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Recruiting active expiration to overcome opioid-induced persistent apnea

招募主动呼气来克服阿片类药物引起的持续性呼吸暂停

基本信息

批准号：
10512706
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：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10512706
关键词：
Absence of pain sensation Acute Adolescent Agonist American Analgesics Apnea Asphyxia Brain Stem Breathing COVID-19 pandemic Carbon Dioxide Cessation of life Coupled Data Depressed mood Disinhibition Dose Drug Receptors Effectiveness Exercise Fentanyl Foundations G alpha q Protein G-Protein-Coupled Receptors Generations Half-Life Hospitalization Hypercapnia Investigation Lateral Mus Naloxone Neurons Opioid Opioid Antagonist Opioid agonist Overdose Pattern Persons Pharmaceutical Preparations Pharmacology Public Health Rattus Receptor Activation Recruitment Activity Relapse Rest Safety Structure Suggestion Testing Therapeutic Urethane Ventilatory Depression associated symptom carfentanil central pattern generator cost designer receptors exclusively activated by designer drugs effectiveness evaluation efficacy testing experimental study expiration mu opioid receptors neuronal excitability novel opiate tolerance opioid epidemic opioid overdose opioid withdrawal optogenetics overdose death parabrachial nucleus pre-clinical preBotzinger complex prescription opioid preservation prevent receptor respiratory side effect single-cell RNA sequencing success synthetic opioid therapeutic development ventilation

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 engage active expiration, thereby increasing tolerance of opioids. Those molecules may supplement current treatments for OIPA, e.g., higher efficacy and safety, longer half-life, possibly preserving opioid-induced analgesia. Opioids depress breathing by actions on inspiratory rhythm generating regions, the preBötzinger Complex (preBötC), either directly by activating µ-opioid receptors (µORs) in preBötC, or indirectly by inhibiting tonic drive from the Parabrachial Nuclei to preBötC. µORs are inhibitory G-protein coupled receptors (GPCRs) that depress neuronal excitability. Parafacial respiratory group (pF) contains an active expiratory oscillator, which is independent of preBötC, is opioid-insensitive and is silent at rest, but can become active during certain conditions, e.g. exercise, high CO2. When it is active, it is tightly coupled to inspiration. We propose to express excitatory GPCR HM3Dq receptors (designer receptors exclusively activated by designer drugs) in pF and test whether activation of these receptors increases the dose of fentanyl required to produce persistent apnea. We will then sequence the pF neurons to determine expression of endogenous excitatory GPCRs and test the efficacy of the agonists of these GPCRs in increasing the dose of fentanyl required to produce persistent apnea 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 preventing OIPA.

摘要