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：
10656563
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：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10656563
关键词：
Absence of pain sensation Acceleration Acute Adolescent Agonist American Analgesics Anesthesia procedures Apnea Asphyxia Brain Stem Breathing COVID-19 pandemic Carbon Dioxide Cessation of life Coupled Data Depressed mood Disinhibition Dose Effectiveness Exercise Fentanyl Foundations G alpha q Protein G-Protein-Coupled Receptors Generations Genetic Half-Life Hospitalization Hypercapnia Lateral Mus Naloxone Neurons Opioid Opioid Antagonist Opioid Receptor Opioid agonist Overdose Pattern Persons Pharmaceutical Preparations Public Health Rattus Receptor Activation Recruitment Activity Relapse Rest Safety Sensory Structure Suggestion Testing Therapeutic Translational Research 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 pharmacologic pre-clinical preBotzinger complex prescription opioid preservation prevent receptor respiratory side effect single-cell RNA sequencing success synthetic opioid therapeutic development ventilation

Absence of pain sensation Acceleration Acute Adolescent Agonist American Analgesics Anesthesia procedures Apnea Asphyxia Brain Stem Breathing COVID-19 pandemic Carbon Dioxide Cessation of life Coupled Data Depressed mood Disinhibition Dose Effectiveness Exercise Fentanyl Foundations G alpha q Protein G-Protein-Coupled Receptors Generations Genetic Half-Life Hospitalization Hypercapnia Lateral Mus Naloxone Neurons Opioid Opioid Antagonist Opioid Receptor Opioid agonist Overdose Pattern Persons Pharmaceutical Preparations Public Health Rattus Receptor Activation Recruitment Activity Relapse Rest Safety Sensory Structure Suggestion Testing Therapeutic Translational Research 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 pharmacologic pre-clinical preBotzinger complex prescription opioid preservation prevent receptor respiratory side effect single-cell RNA sequencing success synthetic opioid therapeutic development ventilation

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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.

抽象的虽然处方Ooids是特殊的镇痛药，但它们具有显着的副作用，尤其是Ooid诱导的持续的呼吸暂停（OIPA）。这些副作用伴随着一个重大的公共卫生问题，因为过量造成了 2019年50,000例死亡，以及非致命的过量服用，导致昂贵且经常延长住院治疗。这 “阿片类流行病”在19日大流行期间进一步加速了，由于合成而导致的死亡增加了38％与2019年相比参与积极的到期，从而增加阿片类药物的耐受性。这些分子可以补充当前治疗对于OIPA，例如，较高的效率和安全性，更长的半衰期，可能保留阿片类药物诱导的镇痛。通过对鼓舞人心的节奏产生区域的呼吸，Prebötzinger综合体（Prebötc），要么直接通过通过抑制从支持解的核抑制补品驱动到prebötc中激活µ-阿片受体（µORS） Prebötc。 µORS是抑制神经元兴奋性的抑制性G蛋白偶联受体（GPCR）。偏执狂呼吸器组（PF）包含一个独立于prebötc的主动呼气因子，是对阿片类药物不敏感的，并且保持静止状态，但在某些条件下可能会变得活跃，例如运动，高二氧化碳。当它活跃时，它很紧张加上灵感。我们建议表达兴奋性GPCR HM3DQ接收器（设计器接收器专门在PF中被设计器药物激活）并测试这些受体的激活是否增加了所需的芬太尼剂量产生持续的呼吸暂停。然后，我们将对PF神经元进行测序，以确定内源性兴奋的表达 GPCR并测试这些GPCR的激动剂的效率，以增加产生所需的芬太尼剂量麻醉小鼠的持续呼吸暂停。该探索性项目的成功将生成数据以进行后续临床前并将这些受体激动剂的研究转化为预防OIPA的潜在疗法。