Perinatal opioids impair maturation of vital respiratory networks

项目总结 母亲接触阿片类药物后出生时患有新生儿禁欲综合征的婴儿人数是 急剧上升，但围产期(母亲+新生儿)阿片类药物对神经成熟的直接影响 网络的特征并不是很好。被诊断为NAS的婴儿表现出各种负面结果，包括 仍然知之甚少的呼吸道并发症。临床上，这些婴儿接受外源性药物治疗。 新生儿阿片类药物可抑制戒断症状，但目前还没有公认的标准临床剂量制度和 新生儿阿片类药物治疗的长期效果尚不清楚。这项建议的目的是 了解母亲和新生儿接触阿片类药物对成熟和完善的直接影响 维持呼吸的重要呼吸控制网络。该项目将利用一种新的动物模型 为制定治疗NAS的临床护理标准提供信息。与其他动物模型不同的是 母体阿片类药物从受孕开始，所提出的模型在呼吸网络活动开始时递送阿片类药物 在子宫内靶向阿片类药物对网络成熟的直接影响。将检验两个具体的假设：1) 母体阿片类药物通过扰乱新生儿呼吸之间的相互交流而导致新生儿呼吸不稳定 呼吸网络；2)母体阿片促进病理后新生儿的急性外源性阿片 呼吸网络的成熟，加强新生儿的呼吸损伤和钝化对 急性阿片类药物。我们最近发表的使用该模型的研究显示，呼吸暂停(呼吸暂停)增加 以及围产期阿片类药物后新生儿的化学反射受损(对呼吸刺激的反应)。此外，我们的 初步数据表明，用急性阿片类药物治疗NAS婴儿随着时间的推移会增加呼吸暂停发作，强调 呼吸衰竭的易感性增加的窗口。我们的数据开始定位呼吸的来源 围产期阿片类药物后的缺陷，我们假设包括Prebötzinger复合体成熟受损 (控制呼吸的基础神经网络和高度阿片类药物敏感)和沟通障碍 在Prebötzinger复合体和面旁呼吸组(第二组，阿片类药物不敏感的呼吸组)之间 网络)，独立于桥式网络。对NAS婴儿呼吸障碍机制的这些见解 只有在啮齿动物模型中采用创新的、多学科的方法才有可能。我们的实验方法 包括：体内呼吸体积描记术评估，体外神经生理学允许直接进入 控制呼吸的孤立神经网络和呼吸控制区阿片受体的识别 用免疫组织化学的方法。拟议的研究结果将极大地促进我们对 围产期阿片类药物损害呼吸控制网络成熟的机制。这些基本 科学研究对于表征阿片类药物对成熟的独立神经网络的直接影响至关重要 潜在的混杂变量，如母亲压力和多种物质的使用，并了解如何 最佳治疗NAS婴儿--所有这些都是制定安全有效的护理标准的必要的第一步。

PROJECT SUMMARY The number of infants born with Neonatal Abstinence Syndrome (NAS) after maternal opioid exposure is dramatically rising, yet the direct effects of perinatal (maternal + neonatal) opioids on the maturation of neural networks is not well-characterized. Infants diagnosed with NAS exhibit diverse negative outcomes, including respiratory complications that remain poorly understood. Clinically, these infants are treated with exogenous neonatal opioids to curb the withdrawal symptoms, but there is no accepted standard clinical dosing regime and the long-term effects of neonatal opioids treatment remain unclear. The objective of this proposal is to understand the direct effects of maternal and neonatal opioid exposure on the maturation and refinement of vital respiratory control networks maintaining breathing. This project will utilize a novel animal model to inform the development of a clinical standard of care to treat NAS. Unlike other animal models delivering maternal opioids from conception, the proposed model delivers opioids at the onset of respiratory network activity in utero to target the direct effects of opioids on network maturation. Two specific hypotheses will be tested: 1) Maternal opioids cause instability in neonatal breathing by disrupting reciprocal communication between two respiratory networks; 2) Acute, exogenous opioids in neonates after maternal opioids promote pathological maturation of respiratory networks, potentiating neonatal breathing impairments and blunting the response to acute opioids. Our recently published work using this model showed increased apneas (pauses in breathing) and impaired chemoreflexes (responses to respiratory stimuli) in neonates after perinatal opioids. Further, our preliminary data suggest treating NAS infants with acute opioids increase apneic episodes over time, highlighting windows of increased vulnerability for respiratory failure. Our data begin to localize the source of breathing deficits after perinatal opioids, which we hypothesize include impaired maturation of the preBötzinger Complex (fundamental neural network controlling breathing and highly opioid-sensitive) and impaired communication between the preBötzinger Complex and parafacial respiratory group (a second, opioid-insensitive respiratory network), independent of pontine networks. Such insights into mechanisms of impaired breathing in NAS infants are only possible with an innovative, multidisciplinary approach in a rodent model. Our experimental approaches include: in vivo plethysmography assessment of breathing, in vitro neurophysiology allowing direct access to the isolated neural networks controlling breathing, and identification of opioid receptors in respiratory control regions using immunohistochemistry. Results from the proposed studies will significantly advance our understanding of the mechanisms by which perinatal opioids impair maturation of respiratory control networks. These basic science studies are vital to characterizing the direct effects of opioids on maturing neural networks, independent of potential confounding variables such as maternal stress and polysubstance use, and to understanding how to best treat NAS infants – all of which are necessary first steps in developing safe and effective standards of care.