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.

阿片类药物过量导致的死亡主要是由于呼吸抑制，但我们对细胞的机制知之甚少。 阿片类药物对呼吸控制神经元的作用机制。呼吸是由高度互连的系统控制的 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 阿片类药物的激活所致 位于整个脑干呼吸网络中的受体，包括位于脑干呼吸网络中的 Kölliker-Fuse (KF) 延髓中的脑桥和呼吸控制区。关于其重要性存在相互矛盾的结果 这些区域存在阿片类药物引起的呼吸抑制。根据初步数据，我们建议阿片类药物发挥作用 在呼吸网络上共同导致呼吸抑制，而不是孤立的一个区域。那里 在理解阿片类药物对呼吸回路的调节，特别是抑制 发射器释放。该提案的目标是确定已确定预测的阿片类药物监管 呼吸回路完全发育的成年小鼠的呼吸控制脑干神经元之间的研究。它 将重点关注表达 mu 阿片受体并具有密集相互投射的三个脑干区域： 延髓中的 preBötzinger 复合体和 Bötzinger 复合体以及脑桥中的 KF。假设是 突触前阿片受体调节这些区域之间的突触连接，以介导阿片类药物诱导的 呼吸抑制。将使用多种方法的组合来在蜂窝、电路上测试这一假设 和行为水平。在目标 1 中，阿片类药物对从 KF 到髓质的兴奋性投射的调节将是 使用脑切片电生理学和光遗传学定义。然后，体内实验将测试其作用 延髓投射介导全身阿片类药物引起的呼吸抑制 清醒的成年动物。在目标 2 中，从髓质投射神经元到 KF 的突触对阿片类药物的敏感性 将使用脑切片电生理学和光遗传学来确定神经元。独特的动脉灌注 维持完整脑干和“体内样”呼吸循环的制剂将用于确定是否 髓质投射神经元控制单个 KF 神经元的活动。在目标 3 中，脆弱性 KF 慢性阿片类药物治疗中的突触前 mu 阿片类受体将使用脑切片确定 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。这可能有助于确定策略 对抗阿片类药物引起的呼吸抑制，并了解突触机制如何影响行为。