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.

项目概要 2017 年，54,000 例与阿片类药物相关的死亡中有许多是由于呼吸抑制所致。 阿片类药物抑制呼吸的机制尚不完全清楚。 呼吸网络内的区域，例如脑桥或前 Bötzinger 复合体，但是，扰动。 根据初步数据和结果，这些领域尚未完全预测阿片类药物抑制呼吸的作用。 通过模型模拟，我们提出了以下假设：阿片类药物给药会诱发 以剂量依赖性方式重新配置呼吸网络。 一些神经元放电模式的改变（放电特性），神经元之间失去同步 腹侧呼吸柱（VRC）中相互连接的吸气神经网络并改变 该项目具有三个呼吸区域内部和之间的功能连接。 具体目标： 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 孤束核 (NTS)、中缝、脑桥和 VRC，调节呼吸运动输出 肌肉，2) 确定阿片类药物在调节吸气神经元回路同步性中的作用 VRC，3）生成脑干回路的网络规模模型，该模型在存在以下情况时控制呼吸 我们预计该项目将导致：a）识别呼吸控制网络的要素。 参与阿片类药物介导的重构，b) 描述 E-T/NBM 之间的功能关系 在脑桥、中缝、NTS 区和 VRC 神经元中，这些神经元有助于阿片类药物抑制呼吸，c) 吸气神经网络同步性受损在阿片类药物产生的运动驱动力降低中的作用，以及 d) 将产生新的预测模型，该模型具有有助于阿片类药物的网络规模机制 这一新知识将为理解网络规模提供关键的一步。 阿片类药物抑制呼吸的作用机制。