Recruiting active expiration to overcome opioid-induced persistent apnea

摘要 虽然处方阿片类药物是特殊的镇痛剂，但它们具有显著的副作用，特别是阿片类药物诱导的副作用。 持续性呼吸暂停（OIPA）。一个重大的公共卫生问题，从这些副作用，因为过量造成几乎 2019年有5万人死亡，沿着非致命性过量用药，导致昂贵且往往延长的住院治疗。的 在COVID-19大流行期间，“阿片类药物流行病”进一步加速，合成阿片类药物导致的死亡增加了38%。 阿片类药物过量（主要是芬太尼）与2019年相比。我们提出了一个合理的途径来识别分子， 积极呼气，从而增加阿片类药物的耐受性。这些分子可以补充目前的治疗方法 对于OIPA，例如，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 通过作用于吸气节律产生区域，即前Bötinger复合体（preBötC）进行呼吸，或者直接通过 激活preBötC中的μ-阿片受体（μ OR），或间接通过抑制臂旁核的紧张性驱动， preBötC.µ OR是抑制性G蛋白偶联受体（GPCR），可抑制神经元兴奋性。面旁的 呼吸组（pF）包含一个主动呼气振荡器，它不依赖于preBötC，对阿片类药物不敏感， 安静时安静，但在某些条件下可以变得活跃，例如运动，高CO2。当它活跃的时候， 再加上灵感。我们提出表达兴奋性GPCR HM 3Dq受体（设计受体仅 并测试这些受体的激活是否会增加所需芬太尼的剂量 造成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。 GPCR的激动剂，并测试这些GPCR的激动剂在增加产生芬太尼所需的剂量中的功效。 麻醉小鼠的持续性呼吸暂停。该探索性项目的成功将为后续临床前研究提供数据。 以及这些受体的激动剂作为预防OIPA的潜在治疗剂的翻译研究。

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.