Neural basis of opioid-induced respiratory depression

阿片类药物引起的呼吸抑制的神经基础

• 批准号: 9893844
• 负责人: Erica Sawyer Levitt
• 金额: $ 33.75万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893844
• 关键词: Adult; Affect; Analgesics; Area; Attenuated; Behavior; Behavioral; Brain; Brain Stem; Breathing; Cause of Death; Cell Nucleus; Chemoreceptors; Chronic; Complex; Conflict (Psychology); Data; Dose; Electrophysiology (science); Functional disorder; Glutamates; Goals; Lateral; Maintenance; Measures; Mediating; Morphine; Mus; Neurons; Opioid; Opioid Receptor; Phase; Plethysmography; Pontine structure; Population; Preparation; Presynaptic Receptors; Public Health; Reflex action; Regulation; Respiratory Center; Respiratory Failure; Respiratory System; Role; Slice; Synapses; Testing; Tracer; Ventilatory Depression; awake; base; brain circuitry; desensitization; experimental study; expiration; extracellular; in vivo; innovation; locus ceruleus structure; mature animal; mu opioid receptors; neural circuit; opioid mortality; opioid overdose; opioid use; optogenetics; preBotzinger complex; presynaptic; receptor; receptor sensitivity; relating to nervous system; respiratory

Death from opioid overdose is primarily due to respiratory depression, yet little is known of the cellular mechanisms of opioids on respiratory-controlling neurons. Breathing is controlled by a highly interconnected network of neurons in the brainstem. Opioid-induced respiratory depression is due to activation of mu opioid receptors located throughout in the brainstem respiratory network, including the Kölliker-Fuse (KF) in the pons and respiratory control areas in the medulla. There are conflicting results regarding the importance of these areas in opioid-induced respiratory depression. Based on preliminary data, we propose that opioids act on the respiratory network collectively to cause respiratory depression rather than one area in isolation. There are major voids in the understanding of opioid modulation of the respiratory circuitry, especially inhibition of transmitter release. The goal of this proposal is to determine opioid regulation of identified projections between respiratory controlling brainstem neurons in adult mice with fully developed respiratory circuitry. It will focus on three brainstem areas that express mu opioid receptors and have dense reciprocal projections: the preBötzinger complex and Bötzinger complex in the medulla and the KF in the pons. The hypothesis is that presynaptic opioid receptors regulate synaptic connections between these areas to mediate opioid-induced respiratory depression. A combination of approaches will be used to test this hypothesis on the cellular, circuit and behavioral level. In Aim 1, opioid regulation of excitatory projections from the KF to the medulla will be defined using brain slice electrophysiology and optogenetics. Then, in vivo experiments will test the role of projections to the medulla in mediating respiratory depression caused by systemic opioid administration in awake adult animals. In Aim 2, the opioid sensitivity of synapses from medullary projection neurons onto KF neurons will be determined using brain slice electrophysiology and optogenetics. A unique arterially perfused preparation that maintains an intact brainstem and “in vivo-like” respiratory cycle will be used to determine if medullary projection neurons control the activity of single KF neurons. In Aim 3, the vulnerability of presynaptic mu opioid receptors in the KF to chronic opioid treatment will be determined using brain slice electrophysiology. Results from this project will provide mechanistic detail on opioid control of the pontomedullary respiratory circuitry that leads to respiratory depression. This may help identify strategies to counter opioid-induced respiratory depression and also inform on how synaptic mechanisms affect behavior.

阿片类药物过量导致的死亡主要是由于呼吸抑制，但对细胞毒性知之甚少。 阿片类药物对神经元的作用机制呼吸是由一个高度互联的 脑干中的神经元网络。阿片诱导的呼吸抑制是由于μ阿片样物质的激活 受体位于整个脑干呼吸网络，包括Köliker-Ehrer（KF）在 脑桥和延髓的呼吸控制区。关于以下问题的重要性， 阿片类药物引起的呼吸抑制。根据初步数据，我们认为阿片类药物 共同作用于呼吸网络，而不是孤立地作用于一个区域，导致呼吸抑制。那里 是理解阿片类药物对呼吸回路调节的主要空白，特别是对 发射器释放该提案的目标是确定阿片类药物对已确定预测的调节 呼吸控制脑干神经元之间的联系。它 将集中在三个脑干区域，表达μ阿片受体，并有密集的相互投射： 延髓中的前Bötzinger复合体和Bötzinger复合体以及脑桥中的KF。前提是 突触前阿片受体调节这些区域之间的突触连接，以介导阿片诱导的 呼吸抑制一个方法的组合将被用来测试这一假设的细胞，电路 行为层面。在目标1中，阿片调节从KF到延髓的兴奋性投射将被证实。 使用脑切片电生理学和光遗传学来定义。然后，体内实验将测试的作用， 在介导全身阿片类药物给药引起的呼吸抑制中向延髓的投射 清醒的成年动物目的2：研究延髓投射神经元到KF的突触对阿片的敏感性 将使用脑切片电生理学和光遗传学确定神经元。一个独特的动脉灌注 将使用保持完整脑干和“体内样”呼吸周期的制剂来确定 延髓投射神经元控制单个KF神经元的活动。在目标3中， 将使用脑切片测定KF中的突触前μ阿片样物质受体对慢性阿片样物质治疗 电生理学该项目的结果将提供阿片类药物控制的机制细节， 导致呼吸抑制的脑桥延髓呼吸回路。这可能有助于确定战略， 对抗阿片类药物引起的呼吸抑制，并告知突触机制如何影响行为。