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治疗挑战，如果更好地理解调节其复杂情绪情感方面的高级大脑功能，将大大受益。人们普遍认为神经性疼痛是由适应不良的神经可塑性引起的，但潜在的机制，特别是高级大脑中枢的机制，尚不清楚。该项目将重点关注杏仁核的异常功能，杏仁核被认为是疼痛情绪情感维度的关键参与者。我们的目标是减轻杏仁核可塑性的适应不良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杏仁核中促肾上腺皮质激素释放因子（CRF）信号传导的血清素 5-HT2C 受体（5-HT2CR）与疼痛相关的可塑性，因为 CRF 与 5-HT2CR 介导的负面情感状态相关，并且CRF1 受体介导炎性疼痛中杏仁核的可塑性。在这里，我们提出了一个新概念，即杏仁核中 5-HT2CR 的异常功能是神经性疼痛及其情绪情感成分发生和持续的关键机制，也是选择性 5-羟色胺再摄取抑制剂疗效有限的可能原因（SSRIs）治疗神经性疼痛。具体来说，我们提出了新的假设，即基底外侧杏仁核（BLA，杏仁核输入区）中的 5-HT2CR 驱动涉及 CRF1 受体的恶性循环，导致中央核（CeA，输出区）异常活动。 BLA-CeA 回路中这种 5-HT2CR 驱动的适应不良可塑性在向慢性神经病理性疼痛的转变中发挥着关键作用。三个特定目标 (SA) 将确定在神经性疼痛的脊髓神经结扎 (SNL) 大鼠模型中操纵杏仁核中 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局部灭活或消除杏仁核中 5-HT2CR 的所有目标。行为实验 (SA1) 将确定 BLA 中 5-HT2CR 和 CRF1 在神经性疼痛的情绪情感成分中的作用。体内电生理学 (SA2) 将检验 BLA 中的 5-HT2CR 驱动 CRF1 激活和 CeA 输出神经元中枢敏化的假设。脑切片 (SA3) 的膜片钳研究将确定 BLA-CeA 网络中可塑性的兴奋性和（去）抑制性突触和细胞机制，这是由驱动持续 CRF1 信号传导的异常 5-HT2CR 功能引起的。这些概念新颖的研究将杏仁核中 5-HT2CR/CRF1 相互作用的特征描述为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机制的策略，以阻止适应不良的杏仁核可塑性，从而阻止神经性疼痛。对高级大脑功能和疼痛药物靶点的机制分析将增强循证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。