Perinatal opioids impair maturation of vital respiratory networks

围产期阿片类药物损害重要呼吸网络的成熟

• 批准号: 10449914
• 负责人: Adrianne Genest Huxtable
• 金额: $ 17.46万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449914
• 关键词: Acute; Animal Model; Apnea; Autonomic nervous system; Basic Science; Birth; Breathing; Carbon Dioxide; Caring; Cells; Cessation of life; Childhood Acute Lymphocytic Leukemia; Clinical; Communication; Communication impairment; Conceptions; Confounding Factors (Epidemiology); Controlled Study; Data; Development; Diagnosis; Dose; Drug usage; Exhibits; Exposure to; Functional disorder; Homeostasis; Human; Immunohistochemistry; Impairment; In Vitro; Infant; Knowledge; Long-Term Effects; Modeling; Neonatal; Neonatal Abstinence Syndrome; Neurotransmitters; Opioid; Opioid Receptor; Outcome; Oxygen; Pathologic; Perinatal; Plethysmography; Pontine structure; Pregnancy; Pregnant Women; Publishing; Respiratory Failure; Respiratory System; Risk; Rodent; Rodent Model; Seizures; Sleep disturbances; Standardization; Stimulus; Sudden infant death syndrome; Symptoms; Syndrome; Temperature; Testing; Time; Tremor; Ventilatory Depression; Vulnerable Populations; Withdrawal Symptom; Work; base; clinical care; environmental stressor; fetal opioid exposure; gastrointestinal system; improved; in utero; in vivo; infant outcome; innovation; insight; interdisciplinary approach; maternal stress; multidisciplinary; neonate; neural circuit; neural network; neurophysiology; novel; opioid exposure; opioid overdose; opioid use; opioid use in pregnancy; polysubstance use; preBotzinger complex; prenatal exposure; relating to nervous system; respiratory; respiratory challenge; response; source localization; standard of care; tool

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.

项目概要 母亲接触阿片类药物后出生的患有新生儿戒断综合症 (NAS) 的婴儿数量为 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 网络的特征不明确。被诊断患有 NAS 的婴儿表现出多种负面结果，包括 对呼吸道并发症的了解仍知之甚少。临床上，这些婴儿接受外源性治疗 新生儿阿片类药物可抑制戒断症状，​​但尚无公认的标准临床剂量方案和 新生儿阿片类药物治疗的长期影响仍不清楚。该提案的目的是 了解孕产妇和新生儿阿片类药物暴露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颖的动物模型 为制定 NAS 治疗临床护理标准提供信息。与其他动物模型不同的是 从受孕开始母体阿片类药物，所提出的模型在呼吸网络活动开始时输送阿片类药物 在子宫内针对阿片类药物对网络成熟的直接影响。将测试两个具体假设：1) 母体阿片类药物通过破坏两个人之间的相互沟通而导致新生儿呼吸不稳定 呼吸网络； 2) 母体阿片类药物后新生儿急性、外源性阿片类药物促进病理 呼吸网络的成熟，加剧新生儿呼吸障碍并减弱对呼吸的反应 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 围产期阿片类药物后新生儿化学反射（对呼吸刺激的反应）受损。此外，我们的 初步数据表明，用急性阿片类药物治疗 NAS 婴儿会随着时间的推移增加呼吸暂停发作，强调 呼吸衰竭的脆弱性增加的窗口。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 Complex 的成熟受损 （控制呼吸的基本神经网络和对阿片类药物高度敏感）和沟通障碍 前Bötzinger复合体和面旁呼吸群（第二个，阿片类药物不敏感的呼吸群）之间 网络），独立于脑桥网络。对 NAS 婴儿呼吸受损机制的见解 只有在啮齿动物模型中采用创新的多学科方法才有可能实现。我们的实验方法 包括：呼吸的体内体积描记法评估、允许直接访问的体外神经生理学 控制呼吸的分离神经网络以及呼吸控制区域阿片受体的识别 使用免疫组织化学。拟议研究的结果将显着增进我们对 围产期阿片类药物损害呼吸控制网络成熟的机制。这些基本的 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，独立的 潜在的混杂变量，例如母亲压力和多物质使用，并了解如何 最好地治疗 NAS 婴儿——所有这些都是制定安全有效的护理标准所必需的第一步。