Mechanisms of opioid and sedative-induced respiratory depression

项目摘要 最近过量死亡的增加，是由于阿片成瘾的增加和高度可用的 像芬太尼这样的强效阿片类药物已经使阿片类药物引起的呼吸抑制(OIRD)成为一个公共卫生问题。 此外，OIRD长期以来一直被认为是围手术期的一个主要危险因素，在那里它可能需要 加强术后处理，或在极少数情况下导致缺氧性损伤。阿片类药物总剂量和 同时使用苯二氮卓类镇静药物会显著增加患糖尿病的风险。 奥利德。因此，迫切需要开发能够在不逆转止痛的情况下缓解OIRD的药物 或导致戒断。在过去的20年里，呼吸刺激药物的开发一直受到 中心教义认为Prebötzinger复合体(PrebötC)是控制呼吸频率的脑干部位 和模式的产生，OIRD是由于对PrebötC的影响，并且为了抵消OIRD药物必须 刺激PrebötC。然而，在动物身上开发的通过影响呼吸来刺激呼吸的药物 PrebötC在人类身上不够有效。基于我们公布的初步数据，我们建议 一种新的模式，呼吸模式在PrebötC产生，但有两个独立的脑干区域， 臂旁核/Kölliker-Fuse复合体(PBN/KF)和尾侧延髓中缝(CMR)参与 对PrebötC神经元的兴奋性驱动，特别是负责从呼气转换到吸气，从而 确定呼吸频率。这些地区对临床阿片类药物剂量也高度敏感。注射阿片类药物 进入这些区域的拮抗剂纳洛酮完全阻止了OIRD，即使在高阿片类药物剂量下也是如此。我们的目标是 研究目的是确定刺激PBN/KF和CMR中的神经元是否可以克服OIRD，以及是否 这种效果是有限度的。我们将使用我们的成年活体去脑兔制剂，它允许 研究阿片类药物和其他药物对单个神经元和功能鉴定的细胞核的影响 基础麻醉，神经网络和生理反射完好无损。我们会测量一下 阿片类药物和其他镇静剂抑制了PBN/KF、CMR和PrebötC的神经元功能和突触输入。 然后我们将测试AMPA和NMDA受体调节剂，即增强血管内皮细胞功能的药物 兴奋性AMPA和NMDA受体，增加PBN/KF，CMR和PrebötC神经元的活性，无论是 这可以抵消阿片类药物和镇静剂造成的抑郁，以及在高阿片类药物和镇静剂的作用是否有限 镇静剂剂量。这些结果将显著提高我们对药物诱导的神经机制的洞察力。 呼吸抑制以及潜在的治疗方法和局限性。

Project Summary The recent increase in overdose deaths, fueled by an increase in opioid addiction and the availability of highly potent opioids like fentanyl has turned opioid-induced respiratory depression (OIRD) into a public health problem. In addition, OIRD has long been recognized as a major risk factor in the perioperative period where it can require intensified postoperative management or, on rare occasions, result in hypoxic injury. Total opioid dose and the concomitant use of sedative drugs like benzodiazepines are significantly associated with an increased risk of OIRD. Consequently, there is great urgency to develop drugs that can alleviate OIRD without reversing analgesia or causing withdrawal. Over the past 20 years, development of respiratory stimulating drugs has been guided by the central dogma that the preBötzinger Complex (preBötC) is the brainstem site that controls respiratory rate and pattern generation, that OIRD is due to an effect on the preBötC, and that to counteract OIRD drugs must stimulate the preBötC. However, drugs that were developed in animals to stimulate breathing through effects on the preBötC were not sufficiently effective in humans. Based on our published and preliminary data we propose a novel paradigm where the respiratory pattern is generated in the preBötC but two separate brainstem areas, the Parabrachial Nucleus/ Kölliker-Fuse Complex (PBN/KF), and the caudal medullary raphe (CMR) contribute excitatory drive to preBötC neurons responsible for switching in particular from expiration to inspiration and thus determine respiratory rate. These areas are also highly sensitive to clinical opioid doses. Injection of the opioid antagonist naloxone into these areas completely prevented OIRD, even at high opioid doses. The goal of our study is to determine whether stimulation of neurons in the PBN/KF and CMR can overcome OIRD and whether there are limits to this effect. We will use our adult, in vivo decerebrate rabbit preparation, which allows to investigate opioid- and other drug effects on single neurons and in functionally identified cell nuclei without baseline anesthesia and with neuronal networks and physiological reflexes intact. We will measure how much opioids and other sedatives depress neuronal function in and synaptic inputs to the PBN/KF, CMR, and preBötC. We will then test how much AMPA and NMDA receptor modulators, i.e., drugs that enhance the function of excitatory AMPA and NMDA receptors, increase the activity of PBN/KF, CMR, and preBötC neurons, whether this can offset the depression from opioids and sedatives and whether the effect is limited at high opioid and sedative doses. The results will significantly improve our insights into the neuronal mechanisms of drug-induced respiratory depression and into potential therapeutic approaches and limitations.