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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结