New brainstem targets for counteracting opioid induced apnea

对抗阿片类药物引起的呼吸暂停的新脑干目标

基本信息

批准号：
10661014
负责人：
JACK L FELDMAN
金额：
$ 15.6万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10661014
关键词：
Absence of pain sensation Acceleration Acute Affect Agonist Airway Resistance American Analgesics Anesthesia procedures Apnea Asphyxia Bombesin Receptor Brain Stem Breathing COVID-19 pandemic Cessation of life Clinical Clinical Research Data Dose Effectiveness Fentanyl Foundations Frequencies G alpha q Protein G-Protein-Coupled Receptors Gastrin releasing peptide Generations Goat Half-Life Hospitalization Human In Vitro Intervention Mammals Mediating Mental Depression Methodology Morphine Motor Motor Neurons Movement Mus Muscle Naloxone Neurons Opioid Opioid Antagonist Opioid Receptor Opioid agonist Overdose Pattern Pharmaceutical Preparations Preparation Public Health Pump RNA Sequences Rattus Research Rodent Safety Serotonin Receptors 5-HT4 Site Slice Structure Substance P Testing Therapeutic Translational Research Ventilatory Depression antagonist awake blood-brain barrier permeabilization carfentanil central pattern generator cost depressive symptoms efficacy evaluation experimental study in vivo morphine administration mouse model mu opioid receptors neural circuit neuronal excitability opioid epidemic opioid overdose opioid withdrawal overdose death parabrachial nucleus pre-clinical preBotzinger complex prescription opioid preservation receptor remifentanil side effect single-cell RNA sequencing success synthetic opioid therapeutic development

项目摘要

ABSTRACT While prescription opioids are exceptional analgesics, they have significant side effects, especially opioid- induced persistent apnea (OIPA). A significant public health problem follows from these side effects, as overdoses caused almost 50,000 deaths in 2019, along with non-fatal overdoses that result in costly and often extended hospitalization. The “opioid epidemic” accelerated further during the COVID-19 pandemic, with a 38% increase in deaths due to synthetic opioid overdose (primarily fentanyl) compared to 2019. We propose a logical path to identifying molecules that can block or reverse OIPA that may supplement current treatments, e.g., higher efficacy and safety, longer half-life, possibly preserving opioid-induced analgesia. Opioids depress breathing by actions on two brainstem neural circuits underlying breathing movements, the preBötzinger Complex (preBötC) and the Parabrachial Nuclei (PB), both of which contains neurons expressing µ-opioid receptors (µORs). µORs are inhibitory G-protein coupled receptors (GPCRs) that depress neuronal excitability. Activation of excitatory GPCRs in preBötC and PB can counteract opioid effects on breathing. We propose to sequence the RNA in preBötC and PB neurons that express µORs to determine expression of excitatory GPCRs. Previous studies in awake mice aimed to determine whether preBötC or PB mediates depression of breathing during opioid overdose; however, opioids evoke only a modest decrease in breathing in awake mice, nowhere near an apnea observed in humans during acute opioid intoxication. We therefore propose to determine whether preBötC and/or PB are primarily responsible for OIPA in mice using a methodology in which we consistently evoke a complete apnea following opioid administration. We will select potential target excitatory GPCR receptors, that are coexpressed with µORs in the structure(s) that we find to be primarily responsible for OIPA (preBötC and/or PB). We will then determine the efficacy of the agonists of these GPCRs in counteracting OIPA in anesthetized mice. Success of this exploratory project will generate data for subsequent preclinical and translational investigation of agonists of these receptors as potential therapeutics for reversing OIPA. Prescription opioids are extremely effective painkillers, but overdose can result in death because they also stop breathing. More that 50,000 Americans die each year from opioid overdose. We propose to identify receptors, whose activation can reverse opioids’ effects on breathing.

抽象的尽管处方阿片类药物是特殊的镇痛药，但它们具有明显的副作用，尤其是阿片类药物诱发持续呼吸暂停（OIPA）。这些副作用伴随着重大的公共卫生问题，如 2019年过量服药造成近50,000例死亡，非致命性过量导致昂贵且经常导致住院延长。 “阿片类流行病”在共同19大流行期间进一步加速了与2019年相比识别可以阻止或反向OIPA的分子的逻辑途径，以补充当前治疗，例如，更高的效率和安全性，更长的半衰期，可能保留阿片类药物诱导的镇痛。呼吸对两个脑干神经回路的呼吸运动，呼吸运动，Prebötzinger 复合物（prebötc）和副核（PB），两者都包含表达µ-阿片类的神经元受体（µors）。 μors是抑制性G蛋白偶联受体（GPCR），使神经元令人兴奋。 Prebötc和Pb中兴奋性GPCR的激活可以抵消阿片类药物对呼吸的影响。我们建议序列的Prebötc和Pb神经元中的RNA表达μors以确定兴奋的表达 GPCR。先前在清醒小鼠中的研究旨在确定prebötc或pb是否介导阿片类药物过量期间的呼吸；但是，阿片类药物只会引起呼吸小鼠呼吸的适度下降，如今，在急性阿片类药物中毒期间，在人类中观察到的呼吸暂停附近。因此，我们建议确定PreBötc和/或Pb是否主要使用一种方法，使用一种方法，使用一种方法论我们将选择潜在的目标兴奋性GPCR受体，与结构中的μ子共表达，我们认为这是主要的负责OIPA（prebötc和/或pb）。然后，我们将确定这些GPCR的激动剂的效率在麻醉小鼠中抵消OIPA。这个探索项目的成功将生成数据随后对这些受体激动剂的临床前和翻译研究作为潜在的治疗用于逆转OIPA。处方阿片类药物是极有效的止痛药，但服用过量会导致死亡因为它们也停止呼吸。每年有50,000名美国人死于阿片类药物过量。我们识别受体的建议，其激活可以逆转阿片类药物对呼吸的影响。