Influence of Opioids on the Brainstem Respiratory Network

项目总结 2017年与阿片类药物相关的死亡人数为5.4万人，其中许多人死于呼吸抑制。具体的 阿片类药物抑制呼吸的机制尚不完全清楚。目前的假说主要集中在 呼吸网络内的区域，如桥脑或Bötzinger前复合体。然而，摄动的 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 模型模拟我们提出了以下假设：阿片类药物的给药诱导 以剂量依赖的方式重新配置呼吸网络。这种重新配置包括 某些神经元放电模式的改变(放电特性)， 腹侧呼吸柱(VRC)内相互连接的吸气神经元网络及其改变 脑干呼吸区内和呼吸区之间的功能连接。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 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环路中的同步性中的作用 VRC，3)生成网络规模的脑干电路模型，该电路在存在的情况下控制呼吸 阿片类药物。我们预计这一项目将导致：a)确定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神经元与阿片类药物引起的呼吸抑制有关，c) 吸气神经元网络中同步性受损在阿片类药物引起的运动驱动力降低中的作用，以及d) 将产生新的预测模型，其特点是网络规模的机制有助于阿片类药物的形成 呼吸困难。这一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.