New brainstem targets for counteracting opioid induced apnea

摘要 虽然处方类阿片是特殊的止痛药，但它们有显著的副作用，特别是阿片类药物- 诱发持续性呼吸暂停(OIPA)。这些副作用带来了一个重大的公共卫生问题，如 2019年，过量服药导致近50,000人死亡，同时非致命性过量导致代价高昂且往往 延长住院时间。新冠肺炎大流行期间，“阿片类药物流行”进一步加速， 与2019年相比，合成阿片类药物过量(主要是芬太尼)导致的死亡增加了38%。我们提出了一个 确定可以阻断或逆转OIPA的分子的逻辑路径，这些OIPA可能是对当前治疗的补充， 例如，更高的有效性和安全性，更长的半衰期，可能保留阿片类药物的镇痛作用。阿片类药物抑郁 通过作用于两个脑干神经回路的呼吸，Prebötzinger是呼吸运动的基础 复合体(PrebötC)和臂旁核(PB)，两者都含有表达µ-阿片的神经元 受体(µOR)。µOR是抑制性G蛋白偶联受体(GPCRs)，可抑制神经元的兴奋性。 激活PrebötC和PB中的兴奋性GPCRs可以抵消阿片类药物对呼吸的影响。我们建议 对表达µORs的PrebötC和PB神经元中的RNA进行测序以确定兴奋性基因的表达 GPCRs。先前在清醒小鼠上的研究旨在确定PrebötC或PB是否介导了 阿片类药物过量时的呼吸；然而，阿片类药物只会引起清醒小鼠呼吸的轻微减少， 在人类急性阿片类药物中毒期间观察到的呼吸暂停。因此，我们建议 确定PrebötC和/或PB是否对小鼠的OIPA负有主要责任 在使用阿片类药物后，我们总是会出现完全的呼吸暂停。我们将选择潜在的目标 兴奋性gpr受体，与uORs在结构(S)中共表达，我们发现主要 负责OIPA(PrebötC和/或PB)。然后我们将确定这些GPCRs激动剂的疗效 在麻醉小鼠中对抗OIPA。这一探索性项目的成功将为 这些受体激动剂作为潜在治疗药物的后续临床前和翻译研究 因为他推翻了OIPA。处方类阿片是非常有效的止痛药，但过量服用会导致死亡 因为它们也会停止呼吸。每年有超过5万美国人死于阿片类药物过量。我们 建议识别受体，其激活可以逆转阿片类药物对呼吸的影响。

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.