Trans-synaptic signaling complex in amygdala pain mechanisms

杏仁核疼痛机制中的跨突触信号复合体

基本信息

批准号：
10455683
负责人：
Shashank Manohar Dravid
金额：
$ 53.04万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10455683
关键词：
3-Dimensional Address Affect Affective American Amygdaloid structure Anxiety Axodendritic Synapse Axosomatic Synapse Behavior Biochemical Biological Brain Calcitonin Gene-Related Peptide Clinical Complex Confocal Microscopy Data Dendrites Development Down-Regulation Drug Addiction Electron Microscopy Electrophysiology (science)Elements Emotional Equilibrium Experimental Designs Foundations Frequencies Freund&apos s Adjuvant Functional disorder Genetic Glutamate Receptor Glutamates Health Care Costs Hypersensitivity Image Immunoelectron Microscopy Impaired cognition Impairment Incidence Inflammatory Infusion procedures Injections Ion Channel Knockout Mice Knowledge Laboratories Lateral Lead Ligation Maintenance Mechanics Mediating Mental Depression Messenger RNA Methods Modeling Molecular Mus Neuronal Plasticity Neurons Neuropathy Nociception Pain Pain management Pathway interactions Peripheral Persistent pain Pharmaceutical Preparations Play Precipitation Presynaptic Terminals Productivity Protein Kinase C Reagent Recombinants Research Research Design Role Sensory Signal Transduction Slice Somatostatin Spinal nerve structure Structure Synapses Synaptic plasticity System Techniques Testing Viral abuse liability anxiety-like behavior base cell type chronic pain comorbidity confocal imaging delta receptors disability economic cost experimental study genetic approach imaging approach inflammatory pain neuronal cell body new therapeutic target novel optogenetics overexpression pain behavior pain model pain processing pain reduction pain relief pain signal painful neuropathy parabrachial nucleus postsynaptic presynaptic receptor receptor expression restoration sex side effect synaptic function vocalization

项目摘要

Summary: Pain is a serious clinical problem that affects more than 100 million Americans. The economic costs of pain have been estimated to be more than several hundred billion dollars including healthcare costs and lost productivity. Persistent pain may produce long-term disability and lead to precipitation of depression, anxiety and cognitive impairment. Currently used medications for chronic pain are not always effective and have limitations in terms of tolerance and abuse liability. Thus, identifying novel therapeutic targets is essential to address this clinical burden. Peripheral and central pathways that encode, transmit, and amplify or reduce pain signals have been identified, including the spinothalamic and spinoparabrachial pathways. Plasticity of glutamatergic synapses along key nodes in the spinoparabrachial-amygdala pathway plays an important role in pain modulation and in the transition from subacute to chronic pain. However, the mechanisms governing the development, maintenance and plasticity of this system and their role in persistence of pain behaviors remain poorly understood. The proposed research will advance the concept that the trans-synaptic signaling complex centered on glutamate delta 1 receptor regulates function of synapses in the laterocapsular region of central amygdala also known as “nociceptive amygdala” and contributes to persistent pain mechanisms. Specific Aim1 will define the cell type- and projection-specific distribution of these receptors and their role in regulating amygdala circuitry and nocifensive and averse-affective behavior under normal conditions. Specific Aim 2 will determine persistent/chronic pain-related changes in glutamate delta 1 signaling using inflammatory and neuropathic pain models and test the effect of a rescue strategy on synaptic neuroplasticity in pain models. Changes in ultrastructure of amygdala synapses in pain models will be evaluated using 3D-electron microscopy. Specific Aim 3 will determine the effect of restoring trans- synaptic signaling through the glutamate delta 1 receptor in mitigating nocifensive and averse-affective behaviors in pain models. Complementary experiments will address the effect of cell-type specific manipulation of central amygdala circuitry in mitigating pain. To accomplish these aims we will utilize a combination of brain slice electrophysiology, behavior, chemo- and opto-genetics, confocal and electron microscopy (immuno and 3D), and genetic approaches to determine the functional and structural mechanisms through which the glutamate delta 1 signaling complex regulates pain-related neuroplasticity and behaviors. This project is significant because it would identify a novel brain mechanism of pain that could be targeted for pain management. Scientific rigor of research design is established by the use of multiple methods and approaches, replication of experiments in independent laboratories, use of validated models and reagents, consideration of blinding, biological variables and sex in addition to other aspects of experimental design.

概括：疼痛是一个严重的临床问题，会影响超过1亿美国人。痛苦的经济成本有据估计，包括医疗费用和生产力损失，估计超过数亿美元。执着的疼痛可能会导致长期残疾，并导致抑郁症，焦虑和认知障碍的精度。目前使用的用于慢性疼痛的药物并不总是有效的，并且在宽容和虐待方面有局限性责任。这是确定新型热目标对于解决这一临床负担至关重要的。外围和中央已经确定了编码，传输和放大或减少疼痛信号的途径，包括脊柱丘脑和 Spinoparabrachial途径。沿着旋转丙型果杏仁核中的关键节点的谷氨酸能突触的可塑性途径在疼痛调节以及从亚急性到慢性疼痛的过渡中起着重要作用。但是，控制该系统的发展，维护和可塑性及其在疼痛持续性中的作用的机制行为仍然知之甚少。拟议的研究将推动反式突触信号传导的概念以谷氨酸三角洲1受体为中心的复合物调节中央后期区域突触的功能杏仁核也称为“伤害感受杏仁核”，并有助于持续的疼痛机制。特定的AIM1会定义这些受体的细胞类型和投影特异性分布及其在调节杏仁核电路中的作用以及在正常条件下的单位性和厌恶性行为。特定目标2将决定持久/慢性使用炎症和神经性疼痛模型，与谷氨酸三角洲1信号传导的疼痛变化，并测试疼痛模型中合成神经质量的救援策略。疼痛中杏仁核突触的超微结构的变化将使用3D电子显微镜评估模型。特定的目标3将决定恢复trans-的效果通过谷氨酸三角洲1受体的突触信号传导，缓解疼痛中的性和厌恶性行为型号。互补实验将解决中央杏仁核特异性操纵的影响缓解疼痛的电路。为了实现这些目标，我们将利用大脑切片电生理学的组合，行为，化学和光基因，共聚焦和电子显微镜（免疫和3D），以及遗传方法确定谷氨酸三角洲1信号传导复合物调节的功能和结构机制与疼痛有关的神经塑性和行为。该项目很重要，因为它可以确定一种新型的大脑机制可能针对疼痛管理的疼痛。研究设计的科学严谨性是通过使用多个的方法和方法，独立实验室中实验的复制，使用经过验证的模型和试剂，除了实验设计的其他方面外，考虑盲目，生物学变量和性别。