Mechanisms of opioid and sedative-induced respiratory depression

阿片类药物和镇静剂引起的呼吸抑制的机制

• 批准号: 10279580
• 负责人: Astrid G Stucke
• 金额: $ 50.66万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-18 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279580
• 关键词: AMPA Receptors; Absence of pain sensation; Acute; Adult; Affect; Analgesics; Anesthesia procedures; Animals; Apnea; Area; Benzodiazepines; Brain Stem; Breathing; Carbon Dioxide; Cell Nucleus; Clinical; Complex; Data; Development; Dose; Fentanyl; Frequencies; Generations; Glutamate Receptor; Glutamates; Goals; Human; Hypoxia; In Vitro; Infusion procedures; Injury; Intravenous; Ketamine; Location; Measures; Mediating; Mental Depression; Microinjections; Minor; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Naloxone; Neurons; Opiate Addiction; Opioid; Opioid Antagonist; Oryctolagus cuniculus; Pattern; Perioperative; Pharmaceutical Preparations; Phase; Physiological; Play; Postoperative Period; Preparation; Public Health; Publishing; Reflex action; Risk; Risk Factors; Role; Site; Synapses; Testing; Therapeutic; Tidal Volume; Ventilatory Depression; Withdrawal; base; drug development; effectiveness evaluation; expiration; improved; in vivo; insight; novel; opioid injection; overdose death; parabrachial nucleus; preBotzinger complex; prevent; respiratory; response; sedative

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.

项目摘要 最近过量死亡的增加，由于阿片类药物成瘾的增加和高度可获得性， 像芬太尼这样的强效阿片类药物已经将阿片类药物诱导的呼吸抑制（OIRD）变成了公共卫生问题。 此外，OIRD长期以来一直被认为是围手术期的一个主要风险因素，可能需要 加强术后管理，或在罕见情况下导致缺氧性损伤。阿片类药物总剂量和 合并使用镇静药物如苯二氮卓类与以下风险增加显著相关： OIRD。因此，迫切需要开发能够缓解OIRD而不逆转镇痛的药物 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以下因素的指导： 中心法则是前Bötzinger复合体（preBötC）是控制呼吸频率的脑干部位 和模式生成，OIRD是由于对preBötC的影响，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对人类的效果不够。根据我们公布的和初步的数据，我们建议 一种新的模式，呼吸模式是在前BötC产生的，但两个独立的脑干区域， 臂旁核/Köliker-Ehrman复合体（PBN/KF）和尾侧髓缝（CMR） 兴奋性驱动前BötC神经元负责切换，特别是从呼气到吸气，因此 测定呼吸频率。这些区域也对临床阿片类药物剂量高度敏感。注射阿片类药物 拮抗剂纳洛酮进入这些区域完全防止OIRD，即使在高阿片类药物剂量下。我们的目标 研究是为了确定刺激PBN/KF和CMR中的神经元是否可以克服OIRD，以及是否 这种影响是有限度的。我们将使用我们的成年，在体内去脑兔制备，这使得 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作用， 基线麻醉，神经网络和生理反射完好。我们将测量 阿片类药物和其他镇静剂抑制PBN/KF、CMR和preBötC的神经元功能和突触输入。 然后，我们将测试有多少AMPA和NMDA受体调节剂，即，增强功能的药物 兴奋性AMPA和NMDA受体，增加PBN/KF，CMR和preBötC神经元的活性，无论 这可以抵消阿片类药物和镇静剂的抑郁，以及在高阿片类药物和 镇静剂剂量这一结果将大大提高我们对药物诱导的神经机制的认识。 呼吸抑制和潜在的治疗方法和局限性。