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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：
10453339
负责人：
JACK L FELDMAN
金额：
$ 27.3万
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/10453339
关键词：
Absence of pain sensation Acute Affect Agonist Airway Resistance American Analgesics 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 GTP-Binding Protein alpha Subunits, Gs Gastrin releasing peptide Generations Goat Half-Life Hospitalization Human In Vitro Intervention Investigation Mammals Mediating Mental Depression Methodology Morphine Motor Neurons Movement Mus Muscle Naloxone Neurons Opioid Opioid Antagonist Opioid agonist Overdose Pattern Pharmaceutical Preparations Preparation Public Health Pump RNA Sequences Rat-1 Rattus Research Rodent Safety Serotonin Receptors 5-HT4 Site Slice Structure Substance P Testing Therapeutic Ventilatory Depression antagonist awake blood-brain barrier permeabilization carfentanil central pattern generator cost depressive symptoms 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.

摘要