Amygdala Serotonin Neurotransmission and Neuropathic Pain

杏仁核血清素神经传递和神经性疼痛

基本信息

批准号：
8917636
负责人：
Thomas Arthur Green
金额：
$ 35.03万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8917636
关键词：
Affect Affective Aftercare Agonist Amygdaloid structure Analgesics Antidepressive Agents Area Automobile Driving Basic Science Behavior Behavioral Behavioral Mechanisms Behavioral Model Biological Markers Brain CRF receptor type 1 Cell Nucleus Cells Chronic Chung model Complex Corticotropin-Releasing Hormone Data Development Dimensions Disease Drug Targeting Drug effect disorder Electrophysiology (science)Emotional Emotions Evidence Based Medicine Generations Genetic Glutamates Goals Health Immunohistochemistry Knowledge Ligands Ligation Literature Mediating Modeling National Institute of Neurological Disorders and Stroke Nature Neuronal Plasticity Neurons Neuropathy Output Pain Pain Research Pain management Peripheral Nervous System Diseases Personal Satisfaction Play Publications Quality of life RNA Interference Rattus Risk Risk Factors Role Selective Serotonin Reuptake Inhibitor Serotonin Serotonin Receptor 5-HT2C Signal Transduction Site Slice Spinal nerve structure Synapses Synaptic plasticity Testing Therapeutic United States National Institutes of Health Viral Viral Vector Western Blotting base cell type central sensitization chronic neuropathic pain driving force extracellular gamma-Aminobutyric Acid gene therapy improved in vivo inflammatory pain innovation member multidisciplinary neuropsychiatry neurotransmission novel novel strategies painful neuropathy patch clamp receptor function research study response small hairpin RNA therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): The multidimensional character of pain presents a therapeutic challenge that would benefit greatly from a better understanding of higher brain functions that regulate its complex emotional-affective aspects. Neuropathic pain is generally believed to result from maladaptive neuroplasticity but underlying mechanisms, particularly those in higher brain centers, are not well understood. This project will focus on abnormal function of the amygdala, a brain area that is recognized as a key player in the emotional-affective dimension of pain. Our goal is to mitigate maladaptive amygdala plasticity and block the development of chronic neuropathic pain. A critical determinant, we believe, is pain-related plasticity of serotonin 5-HT2C receptor (5-HT2CR) control of corticotropin-releasing factor (CRF) signaling in the amygdala because CRF is associated with 5-HT2CR- mediated negative affective states and CRF1 receptors mediate amygdala plasticity in inflammatory pain. Here we advance the novel concept that abnormal function of 5-HT2CR in the amygdala is a critical mechanism for the development and persistence of neuropathic pain and its emotional-affective component, and is also the likely cause of the limited efficacy of selective serotonin reuptake inhibitors (SSRIs) to treat neuropathic pain. Specifically, we propose the novel hypothesis that 5-HT2CR in the basolateral amygdala (BLA, amygdala input region), drives a vicious cycle involving CRF1 receptors that results in abnormal activity in the central nucleus (CeA, output region). This 5-HT2CR-driven maladaptive plasticity in the BLA-CeA circuitry plays a critical role in the transition to chronic neuropathic pain. Three Specific Aims (SAs) will determine synaptic and cellular mechanisms and behavioral consequences of manipulation of 5-HT2CR function in the amygdala in the spinal nerve ligation (SNL) rat model of neuropathic pain. Complementary pharmacological and novel viral vector knockdown strategies will be utilized in all aims for local inactivation or elimination of 5-HT2CR in the amygdala. Behavioral experiments (SA1) will determine the role of 5-HT2CR and CRF1 in the BLA in the emotional-affective component of neuropathic pain. Electrophysiology in vivo (SA2) will examine the hypothesis that 5-HT2CR in the BLA drives CRF1 activation and central sensitization of CeA output neurons. Patch-clamp studies in brain slices (SA3) will determine excitatory and (dis-)inhibitory synaptic and cellular mechanisms of plasticity in the BLA-CeA network that results from abnormal 5-HT2CR function driving persistent CRF1 signaling. These conceptually novel studies will characterize the 5-HT2CR/CRF1 interaction in the amygdala as an important mechanism of chronic neuropathic pain. We will also identify strategies to eliminate or disrupt this signaling mechanism to block maladaptive amygdala plasticity and thus neuropathic pain. The mechanistic analysis of higher brain functions and drug targets in pain will boost basic science knowledge required for evidence-based medicine and provide translational strategies for pharmacotherapeutics and/or gene therapy.

描述（由申请人提供）：疼痛的多维特征提出了一种治疗性挑战，该挑战将从对更高的大脑功能的更好理解中受益于调节其复杂的情绪影响方面的较高脑功能。通常认为神经性疼痛是由于适应不良的神经塑性而引起的，但根本的机制，尤其是较高大脑中心的机制，尚不清楚。该项目将集中于杏仁核的异常功能，杏仁核是一个大脑区域，被认为是疼痛情绪影响维度的关键人物。我们的目标是减轻适应不良的杏仁核可塑性并阻止慢性神经性疼痛的发展。我们认为，一个关键的决定因素是5-羟色胺5-HT2C受体（5-HT2CR）对杏仁核中皮质激素释放因子（CRF）信号的控制的可塑性，因为CRF CRF与5-HT2CR介导的负面影响态和CRF1受体相关，而CRF1受体介导了Amygdala Perions instramy plostermation intermygdala plosollation intermygdalation compormational intermygdalation。在这里，我们推进了一个新颖的概念，即5-HT2CR在杏仁核中的异常功能是神经性疼痛发育和持久性及其情绪影响成分的关键机制，并且也是选择性血清素蛋白抑制抑制剂（SSRIS）治疗神经疗法疼痛的有限效率的可能原因。具体而言，我们提出了一种新的假设，即基底外侧杏仁核（BLA，杏仁核输入区域）中的5-HT2CR驱动涉及CRF1受体的恶性循环，从而导致中央核中中央核中异常活性（CEA，输出区域）。 BLA-CEA电路中这种5-HT2CR驱动的不良适应性可塑性在向慢性神经性疼痛的过渡中起关键作用。三个具体目的（SAS）将确定神经性疼痛的杏仁核（SNL）大鼠模型中5-HT2CR功能操纵5-HT2CR功能的突触和细胞机制以及行为后果。补充药理学和新型病毒载体敲低策略将用于杏仁核中局部失活或消除5-HT2CR的所有目的。行为实验（SA1）将确定5-HT2CR和CRF1在BLA中的作用在神经性疼痛的情绪影响成分中。体内电生理学（SA2）将检查以下假设：BLA中的5-HT2CR驱动CRF1激活和CEA输出神经元的中心敏化。在BLA-CEA网络中，在脑切片中的斑块钳研究（SA3）将确定可塑性的兴奋性和（解除）抑制性突触和细胞机制，这是由异常的5-HT2CR功能驱动持续性CRF1信号传导引起的。这些概念上的新研究将表征杏仁核中5-HT2CR/CRF1相互作用是慢性神经性疼痛的重要机制。我们还将确定消除或破坏这种信号传导机制以阻断适应不良的杏仁核的策略，从而消除了适应不良的杏仁核，从而阻止了神经性疼痛。疼痛中较高的大脑功能和药物靶标的机械分析将促进基于证据的医学所需的基础科学知识，并为药物治疗和/或基因治疗提供转化策略。