Mechanism and Countermeasure of Fentanyl-Induced Sudden Death

芬太尼致猝死的机制及对策

• 批准号: 10586701
• 负责人: Fadi Xu
• 金额: $ 94.08万
• 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: 2023-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586701
• 关键词: Abbreviations; Absence of pain sensation; Accountability; Acute; Adult; Afferent Neurons; Agonist; Analgesics; Anesthesia and Analgesia; Anesthesia procedures; Animal Model; Apnea; Binding; Biochemistry; C Fiber; Capsaicin; Cause of Death; Cell Nucleus; Cells; Central Sleep Apnea; Cessation of life; Chest wall structure; Clinical; Collection; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dependence; Deposition; Depressed mood; Disease; Dose; Electrophysiology (science); Emergency medical service; Female; Fentanyl; Ganglia; Gender; Glutamates; Heroin; Immunohistochemistry; In Vitro; Individual; Injections; Intravenous Bolus; Larynx; Life; Lung; Mediating; Microinjections; Modeling; Muscle; Naloxone; Neurons; Opioid; Opioid Receptor; Overdose; Pathogenesis; Pathway interactions; Peripheral; Pharmacology; Pharyngeal structure; Pilot Projects; Play; Rattus; Reporting; Reproducibility; Sensory Nerve Endings; Signal Pathway; Signal Transduction; Spinal Ganglia; Substance P; Sudden Death; TACR1 gene; Testing; Therapeutic; Time; afferent nerve; airway obstruction; antagonist; awake; beta-arrestin; constriction; dermorphin; desensitization; fentanyl overdose; in vivo; interdisciplinary approach; intravenous injection; male; mu opioid receptors; mu receptors; neural; novel; opioid abuse; opioid mortality; overdose death; prevent; receptor internalization; respiratory; response; side effect; stem; ventilation

PROJECT SUMMARY Opioids were involved in 75,673 overdose deaths in 2020 in the U.S. Fentanyl, an opioid mu-receptor (MOR) agonist acting on central MORs produces analgesia, but depresses ventilation that could be lethal. Rapid intravenous injection of overdose fentanyl, particularly in Illicit use, is the deadliest. It triggers an apnea leading to sudden death within minutes in ~1/3 of adults (male > female) with ~75% of fentanyl sequestered by the lungs after injection. Naloxone is the preferable treatment for post-overdose, but not viable for the illicit FNT users who are found pulseless upon the arrival of emergency medical services. Moreover, naloxone counteracts analgesia with potentially life-threatening side effects. Central apnea, upper airway obstruction, and chest wall rigidity are assumed to be accountable for the sudden death, but the exact cause of the death and the effective countermeasure remain unknown, constituting a critical and unmet therapeutic clinical need. Bronchopulmonary C-fibers (PCFs) are the major sensory nerve endings innervating the airways and lungs and crucial in the control of respiratory rhythm. PCF stimulation could elicit central apnea and vocal closure likely by promoting release of glutamate or substance P to activate PCF 2nd-order neurons in the nucleus tractus solitarius via AMPA and neurokinin-1 receptor. We have reported that intravenous bolus injection of a low dose fentanyl triggers a PCF-mediated brief apnea, consistent with previously reported excitation of dorsal root ganglion C- neurons by MOR agonists via Gs-cAMP pathway. Our preliminary data show a triple apnea (central apnea, vocal closure and laryngeal constriction/collapse) coupled with chest wall rigidity, resulting in death within minutes in anesthetized adult rats after overdose fentanyl is rapidly injected. In this proposal, we seek to establish the first animal model of fentanyl-induced sudden death following triple apnea in awake adult rats and determine the dependency of triple apnea (death) on the gender and peripheral (especially vagal) MORs/µ1Rs (Aim 1). We will further demonstrate that fentanyl directly stimulates PCFs to evoke triple apnea by acting on MOR/µ1R and Gs- cAMP pathway, thereby promote PCF release of glutamate and SP to activate the 2nd-order neurons (Aim 2). Our pilot study has shown that intravenous injection of dermorphin (a peripherally acting MOR agonist) induces MOR internalization in vagal sensory neurons and blocks fentanyl-induced triple apnea. The β-arrestin-mediated signaling is known to be responsible for MOR desensitization/internalization. We will define that diamorphine has limited impact on baseline cardiorespiratory activity, but internalizes PCFs' MORs/µ1Rs via activation of β- arrestin-signaling to prevents the triple apnea (death) with no change in analgesia. This will present a potential safer and translational pretreatment for overdose fentanyl in clinical settings (Aim 3). A multidisciplinary approach (electrophysiology, immunohistochemistry, pharmacology and biochemistry) at systemic and cellular levels will be applied to elucidate the mechanisms underlying not only triple apnea (death) but also the lack of triple apnea after dermorphin pretreatment. The expected data will, for the first time, mechanistically reveal the key role of PCFs in generating fentanyl-induced triple apnea and provide a novel and potential countermeasure of dermorphin pretreatment to prevent/diminish the sudden death.

项目摘要 2020年美国有75,673例过量死亡与阿片类药物有关，芬太尼是一种阿片类μ受体（莫尔） 作用于中枢MORs的激动剂产生镇痛作用，但抑制可能致命的通气。快速 静脉注射过量芬太尼，特别是非法使用，是最致命的。会引发呼吸暂停 约1/3的成年人（男性>女性）在几分钟内猝死，约75%的芬太尼被肺部隔离 注射后纳洛酮是药物过量后的首选治疗方法，但对非法FNT使用者不可行， 在紧急医疗服务到达时被发现没有脉搏。此外，纳洛酮抵消镇痛 可能有危及生命的副作用中枢性呼吸暂停、上呼吸道阻塞和胸壁僵硬是 被认为是负责突然死亡，但死亡的确切原因和有效的 对策仍然未知，构成了关键的和未满足的治疗临床需求。 支气管肺泡C纤维（PCF）是支配气道和肺的主要感觉神经末梢， 对控制呼吸节律至关重要。PCF刺激可能引起中枢性呼吸暂停和声带闭合， 促进谷氨酸或P物质释放激活孤束核PCF二级神经元 通过AMPA和神经激肽-1受体。我们曾报道，静脉推注小剂量芬太尼 触发PCF介导的短暂呼吸暂停，与先前报道的背根神经节C的兴奋一致， 莫尔激动剂通过Gs-cAMP途径作用于神经元。我们的初步数据显示，三重呼吸暂停（中枢性呼吸暂停，声带 闭合和喉部收缩/塌陷），再加上胸壁僵硬，导致几分钟内死亡， 在过量芬太尼后迅速注射麻醉的成年大鼠。在本建议中，我们寻求建立第一个 在清醒的成年大鼠中建立芬太尼诱导的三重呼吸暂停后猝死的动物模型， 三重呼吸暂停（死亡）对性别和外周（尤其是迷走神经）MORs/µ 1Rs的依赖性（目的1）。我们将 进一步证明芬太尼通过作用于莫尔/µ 1 R和Gs直接刺激PCF诱发三重呼吸暂停。 cAMP途径，从而促进PCF释放谷氨酸和SP，激活二级神经元（目的2）。 我们的初步研究表明，静脉注射皮吗啡肽（外周作用的莫尔激动剂）诱导 迷走神经感觉神经元中的莫尔内化并阻断芬太尼诱导的三重呼吸暂停。β-arrestin介导 已知信号传导负责莫尔脱敏/内化。我们将定义海洛因 对基线心肺活动的影响有限，但通过激活β- 抑制蛋白信号传导以防止三重呼吸暂停（死亡），而镇痛没有变化。这将是一个潜在的 在临床环境中对过量芬太尼进行更安全和转化的预处理（目标3）。多学科方法 （电生理学，免疫组织化学，药理学和生物化学）在全身和细胞水平的研究将 不仅可用于阐明三重呼吸暂停（死亡）的潜在机制，还可用于阐明缺乏三重呼吸暂停的潜在机制 皮吗啡预处理后。预期的数据将首次从机械上揭示 PCF在芬太尼诱导的三重呼吸暂停中的作用，并提供了一种新的和潜在的对策， 皮吗啡预处理以预防/减少猝死。