Amygdala Serotonin Neurotransmission and Neuropathic Pain

杏仁核血清素神经传递和神经性疼痛

• 批准号: 9250231
• 负责人: Thomas Arthur Green
• 金额: $ 45.19万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250231
• 关键词: Affect; Affective; Amygdaloid structure; Analgesics; Antidepressive Agents; Area; Automobile Driving; Basic Science; Behavior; Behavioral; Behavioral Model; Brain; CRF receptor type 1; Cell Nucleus; Cells; Chronic; Chung model; Clinical; Complex; Corticotropin-Releasing Hormone; Data; Development; Dimensions; Dose; Drug Targeting; Drug effect disorder; Electrophysiology (science); Emotional; Emotions; Evidence Based Medicine; Genetic; Glutamates; Goals; Immunohistochemistry; Knowledge; Ligands; Ligation; Literature; Mediating; Microdialysis; Modeling; National Institute of Neurological Disorders and Stroke; Nature; Neuronal Plasticity; Neurons; Neuropathy; Output; Pain; Pain Research; Pain management; Peripheral Nervous System Diseases; Pharmacology; Play; Publications; Quality of life; RNA Interference; Rattus; 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; behavior test; cell type; central sensitization; chronic neuropathic pain; driving force; experimental study; extracellular; gamma-Aminobutyric Acid; gene therapy; improved; in vivo; inflammatory pain; innovation; knock-down; member; multidisciplinary; negative affect; neuropsychiatric disorder; neurotransmission; novel; novel strategies; painful neuropathy; patch clamp; public health relevance; response; small hairpin RNA; therapeutic target; tool; translational approach

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 of chronic 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). 5- HT2CR-driven maladaptive plasticity in the BLA-CeA circuitry plays a critical role in 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. Systemic application of a 5-HT2CR antagonist and SSRI in SA1 and SA2 will validate their clinical utility and viability. 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)：疼痛的多维特征是一个治疗挑战，更好地了解调节其复杂情感方面的高级大脑功能将极大地受益。神经病理性疼痛通常被认为是由适应不良的神经可塑性引起的，但其潜在的机制，特别是高级大脑中心的机制，尚不清楚。这个项目将集中在杏仁核的异常功能上，杏仁核是公认的在疼痛的情绪情感维度中起关键作用的大脑区域。我们的目标是减轻杏仁核适应不良的可塑性，阻止慢性神经病理性疼痛的发展。我们认为，一个关键的决定因素是5-HT2C受体(5-HT2CR)控制杏仁核促肾上腺皮质激素释放因子(CRF)信号的痛相关可塑性，因为CRF与5-HT2CR介导的负性情感状态有关，而CRF1受体介导炎性疼痛中杏仁核的可塑性。在此，我们提出了杏仁核5-HT2CR功能异常是慢性神经病理性疼痛及其情感成分的重要机制，也是选择性5-羟色胺再摄取抑制剂(SSRIs)治疗神经病理性疼痛疗效有限的可能原因。具体地说，我们提出了一个新的假设，即杏仁核基底外侧区(BLA，杏仁核输入区)的5-HT2CR驱动了CRF1受体参与的恶性循环，导致中央核(CEA，输出区)的异常活动。5-HT2CR驱动的BLA-CEA回路中的适应不良可塑性在慢性神经病理性疼痛中起着关键作用。三个特定目标(SAS)将确定神经病理性疼痛的脊神经结扎(SNL)大鼠模型中杏仁核5-HT2CR功能的突触和细胞机制以及操作的行为后果。在杏仁核局部灭活或消除5-HT2CR的所有目标中，将使用互补的药理和新型病毒载体击倒策略。行为实验(SA1)将确定5-HT2CR和CRF1在BLA中在神经病理性疼痛的情绪-情感部分中的作用。体内电生理学(SA2)将验证BLA中的5-HT2CR驱动CRF1激活和CEA输出神经元的中枢敏化的假设。脑片(SA3)的膜片钳研究将确定BLA-CEA网络的兴奋性和(去)抑制性突触和可塑性的细胞机制，这是由于5-HT2CR功能异常驱动持久CRF1信号所致。5-HT2CR拮抗剂和SSRI在SA1和SA2中的系统应用将验证它们的临床实用性和生存能力。这些概念新颖的研究将确定杏仁核中5-HT2CR/CRF1的相互作用是慢性神经病理性疼痛的重要机制。我们还将确定消除或破坏这一信号机制的策略，以阻止适应性不良的杏仁核可塑性，从而阻止神经病理性疼痛。对疼痛中高级大脑功能和药物靶点的机制分析将提高循证医学所需的基础科学知识，并为药物治疗和/或基因治疗提供翻译策略。