Unraveling the dynamic mechanisms underlying opioid respiratory depression

项目总结 阿片类药物的流行每年夺走5万多人的生命，并导致总体上大幅下降 美国人的预期寿命。与阿片类镇痛剂和药物有关的主要死亡原因 滥用是阿片类药物介导的呼吸抑制(ORS)。不过，死亡风险会随着剂量的增加而增加- 由于阿片类药物依赖的方式，它的使用特别危险，因为它是不可预测的。许多条件都在增加 对阿片类药物的脆弱性，包括睡眠呼吸障碍，这在阿片类药物使用者中非常常见。 阿片类药物通过抑制体内节律网络而导致呼吸抑制和终末性呼吸暂停 延髓腹外侧。该项目有4个目标，旨在探索ORS背后的髓质机制。目标1 在体外和体内采用各种电生理学、药理学和光遗传学方法来 探索阿片类药物如何抑制吸气节律网络。这个对阿片类药物敏感的网络形成了一列 这种动态扩展超越了众所周知的Prebötzinger复合体，这是一种微电路，对于 呼吸。目标2将从这个节律柱获得水平切片来解剖突触前和突触后 导致吸气活动停止的机制。AIM 3将调查阿片类药物如何 抑制吸气后复合体(Pico)内的后吸气，这是一个数量级的兴奋网络 比PrebötC对阿片类药物更敏感。目标1-3中揭示的机制将提供 目标4的基础，它将探索能够逆转警觉动物ORS的物质的组合。这 该项目引入了呼吸节律发生的新概念，并描述了阿片类药物的多种机制 这可以解释为什么阿片类呼吸抑制如此不可预测。我们测试阿片类药物 高碳酸血症和慢性间歇性低氧会使调制变得敏感，这两种情况通常 阿片类药物使用者的经验。拟议中的研究可能有助于更好地理解这种机制。 与阿片类药物危机有关的死亡率和发病率的根本原因。

PROJECT SUMMARY The opioid epidemic claims more than 50,000 lives every year and contributes to a significant drop in overall life expectancy in the USA. The primary cause of death associated with opioid-based analgesics and drugs of abuse is Opioid-mediated Respiratory Suppression (ORS). Although, the mortality risk increases in a dose- dependent manner, opioid use is particularly dangerous because it is unpredictable. Many conditions increase the vulnerability to opioids, including sleep disordered breathing, which is very common among opioid users. Opioids cause respiratory depression and terminal apnea by inhibiting rhythmogenic networks within the ventrolateral medulla. This project has 4 aims to explore the medullary mechanisms underlying ORS. Aim 1 employs a variety of electrophysiological, pharmacological, and optogenetic approaches in vitro and in vivo to explore how opioids inhibit the inspiratory rhythmogenic network. This opioid-sensitive network forms a column that dynamically extends beyond the well-known preBötzinger complex, a microcircuit that is essential for breathing. Aim 2 will obtain horizontal slices from this rhythmogenic column to dissect the pre-and postsynaptic mechanisms that are responsible for the cessation of inspiratory activity. Aim 3 will investigate how opioids inhibit Postinspiration within the postinspiratory complex (PiCo), an excitatory network that is an order of magnitude more sensitive to opioids than the preBötC. The mechanisms revealed in aim 1-3 will provide the basis for aim 4, which will explore combinations of substances capable of reversing ORS in alert animals. This project introduces novel concepts of respiratory rhythmogenesis and describes multiple mechanisms of opioid actions, which could explain why opioid respiratory depression is so unpredictable. We test how opioid modulation is sensitized by hypercapnic conditions and chronic intermittent hypoxia, both conditions are often experienced by opioid users. The proposed research may lead to a better understanding of the mechanisms underlying the mortality and morbidity associated with the opioid crisis.