Influence of Opioids on the Brainstem Respiratory Network

项目摘要 2017年54，000例阿片类药物相关死亡中有许多是由于呼吸抑制。具体 阿片类药物抑制呼吸的机制还不完全清楚。目前的假设集中在单一的 呼吸网络内的区域，如脑桥或前Bötzinger复合体。然而，扰动 这些区域还没有完全预测阿片类药物抑制呼吸的作用。根据初步数据和 模型模拟，我们已经开发了以下假设：阿片类药物管理诱导 以剂量依赖的方式重新配置呼吸网络。此重新配置涉及 一些神经元放电模式的改变（放电身份）， 腹侧呼吸柱（VRC）中相互连接的吸气神经元网络， 脑干中呼吸区域内和呼吸区域之间的功能连接。该项目有三个 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， 孤束核（NTS）、中缝核、脑桥核和VRC调节运动输出， 2）确定阿片类药物在调节吸气神经元电路内的同步性中的作用， VRC，3）生成脑干回路的网络规模模型，该脑干回路在存在 阿片类药物。我们预计该项目将导致：a）识别呼吸控制网络的要素 B）描绘E-T/NBM之间功能关系 在脑桥、中缝、NTS区和VRC神经元中，其有助于阿片类物质抑制呼吸，c） 吸气神经元网络中受损的同步性在阿片类药物产生的运动驱动减少中的作用，以及d） 将产生一个新的预测模型，其特征是有助于阿片类药物的网络规模机制。 呼吸的压抑。这些新知识将为理解网络规模提供关键一步 阿片类药物抑制呼吸的作用机制。

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.