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 阿片类药物成瘾的增加和高度可用性的推动力，最近的过量死亡人数增加了 像芬太尼这样的有效阿片类药物已将阿片类药物引起的呼吸道抑郁症（OIRD）变成了公共卫生问题。 此外，在可能需要的时期，长期以来，Oird一直被认为是主要危险因素 加强术后管理或极少数情况下会导致低氧损伤。总阿片类药物剂量和 伴随使用镇静药（如苯二氮卓类药物）的使用与增加的风险显着相关 哦。因此，有很大的迫切需要开发可以减轻oird而不会逆转镇痛的药物 或引起撤离。在过去的20年中，呼吸道刺激药物的开发得到了指导 Prebötzinger综合体（PreBötc）的中心教条是控制呼吸率的脑干部位 和模式产生，这是由于对prebötc的影响，必须抵消药物 刺激prebötc。但是，在动物中开发的药物通过对 prebötc在人类中没有足够的有效性。根据我们已发布的初步数据，我们提出了 一种新型的范式，在Prebötc中产生呼吸模式，但两个独立的脑干区域， 副核/köllliker-Fuse配合物（PBN/ KF）和尾髓质raphe（CMR）有助于 兴奋性驱动器向Prebötc神经元负责转换到启发到灵感，从而使 确定呼吸率。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 纳洛酮进入这些区域，即使在高阿片剂量下，也完全阻止了OIRD。我们的目标 研究是确定PBN/KF和CMR中神经元的刺激是否可以克服OIRD，以及是否是否 这种效果有限制。我们将使用我们的成年人，体内杂交兔子的准备，这允许 研究阿片类药物和其他药物对单个神经元以及功能鉴定的细胞核病的影响 基线麻醉，神经元网络和身体反射完整。我们将衡量多少 卵形和其他镇静剂在PBN/KF，CMR和Prebötc中降低神经元功能和突触输入。 然后，我们将测试多少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 这可以抵消卵毒素和镇静剂的抑郁 镇静剂剂量。结果将显着改善我们对药物诱导的神经元机制的见解 呼吸道抑郁症以及潜在的治疗方法和局限性。