findings. New tools and knowledge are now available to overcome some limitations of previous work in this field, as proposed: 1) The contribution of sympathetic transmitters other than norepinephrine (NE) will be examined. Many previous studies relied solely on NE antagonists, ignoring known sympathetic co-transmitters such as ATP, which is particularly important in pathological conditions. New reagents for specific ATP receptor subtypes will help investigate its role. 2) Functional studies of the sympathetic-sensory neuron connection were very limited. The proposed research will use a described new preparation for stimulating the sympathetic fibers that have sprouted into the DRG while recording intracellularly many parameters of sensory neuron excitability. 3) The possible interaction of satellite glial cells and sympathetic sprouts has not been investigated. The importance of activated glia in pathological pain has been recognized only recently. Experiments will test possible mechanisms by which reverberating interactions between sprouting sympathetic fibers, sensory neurons, and satellite glia cells might play key roles in initiating the pathological pain state. 4) Sympathetic effects on sensory neurons may shift from early excitatory to later inhibitory ones, accounting for conflicting findings. This shift occurs in other model systems of chronic inflammation. The function of sympathetic sprouts at later time points will be examined. 5) The role of local inflammation in promoting sympathetic sprouting has not been fully recognized. Local DRG inflammation is sufficient to induce sprouting, and can enhance sprouting caused by axotomy. Functional mechanisms and behavioral relevance of sympathetic - sensory neuron interactions in pain models will be examined using 3 specific aims: SA1: To characterize functional effects of sympathetic fibers on DRG excitability, spontaneous activity and pain behavior, including determining the effects of a very limited form of surgical sympathectomy that eliminates sprouting in a single DRG. SA2: To determine whether sympathetic transmitters in addition to NE play important excitatory roles in abnormal sympathetic-sensory neuron interactions, focusing on possible roles of ATP and satellite glia cells. SA3: To determine the interactions between localized inflammation, sympathetic outgrowth and neuropathic pain. We will determine whether sympathetic spouts regulate inflammatory responses in the early phases of two pain models, as suggested by work in other models of chronic inflammation. The proposed experiments will reinvigorate the study of sympathetic-sensory interactions in chronic pain conditions, and help find new approaches to this serious clinical problem. PUBLIC HEALTH RELEVANCE: Chronic pain conditions such as CRPS are common, long-lasting, and debilitating. We propose to continue the study of sympathetic component in neuropathic pain. Using a rat/mouse model, we will determine how abnormal activity, inflammation, ATP release affect sympathetic outgrowth and the neurons that sense pain.

描述（由申请人提供）：许多慢性疼痛状况仍然难以治疗，给社会带来了很大的负担。诸如复杂区域疼痛综合征之类的疾病可以通过交感神经活动来维持或加剧。同情和感觉神经元之间的异常联系，例如周围神经损伤后，交感神经纤维在感觉神经节（DRG）中提供了一种可能的解释，但对这种作用的研究产生了矛盾的发现。如下所建议，现在可以使用新的工具和知识来克服该领域的先前工作的某些局限性：1）将检查除去甲肾上腺素（NE）以外的其他交感发射器的贡献。许多先前的研究仅依赖于NE拮抗剂，忽略了已知的交感神经副传播者，例如ATP，这在病理条件下尤为重要。特定ATP受体亚型的新试剂将有助于研究其作用。 2）交感神经神经元连接的功能研究非常有限。拟议的研究将使用所描述的新准备工作来刺激已在DRG中发芽的交感神经纤维，同时记录了感觉神经元兴奋性的许多参数。 3）尚未研究卫星神经胶质细胞和交感神经芽的可能相互作用。直到最近才识别出活化神经胶质在病理疼痛中的重要性。实验将测试可能的机制，通过这些机制，通过这些机制来回顾发芽纤维，感觉神经元和卫星胶质细胞之间的相互作用在启动病理疼痛状态中起关键作用。 4）对感觉神经元的同情影响可能会从早期兴奋性转变为抑制性神经元，这是矛盾的发现。这种转变发生在其他慢性炎症模型系统中。将检查稍后时间点同情芽的功能。 5）尚未完全认识到局部炎症在促进交感神经发芽中的作用。局部DRG炎症足以诱导发芽，并且可以增强由轴切开术引起的发芽。疼痛模型中的交感神经 - 感觉神经元相互作用的功能机制和行为相关性将使用3个特定目的进行检查：SA1：表征交感神经纤维对DRG兴奋性，自发活动和疼痛行为的功能效应，包括确定非常有限的手术性交感神经术的效果，以消除单个DRG中的效果。 SA2：确定除NE之外的交感神经发射器是否在异常的交感神经神经元相互作用中起重要的兴奋性作用，以关注ATP和卫星胶质细胞的可能作用。 SA3：确定局部炎症，交感神经产物和神经性疼痛之间的相互作用。我们将确定同情吐出是否在两个疼痛模型的早期阶段调节炎症反应，这是由其他慢性炎症模型中的工作所表明的。提出的实验将重振慢性疼痛条件下的交感神经相互作用的研究，并帮助找到解决这一严重临床问题的新方法。 公共卫生相关性：CRP等慢性疼痛状况是常见的，持久的和使人衰弱的。我们建议继续研究神经性疼痛中的交感神经成分。使用大鼠/小鼠模型，我们将确定异常的活性，炎症，ATP释放如何影响交感神经的生长和感觉疼痛的神经元。