Influence of Opioids on the Brainstem Respiratory Network

阿片类药物对脑干呼吸网络的影响

• 批准号: 10322091
• 负责人: DONALD C BOLSER
• 金额: $ 68.16万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322091
• 关键词: Address; Anatomy; Animal Model; Area; Behavior; Behavioral; Brain; Brain Stem; Breathing; Cell Nucleus; Cells; Cessation of life; Chemoreceptors; Complex; Coughing; Data; Development; Dose; Elderly; Elements; Exhibits; Feedback; Goals; Impairment; Knowledge; Life; Mediating; Modeling; Motor; Motor Neurons; Motor output; Neuraxis; Neurons; Opioid; Outcome; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Pneumonia; Pontine structure; Population; Positioning Attribute; Probability; Regulation; Research; Respiratory Muscles; Respiratory System; Risk; Role; Sleep Apnea Syndromes; System; Technology; Ventilatory Depression; Work; addiction; base; drug discovery; models and simulation; neural network; novel strategies; opioid mortality; opioid overdose; opioid use; predictive modeling; prescription opioid; presynaptic; programs; protective behavior; raphe nuclei; respiratory; success

PROJECT SUMMARY Many of the 54,000 opioid-related deaths in 2017 were due to respiratory depression. The specific mechanisms by which opioids depress breathing are not fully understood. Current hypotheses focus on single areas within the respiratory network, such as the pons or pre-Bötzinger complex. However, perturbation of these areas has not fully predicted the actions of opioids to depress breathing. Based on preliminary data and model simulations we have developed the following hypothesis: opioid administration induces reconfiguration of the respiratory network in a dose-dependent manner. This reconfiguration involves alterations in the pattern of discharge of some neurons (discharge identity), loss of synchrony among interconnected inspiratory neuron networks in the ventral respiratory column (VRC) and altered functional connectivity within and between respiratory areas in the brainstem. This project has three Specific Aims: 1) Determine the influence of opioids on functional network interactions between neurons in the nucleus tractus solitarius (NTS), raphe, pontine, and VRC that regulate motor output to respiratory muscles, 2) Determine the role of opioids in modulating synchrony within inspiratory neuron circuits in the VRC, 3) Generate a network-scale model of the brainstem circuits that control breathing in the presence of opioids. We anticipate this project will lead to: a) identification of elements of the respiratory control network that participate in opioid-mediated reconfiguration, b) delineation of functional relationships between E-T/NBM in the pons, raphe, NTS area and VRC neurons that contribute to depression of breathing by opioids, c) the role of impaired synchrony in inspiratory neuron networks in reduced motor drive produced by opioids, and d) new predictive model will be produced featuring the network-scale mechanisms that contribute to opioid depression of breathing. This new knowledge will provide a critical step in understanding the network scale mechanisms of action of opioids to depress breathing.

项目摘要 2017年与阿片类药物相关的54,000例死亡中有许多是由于呼吸道抑郁症。具体 阿片类药物抑制呼吸的机制尚未完全理解。当前的假设专注于单个 呼吸网络中的区域，例如PON或Bötzinger综合体。但是，扰动 这些地区尚未完全预测阿片类药物对呼吸的抑制作用。基于初步数据和 模型模拟我们已经制定了以下假设：阿片类药物给药的影响 以剂量依赖性方式重新配置呼吸网络。这种重新配置涉及 某些神经元（放电身份）排放模式的改变，同步损失 腹侧呼吸柱（VRC）中的相互连接的吸气神经元网络并改变了 脑干的呼吸区域内和之间的功能连通性。这个项目有三个 具体目的：1）确定阿片类药物对神经元之间功能网络相互作用的影响 核心核团结（NTS），raphe，pontine和vrc，调节电动机输出至呼吸系统 肌肉，2）确定阿片类药物在调节励志神经元电路中调节同步中的作用 VRC，3）生成一个网络规模的脑干电路模型，该电路在存在下控制呼吸 OOPIOIDS。我们预计该项目将导致：a）识别呼吸控制网络元素 参与阿片类药物介导的重新配置，b）划定E-T/NBM之间的功能关系 在PON，RAPHE，NTS区域和VRC神经元中，导致阿片类药物呼吸抑制，c） 同步在降低阿片类药物产生的降低运动驱动器中的同步性障碍的作用，D） 将生产新的预测模型，具有有助于阿片类药物的网络规模机制 呼吸抑郁。这些新知识将为了解网络规模提供关键的一步 阿片类药物的作用机制减轻呼吸。