Stress-induced plasticity in noradrenergic analgesia

去甲肾上腺素能镇痛中应激诱导的可塑性

• 批准号: 10437731
• 负责人: Jordan G. McCall
• 金额: $ 36.58万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437731
• 关键词: Absence of pain sensation; Acute; Affect; Analgesics; Anhedonia; Antidepressive Agents; Anxiety; Behavior; Brain; Brain Stem; Chronic; Chronic stress; Data; Electrophysiology (science); Enzymes; Exposure to; Fiber; Genetic Models; Goals; Hyperalgesia; Individual; Injury; Intervention; Lead; Link; Mechanics; Mediating; Mental Depression; Mental disorders; Modeling; Modification; Monitor; Neuraxis; Neurons; Neurosciences; Neurotransmitters; Nociception; Norepinephrine; Pain; Pain Disorder; Pain management; Phenotype; Photometry; Physiological Adaptation; Property; Prosencephalon; Psychological Stress; Quality of life; Research; Role; Series; Serotonin; Slice; Social isolation; Spinal; Spinal Cord; Stimulus; Stress; Stressful Event; Study models; System; Targeted Research; Testing; Translational Research; Work; acute stress; chronic pain; chronic pain management; conditional knockout; emotion regulation; experience; experimental study; in vivo; inhibitor; locus ceruleus structure; multidisciplinary; neuropsychiatric disorder; noradrenergic; norepinephrine system; optogenetics; pain processing; patch clamp; prevent; psychological trauma; response; restraint stress; reuptake; stressor

Project Summary The overall goal of this research is to better understand the analgesic properties of central noradrenergic systems. Emotional regulation in the face of physical injury and psychological trauma is critical to long-term survival and quality of life. Uncontrollable anxiety, anhedonia, and depression often result following periods of prolonged stress or chronic pain. Both chronic pain and stress lead to overlapping physiological adaptations such that the same tricyclic and serotonin/norepinephrine reuptake inhibitors (SNRIs) developed and used to treat depression are also effective in treating chronic pain. Therefore, norepinephrine (NE) is likely one of the key neurotransmitters regulating pain processing during stress. In this proposal we seek to define the role of NE in stress-induced modification of pain. The locus coeruleus-noradrenergic (LC-NE) system is one particular central nervous system target that holds promise for interventions in both chronic pain and stress-induced psychiatric disorders. This research focuses on understanding the mechanisms by which the LC-NE system modulates endogenous analgesia and how chronic stress affects this system. The central hypothesis of this proposal is that LC-NE neuronal activity is critical for stress-induced modulation of nociception. The first aim of this proposal will assess the role of LC-NE neurons in acute stress-induced antinociception using in vivo optogenetics and chemogenetics. The second aim seeks to understand the mechanism for the transition from acute stress-induced antinociception to chronic stress-induced pronociception. In particular, this aim seeks to determine whether repeated LC-NE stimulation from repeated stress exposure drives stress-induced pronociception. To do so we will use, using in vivo optogenetics, chemogenetics, and intersectional genetic models to remove LC-NE function during repeated restraint stress. The final aim seeks to clarify how two different models for studying chronic stress reveal opposing pain-related phenotypes. Here, we will use brain slice electrophysiology and in vivo fiber photometry to monitor LC-NE activity following these stress paradigms and in response to noxious stimuli. Together these experiments will generate previously unattainable information about LC-NE neurons and associated efferent circuitry that regulate the pain-related behaviors in response to stressors. These studies will define the role of the LC-NE system; 1) in acute stress-induced analgesia, 2) the transition to chronic stress-induced hyperalgesia, and 3) identify mechanisms by which different forms of stress alter LC-NE function and nociception. This information will be critical for translational research targeting the noradrenergic system in the treatment of pain and neuropsychiatric disorders.

项目摘要 本研究的总体目标是更好地了解中枢去甲肾上腺素能神经元的镇痛特性。 系统.面对身体伤害和心理创伤时的情绪调节对长期的 生存和生活质量。无法控制的焦虑，快感缺乏和抑郁症往往导致以下时期的 长期压力或慢性疼痛。慢性疼痛和压力都会导致重叠的生理适应 因此，同样的三环和5-羟色胺/去甲肾上腺素再摄取抑制剂（SNRI）被开发并用于 治疗抑郁症对治疗慢性疼痛也有效。因此，去甲肾上腺素（NE）可能是其中之一， 压力下调节疼痛过程的关键神经递质。在这一建议中，我们试图界定以下方面的作用： NE在应激引起的疼痛改变中的作用。蓝斑-去甲肾上腺素能（LC-NE）系统是一个特殊的 中枢神经系统靶点，有望干预慢性疼痛和压力诱导的 精神疾病本研究的重点是了解LC-NE系统的机制 调节内源性镇痛和慢性应激如何影响这一系统。这个问题的核心假设是 提出LC-NE神经元活性对于应激诱导的伤害感受调节是关键的。的首要目标 该建议将评估LC-NE神经元在急性应激诱导的抗伤害感受中的作用， 光遗传学和化学遗传学。第二个目标是了解从 急性应激诱导的抗伤害感受到慢性应激诱导的伤害感受。具体而言，这一目标旨在 确定来自重复应激暴露的重复LC-NE刺激是否驱动应激诱导的 前感受性为此，我们将使用体内光遗传学、化学遗传学和交叉遗传学， 模型，以消除LC-NE功能在重复约束应力。最后一个目的是澄清两个 研究慢性压力的不同模型揭示了相反的疼痛相关表型。在这里，我们将使用大脑 切片电生理学和体内纤维光度测定以监测这些应激范例后LC-NE活性 以及对有害刺激的反应。这些实验将产生以前无法实现的 关于LC-NE神经元和相关的传出回路的信息，调节疼痛相关的行为， 对压力的反应。这些研究将确定LC-NE系统的作用; 1）在急性应激诱导的 镇痛，2）过渡到慢性应激诱导的痛觉过敏，和3）确定的机制， 不同形式的应激改变LC-NE功能和伤害感受。这些信息对于翻译至关重要。 针对去甲肾上腺素能系统治疗疼痛和神经精神疾病的研究。