Perinatal opioids impair maturation of vital respiratory networks

项目摘要 在母亲暴露于阿片类药物后出生的新生儿戒断综合征（NAS）的婴儿数量是 急剧上升，但围产期（母体+新生儿）阿片类药物对神经成熟的直接影响， 网络没有很好的特点。被诊断患有NAS的婴儿表现出多种负面结果，包括 呼吸系统并发症仍然知之甚少。临床上，这些婴儿接受外源性 新生儿阿片类药物，以遏制戒断症状，但没有公认的标准临床给药方案， 新生儿类阿片治疗的长期效果仍不清楚。这项建议的目的是 了解母体和新生儿阿片类药物暴露对成熟和精炼的直接影响 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， 母体阿片类药物从概念，提出的模型提供阿片类药物在呼吸网络活动的发病 在子宫内靶向阿片类药物对网络成熟的直接影响。将检验两个具体假设：1） 母体阿片类药物通过破坏两个之间的相互通信导致新生儿呼吸不稳定 2）母体阿片类药物促进病理性阿片类药物后新生儿中的急性外源性阿片类药物 成熟的呼吸网络，加强新生儿呼吸障碍和钝化的反应， 急性阿片类药物我们最近发表的使用该模型的工作显示，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（对呼吸刺激的反应）受损。此外，我们的 初步数据表明，随着时间的推移，用急性阿片类药物治疗NAS婴儿会增加呼吸暂停发作， 呼吸衰竭的脆弱性增加的窗口。我们的数据开始定位呼吸源 围产期阿片类药物后的缺陷，我们假设包括前Bötzinger复合体成熟受损 （控制呼吸和高度阿片类药物敏感的基本神经网络）和受损的沟通 在前Bötzinger复合体和旁面呼吸组之间（第二，阿片类不敏感的呼吸组）， 网络），独立于脑桥网络。这些见解的机制，呼吸受损的NAS婴儿 只有在啮齿动物模型中采用创新的多学科方法才有可能。我们的实验方法 包括：呼吸的体内体积描记法评估，允许直接进入 控制呼吸的孤立神经网络，以及呼吸控制区域中阿片受体的识别 免疫组织化学。拟议研究的结果将大大促进我们对以下问题的理解： 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 科学研究对于描述阿片类药物对成熟神经网络的直接影响至关重要， 潜在的混杂变量，如产妇压力和多种物质的使用，并了解如何 最好的治疗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.