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Inflammation-Induced Plasticity in Sensory Neurons

炎症诱导的感觉神经元可塑性

基本信息

批准号：
7342698
负责人：
MICHAEL S GOLD
金额：
$ 34.4万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7342698
关键词：
Freund&apos s adjuvant afferent nerve calcium flux colon fluorimetry inflammation innervation laboratory rat lumbosacral region neural plasticity polymerase chain reaction potassium channel protein localization protein structure function spinal ganglion temporomandibular joint syndrome voltage /patch clamp

项目摘要

DESCRIPTION (provided by applicant): Pain resulting from inflammation of is one of the most common reasons people seek medical attention. Inflammatory pain is associated with the sensitization of primary afferent neurons innervating injured tissue; i.e., those arising from trigeminal ganglia (TG) or dorsal root ganglia (DRG). Pain arising from specific structures such as the colon or TMJ is often the most difficult pain to treat possibly reflecting the unique properties of these afferents and/or the unique structures these afferents innervate. Nevertheless, our present understanding of the neurobiology of sensory neurons and their response to injury is derived largely from studies on somatic afferents. In normal tissue, voltage- and Ca2+-activatedchannels present in the plasma membrane of the afferent terminal control afferent excitability. Primary afferent neurons are hyper-excitable in the presence of persistent inflammation. However little is known about the mechanisms underlying this increase in excitability? This is particularly true for visceral and joint afferents given the dearth of data on the basic membrane properties of these afferents innervating normal tissue. One class of ion channels that may be particularly important for the expression of inflammation-induced hyperexcitability is Ca2+activated K+(CaK) channels. Inhibition of CaK channels appears to underlie sensitization of vagal afferents following airway inflammation and our preliminary data suggest that these channels are likely to contribute to inflammation-induced changes in the excitability DRG and TG neurons innervating several structures. Importantly, there have been only two studies on the function of CaK channels in sensory neurons from naive animals and none on the function of CaK channels in sensory neurons from inflamed animals. Therefore, we propose to test the following hypotheses: 1) that the distribution and functional role of CaK channels varies with respect to target of innervation (i.e., colon, TMJ, muscle and skin); and 2) that inflammation results in changes in the pattern of expression of CaK channels, which underlies changes in excitability that are unique to specific targets of innervation. We will test these hypotheses in experiments described under 2 Specific Aims employing a combination of retrograde tracing, in vitro patch-clamp electrophysiology, Ca2+imaging and RT-PCR analysis on adult rats either in the presence of absence of inflammation.

描述（由申请人提供）：炎症引起的疼痛是人们寻求医疗照顾的最常见原因之一。炎性疼痛与支配受损组织的初级传入神经元的敏化有关;即，三叉神经节（TG）或背根神经节（DRG）产生的那些。由诸如结肠或TMJ的特定结构引起的疼痛通常是最难治疗的疼痛，这可能反映了这些传入神经的独特性质和/或这些传入神经支配的独特结构。然而，我们目前对感觉神经元的神经生物学及其对损伤的反应的理解主要来自于对躯体传入的研究。在正常组织中，存在于传入终末质膜上的电压和Ca ~（2+）激活通道控制传入兴奋性。初级传入神经元在持续性炎症的存在下是过度兴奋的。然而，人们对这种兴奋性增加的机制知之甚少？这是特别真实的内脏和关节传入的数据缺乏这些传入神经支配正常组织的基本膜特性。对于炎症诱导的过度兴奋性的表达可能特别重要的一类离子通道是Ca 2+激活的K+（CaK）通道。抑制CaK通道似乎是致敏迷走神经传入后气道炎症和我们的初步数据表明，这些通道可能有助于炎症诱导的变化的兴奋性DRG和TG神经元支配的几个结构。重要的是，只有两项关于幼稚动物感觉神经元中CaK通道功能的研究，而没有关于发炎动物感觉神经元中CaK通道功能的研究。因此，我们建议测试以下假设：1）CaK通道的分布和功能作用随神经支配的靶点而变化（即，结肠、颞下颌关节、肌肉和皮肤）;和2）炎症导致CaK通道表达模式的变化，这是神经支配的特定靶点所特有的兴奋性变化的基础。我们将在2个特定目的下描述的实验中，在存在或不存在炎症的情况下，采用逆行追踪、体外膜片钳电生理学、Ca 2+成像和RT-PCR分析的组合，对成年大鼠进行这些假设进行检验。