Mechanism and Countermeasure of Carfentanil-induced Respiratory Disorder and Death

卡芬太尼引起呼吸系统疾病及死亡的机制及对策

• 批准号: 10743181
• 负责人: Fadi Xu
• 金额: $ 65.1万
• 依托单位: LOVELACE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743181
• 关键词: Abbreviations; Acute; Afferent Neurons; Agonist; Anesthesia procedures; Animals; Apnea; Binding; Blood; Brain Stem; C Fiber; Carbon Dioxide; Carotid Body; Cell Nucleus; Cells; Central Sleep Apnea; Cerebrospinal Fluid; Cessation of life; Characteristics; Chemoreceptors; Chest; Chest wall structure; Clinical; Coupled; Data; Dependence; Deposition; Depressed mood; Dose; Doxapram; Electrophysiology (science); Exposure to; External Intercostal Muscle; Fentanyl; Frequencies; Ganglia; Gender; Human; Hypoxia; Immunohistochemistry; In Vitro; Inhalation; Injections; Intravenous; Intravenous Bolus; Larynx; Lung; Mediating; Modeling; Muscle; Naloxone; Neurons; Opioid; Overdose; Perfusion; Peripheral; Pharmacology; Pilot Projects; Play; Rattus; Receptor Inhibition; Reporting; Reproducibility; Respiration Disorders; Respiratory Muscles; Respiratory Stimulants; Resuscitation; Role; Stimulant; Survival Rate; Therapeutic Uses; Thyroarytenoid Muscle; Tidal Volume; Time; Ventilatory Depression; aerosolized; afferent nerve; antagonist; awake; bioweapon; carfentanil; constriction; dermorphin; desensitization; efficacy evaluation; fentanyl overdose; hypoxic depression; improved; in vivo; interdisciplinary approach; intravenous injection; mu opioid receptors; mu receptors; novel; opioid abuse; opioid overdose; overdose death; preBotzinger complex; prevent; receptor; receptor internalization; respiratory; response; synthetic opioid; ventilation

PROJECT SUMMARY Opioids were involved in 75,673 overdose deaths in 2020 in the U.S, in which fentanyl, a synthetic opioid, is the deadliest due to induction of ventilatory depression. Carfentanil (CFN) is another synthetic opioid acting on opioid mu-receptors (MORs) with a potency 100 times that of fentanyl. Though no intending for therapeutic use, aerosolized CFN has been applied as a lethal agent (bioweapon) to cause respiratory disorder (RD) and death in humans. Naloxone increases survival rate of overdose opioids in early reports; however, deaths have been increasing after synthetic opioid era due to unsuccessful resuscitation attempts in clinical settings. It also fails to reverse aerosolized CFN-induced RD/death in animals. To date, the characteristics, mechanisms, and effective countermeasure of acute CFN exposure-induced RD/death are still unclear. Overdose fentanyl via intravenous (IV) perfusion produces RD including gradual ventilatory depression (dVE) and then apneas/gasping before death. The RD is believed to result from inhibiting the carotid body O2-receptor and central CO2-chemoreceptors, especially those in the retrotrapezoid and parafacial nucleus (RTN/PFN) and the respiratory neurons in the pre-Bötzinger complex (PBC, the respiratory rhythm-generator). Interestingly, we recently reported that IV bolus injection of fentanyl induced an immediate apnea solely mediated by bronchopulmonary C-fibers (PCFs) in anesthetized rats. Our pilot study further shows that the apnea is associated with closure of the larynx, constriction of chest expiratory muscles, and silence of inspiratory muscles (i.e., obstructive and central apnea with chest wall rigidity), which is lethal if overdosed. Moreover, aerosolized fentanyl (100 mg/m3 for 10 min) initially triggers the similar apnea followed by dVE and gasping, leading to death ~10 min post exposure in anesthetized rats. In this proposal, we, therefore, will characterize the cardiorespiratory (respiratory muscles’) responses to acute CFN exposure in awake rats and determine the causal roles of peripheral and central MORs (Aim 1). Subsequently, we will mechanistically demonstrate that CFN exposure stimulates PCFs to trigger the initial apneas and then inhibits the carotid body, RTN/PFN CO2-sensitive and PBC respiratory neurons to produce dVE and gasping (apneas) by acting on local MORs (Aim 2). Doxapram is a potent respiratory stimulant to the carotid body, while CX717 can enhance respiratory frequency and respiratory drive via acting on the PBC and strengthen central CO2-chemoreception. Both agents are capable of reversing opioid-induced RD in animals and humans. This, along with MOR internalization in vagal sensory neurons and blockade of IV injection of fentanyl-induced apnea by dermorphin pretreatment (a peripherally acting MOR agonist, IV) in our pilot study, allows us to define if a cocktail pretreatment of dermorphin, doxapram, and CX717 is a countermeasure for CFN-induced RD/death (Aim 3). A multidisciplinary approach (electrophysiology, immunohistochemistry, and pharmacology) at systemic and cellular levels will be employed to elucidate the mechanisms underlying acute CFN exposure-induced RD/death and evaluate the efficacy of the cocktail pretreatment. The expected data will, for the first time, mechanistically reveal the key roles of PCFs, the carotid body, RTN/PFN and PBC in generating the CFN-induced RD and provide a novel and potential countermeasure to prevent/diminish the RD/death.

项目摘要 阿片类药物在2020年在美国涉及75,673例过量死亡，其中芬太尼是一种合成阿片类药物，是 由于诱导通气抑郁症而导致的最致命。 Carfentanil（CFN）是作用于Ooid的另一种合成Ooid MU受体（MOR）具有100倍芬太尼的效力。尽管无意使用治疗，但 雾化的CFN已被用作致死剂（Biowapon）引起呼吸障碍（RD）和死亡 在人类中。纳洛酮在早期报告中提高了阿片类药物过量的生存率；但是，死亡已经 由于临床环境中的复苏尝试失败而导致合成阿片类药物时代后的增加。它也无法 反向雾化的CFN诱导的动物诱导的RD/死亡。迄今为止，特征，机制和有效 急性CFN暴露引起的RD/死亡的对策仍不清楚。 通过静脉内（IV）灌注过量芬太尼产生RD，包括级通气抑郁症（DVE） 然后在死亡前喘着粗气。据信，RD是由于抑制颈动脉体O2受体而产生的 和中央二氧化碳受体受体，尤其是逆转肌核和偏型核（RTN/PFN）和 前胞辛格复合物（PBC，呼吸节奏生成剂）中的呼吸神经元。有趣的是，我们 最近报道说，芬太尼注射静脉注射注入芬太尼诱导的直接呼吸暂停仅由 麻醉大鼠的支气管肺C纤维（PCF）。我们的试点研究进一步表明呼吸暂停是 与喉部关闭，胸部呼气肌肉的收缩和灵感肌肉的沉默相关 （即，阻塞性和中央呼吸暂停具有胸壁刚度），如果服用过量，这是致命的。此外，雾化 芬太尼（100 mg/m3持续10分钟）最初会触发类似的呼吸暂停，然后散发出来，导致死亡 在麻醉大鼠中暴露后约10分钟。因此，在此提案中，我们将表征心肺 （呼吸道肌肉）对醒着大鼠急性CFN暴露的反应，并确定 外围和中央摩尔（AIM 1）。随后，我们将机械地证明CFN暴露 刺激PCF以触发初始apneas，然后抑制颈动脉体，RTN/PFN CO2敏感和PBC 呼吸神经元可通过作用于当地的MOR（AIM 2）来产生DVE和喘气（apneas）。 doxapram是一个 颈动脉体的潜在呼吸刺激剂，而CX717可以增强呼吸频率和呼吸系统 通过作用于PBC和强中央CO2-脱脂受体的驱动。两种代理都能够逆转 动物和人类中的Oopioid诱导的RD。这是迷走性感觉神经元中的MOR内在化和 静脉注射二烷基诱导的呼吸暂停的二囊（一种外周作用MOR） 激动剂，iv）在我们的试点研究中，我们可以定义鸡尾酒预处理，doxapram和cx717 是CFN引起的RD/死亡的对策（AIM 3）。 全身性和 将雇用细胞水平来阐明急性CFN暴露诱导的RD/死亡的机制 并评估鸡尾酒预处理的效率。预期的数据将首次机械机械地 揭示PCF，颈动脉体，RTN/PFN和PBC的关键作用在生成CFN诱导的RD和 提供一种新颖和潜在的对策，以防止/减少RD/死亡。