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: 10652428
• 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/10652428
• 关键词: Absence of pain sensation; Acute; Affect; Analgesics; Anhedonia; Antidepressive Agents; Anxiety; Behavior; Brain; Brain Stem; Central Nervous System; Chronic; Chronic stress; Data; Electrophysiology (science); Enzymes; Exposure to; Fiber; Genetic; Genetic Models; Goals; Hyperalgesia; Individual; Injury; Intervention; Lead; Link; Mechanics; Mediating; Mental Depression; Mental disorders; Modeling; Modification; Monitor; Neurons; Neurosciences; Neurotransmitters; Nociception; Norepinephrine; Pain; Pain Disorder; Pain management; Periodicity; 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; Vertebral column; Work; acute stress; antinociception; 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.

项目概要 本研究的总体目标是更好地了解中枢去甲肾上腺素能的镇痛特性 系统。面对身体伤害和心理创伤时的情绪调节对于长期生存至关重要 生存和生活质量。无法控制的焦虑、快感缺乏和抑郁通常会在一段时间后出现 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，相同的三环和血清素/去甲肾上腺素再摄取抑制剂（SNRI）被开发并用于 治疗抑郁症也能有效治疗慢性疼痛。因此，去甲肾上腺素（NE）可能是其中之一 压力期间调节疼痛处理的关键神经递质。在本提案中，我们寻求定义以下角色： NE 在压力引起的疼痛缓解中的作用。蓝斑-去甲肾上腺素能（LC-NE）系统是一种特殊的系统。 中枢神经系统目标有望干预慢性疼痛和压力引起的疼痛 精神疾病。本研究的重点是了解 LC-NE 系统的机制 调节内源性镇痛以及慢性压力如何影响该系统。这个假设的中心假设 建议认为 LC-NE 神经元活动对于应激诱导的伤害感受调节至关重要。第一个目标是 该提案将使用体内评估 LC-NE 神经元在急性应激诱导的抗伤害作用中的作用 光遗传学和化学遗传学。第二个目标旨在了解从 急性应激诱发的抗伤害感受到慢性应激诱发的伤害感受。特别是，这一目标旨在 确定重复压力暴露引起的重复 LC-NE 刺激是否会导致压力诱发 伤害感受。为此，我们将使用体内光遗传学、化学遗传学和交叉遗传学 在重复约束应力期间消除 LC-NE 功能的模型。最终目标旨在阐明两者如何 研究慢性压力的不同模型揭示了与疼痛相关的相反表型。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法以监测遵循这些应激范例的 LC-NE 活性 以及对有害刺激的反应。这些实验共同将产生以前无法实现的 有关 LC-NE 神经元和调节疼痛相关行为的相关传出回路的信息 对压力源的反应。这些研究将定义 LC-NE 系统的作用； 1）急性应激引起的 镇痛，2) 向慢性应激诱发的痛觉过敏的转变，以及 3) 确定机制 不同形式的压力会改变 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。

项目成果

Customizable, wireless and implantable neural probe design and fabrication via 3D printing.

• DOI: 10.1038/s41596-022-00758-8
• 发表时间: 2023-01
• 期刊: NATURE PROTOCOLS
• 影响因子: 14.8
• 作者: Parker, Kyle E.;Lee, Juhyun;Kim, Jenny R.;Kawakami, Chinatsu;Kim, Choong Yeon;Qazi, Raza;Jang, Kyung-In;Jeong, Jae-Woong;McCall, Jordan G.
• 通讯作者: McCall, Jordan G.