Recruiting active expiration to overcome opioid-induced persistent 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，特别是阿片类药物引起的副作用。 持续性呼吸暂停(OIPA)。这些副作用随之而来的是一个重大的公共卫生问题，因为过量服用几乎导致 2019年有5万人死亡，加上非致命的过量，导致昂贵的住院治疗，而且往往延长了住院时间。这个 新冠肺炎大流行期间阿片类药物流行进一步加速，人工合成致死病例增加38% 与2019年相比，阿片类药物过量(主要是芬太尼)。我们提出了一种逻辑路径来识别能够 主动呼气，从而增加对阿片类药物的耐受性。这些分子可能会补充目前的治疗方法 对于OIPA，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。阿片类药物抑郁 通过作用于吸气节律产生区域的呼吸，Prebötzinger复合体(PrebötC)，直接通过 激活PrebötC的微阿片受体，或通过抑制臂旁核的紧张性驱动间接激活 PrebötC.µOR是抑制性G蛋白偶联受体(GPCRs)，可抑制神经元的兴奋性。副面肌 呼吸组(PF)包含一个主动呼气振荡器，它独立于PrebötC，对阿片类药物不敏感， 在休息时是安静的，但在某些情况下会变得活跃，例如运动、高二氧化碳。当它处于活动状态时，它被紧紧地 再加上灵感。我们建议表达兴奋性GPCRHM3Dq受体(设计者受体 被特制药物激活)，并测试这些受体的激活是否会增加所需的芬太尼剂量 会导致持续性呼吸暂停。然后，我们将对PF神经元进行测序，以确定内源性兴奋性神经元的表达 并测试这些GPCRs激动剂在增加生产所需的芬太尼剂量方面的效果 麻醉小鼠的持续性呼吸暂停。这一探索性项目的成功将为后续的临床前研究提供数据 以及这些受体激动剂作为预防OIPA的潜在治疗药物的翻译研究。

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.