New brainstem targets for counteracting opioid induced apnea

摘要 虽然处方阿片类药物是特殊的镇痛药，但它们具有显著的副作用，特别是阿片类药物， 持续性呼吸暂停（OIPA）。这些副作用导致了一个重大的公共卫生问题， 过量用药在2019年造成近5万人死亡，沿着的还有非致命性过量用药，这些过量用药会导致昂贵的， 延长住院时间。在COVID-19大流行期间，“阿片类药物流行病”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 识别可以阻断或逆转OIPA的分子的逻辑路径可以补充当前的治疗， 例如，在一个实施例中，有效性和安全性更高，半衰期更长，可能保留阿片类药物诱导的镇痛作用。阿片类药物抑制 呼吸由两个脑干神经回路的动作呼吸运动，前Bötzinger 复合体（preBötC）和臂旁核（PB），两者都含有表达μ-阿片样物质的神经元 受体（µ OR）。µ OR是抑制性G蛋白偶联受体（GPCR），可抑制神经元兴奋性。 前BötC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 对表达µ OR的preBötC和PB神经元中的RNA进行测序，以确定兴奋性 GPCR。先前在清醒小鼠中的研究旨在确定preBötC或PB是否介导了 阿片类药物过量期间的呼吸;然而，阿片类药物仅引起清醒小鼠中呼吸的适度减少， 与人类急性阿片类药物中毒时观察到的呼吸暂停相差甚远。因此我们建议 使用以下方法确定preBötC和/或PB是否是小鼠OIPA的主要原因， 我们一直在阿片类药物给药后引发完全呼吸暂停。我们将选择潜在目标 兴奋性GPCR受体，与µ OR共表达的结构，我们发现主要是 负责OIPA（preBötC和/或PB）。然后，我们将确定这些GPCR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产生数据， 这些受体激动剂作为潜在治疗剂的后续临床前和转化研究 逆转OIPA。处方阿片类药物是非常有效的止痛药，但过量可导致死亡 因为他们也停止了呼吸。每年有超过5万美国人死于阿片类药物过量。我们 他们建议识别受体，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.