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: 10323043
• 负责人: Erica Sawyer Levitt
• 金额: $ 34万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323043
• 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.

阿片类药物过量死亡主要是由于呼吸抑制，但对细胞内的情况知之甚少。 阿片类药物对呼吸控制神经元的作用机制。呼吸是由高度互联的 脑干中的神经元网络。阿片类药物引起的呼吸抑制是由于Mu阿片类药物激活所致 受体分布于脑干呼吸网络，包括脑干呼吸网络中的Kölliker-Fuse(KF)。 延髓中的桥脑和呼吸控制区。关于这一点的重要性，有相互矛盾的结果 这些区域中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起作用 在呼吸网络上集体造成呼吸抑制，而不是孤立地在一个区域。那里 是理解阿片类药物对呼吸回路的调节的主要空白，特别是抑制 发射机释放。这项提案的目标是确定已确定的投射的阿片类药物调节。 在呼吸回路完全发达的成年小鼠的呼吸控制脑干神经元之间。它 将专注于三个表达u阿片受体并具有密集相互投射的脑干区域： 延髓的Prebötzinger复合体和Bötzinger复合体，脑桥的KF复合体。假设是这样的 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类药物诱导 呼吸抑制。一种方法的组合将被用来在细胞电路上检验这一假设。 和行为层面。在目标1中，从KF到延髓的兴奋性投射的阿片类调节将是 使用脑片电生理学和光遗传学来定义。然后，在体内实验将测试的作用 延髓投射在介导阿片类药物全身给药所致呼吸抑制中的作用 醒着的成年动物。在目标2中，来自延髓投射神经元的突触对KF的阿片敏感性 将使用脑片电生理学和光遗传学来确定神经元。一种独特的动脉灌流 保持完整的脑干和类似活体的呼吸周期的准备将用于确定 延髓投射神经元控制单个KF神经元的活动。在目标3中， 用脑片测定突触前MU阿片受体在KF对慢性阿片类药物治疗中的作用 电生理学。该项目的结果将提供阿片类药物控制的机械细节 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，以 对抗阿片类药物诱导的呼吸抑制，并告知突触机制如何影响行为。