Unraveling the dynamic mechanisms underlying opioid respiratory depression

项目摘要 阿片类药物流行病每年夺去5万多人的生命，并导致总体死亡率大幅下降。 美国的预期寿命。与阿片类镇痛药和阿片类药物相关的主要死亡原因 阿片类药物介导的呼吸抑制（ORS）不过，死亡风险随着剂量的增加而增加- 由于依赖性，阿片类药物的使用特别危险，因为它是不可预测的。许多条件增加 易受类阿片侵害，包括睡眠呼吸障碍，这在类阿片使用者中非常常见。 阿片类药物通过抑制中枢神经系统内的节律性网络引起呼吸抑制和终末呼吸暂停。 延髓腹外侧本项目有4个目的，探讨ORS的髓内机制。要求1 采用多种体外和体内电生理学、药理学和光遗传学方法， 探索阿片类药物如何抑制吸气节律网络。这个阿片类药物敏感的网络形成了一列 它动态地扩展到众所周知的前Bötzinger复合体之外，这是一种对 呼吸了AIM 2将从这个节律发生柱获得水平切片，以解剖突触前和突触后 这些机制负责停止吸气活动。Aim 3将研究阿片类药物如何 抑制吸气后复合体（皮科）内的吸气后，这是一种兴奋性网络， 对阿片类药物的敏感程度比preBötC更高。目标1-3中揭示的机制将提供 目标4的基础，该目标将探索能够在警觉动物中逆转ORS的物质组合。这 项目介绍了呼吸节律的新概念，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药物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缺氧会使调节敏感，但这两种情况通常都是 阿片类药物使用者的经验。拟议的研究可能会导致更好地了解机制 与阿片类药物危机相关的死亡率和发病率。

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.