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.

项目概要 2020 年，美国有 75,673 例阿片类药物过量死亡，其中芬太尼（一种合成阿片类药物）是最主要的药物。 卡芬太尼 (CFN) 是另一种作用于阿片类药物的合成阿片类药物，因诱导通气抑制而最为致命。 mu 受体 (MOR) 的效力是芬太尼的 100 倍，虽然不打算用于治疗用途， 雾化 CFN 已被用作致死剂（生物武器），导致呼吸系统疾病 (RD) 和死亡 在早期报告中，纳洛酮可提高过量服用阿片类药物的存活率，但死亡人数却有所增加。 在合成阿片类药物时代之后，由于临床上的复苏尝试不成功，这一数字也有所增加。 迄今为止，逆转雾化 CFN 引起的动物 RD/死亡的特征、机制和有效性。 急性CFN暴露引起的RD/死亡的对策尚不清楚。 通过静脉 (IV) 灌注过量芬太尼会产生 RD，包括逐渐通气抑制 (dVE) 死前呼吸暂停/喘气被认为是由于抑制颈动脉体 O2 受体造成的。 和中央 CO2 化学感受器，尤其是梯形后核和面旁核 (RTN/PFN) 中的那些 前 Bötzinger 复合体（PBC，呼吸节律发生器）中的呼吸神经元。 最近报道，芬太尼的静脉推注仅引起立即呼吸暂停 我们的初步研究进一步表明，麻醉大鼠的支气管肺 C 纤维（PCF）是呼吸暂停的原因。 与喉部闭合、胸部呼气肌收缩和吸气肌沉默有关 （即伴有胸壁僵硬的阻塞性和中枢性呼吸暂停），如果服药过量是致命的。 芬太尼（100 mg/m3，持续 10 分钟）最初会引发类似的呼吸暂停，随后出现 dVE 和喘气，最终导致死亡 因此，在麻醉大鼠中暴露后约 10 分钟，我们将描述心肺功能的特征。 （呼吸肌）对清醒大鼠急性 CFN 暴露的反应，并确定以下因素的因果作用： 随后，我们将机械地演示 CFN 暴露。 刺激 PCF 触发初始呼吸暂停，然后抑制颈动脉体、RTN/PFN CO2 敏感和 PBC 呼吸神经元通过作用于局部 MOR 产生 dVE 和呼吸暂停（目标 2）。 对颈动脉体有强效的呼吸兴奋剂，而CX717可以增强呼吸频率和呼吸强度 通过作用于 PBC 来驱动并增强中枢 CO2 化学感受 两种药物都能够逆转。 阿片类药物在动物和人类中诱导的 RD，以及迷走神经感觉神经元中的 MOR 内化。 通过皮吗啡预处理（一种外周作用的 MOR）阻断静脉注射芬太尼引起的呼吸暂停 激动剂，IV）在我们的试点研究中，使我们能够确定皮吗啡、多沙普仑和 CX717 的混合物预处理是否有效 是 CFN 引起的 RD/死亡的对策（目标 3）。 多学科方法（电生理学、免疫组织化学和药理学） 将利用细胞水平来阐明急性 CFN 暴露引起的 RD/死亡的机制 并首次机械地评估鸡尾酒预处理的功效。 揭示了 PCF、颈动脉体、RTN/PFN 和 PBC 在产生 CFN 诱导的 RD 和 提供一种新颖且潜在的对策来预防/减少 RD/死亡。