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

基本信息

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
项目类别：
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

项目摘要

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被诊断患有 NAS 的婴儿表现出多种负面结果，包括临床上对这些婴儿的呼吸系统并发症仍知之甚少。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该项目将利用一种新颖的动物模型来维持呼吸。与其他动物模型不同的是，它为治疗 NAS 的临床护理标准的制定提供了信息。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进行测试：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 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的化学反射（对呼吸刺激的反应）受损。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，我们能够将其包括 preBötzinger 复合物的成熟受损（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 复合体和面旁呼吸组（第二种对阿片类药物不敏感的呼吸组）之间网络），独立于脑桥网络，这种对 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能实现。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所提出的研究结果将显着增进我们的理解。围产期阿片类药物损害呼吸网络控制成熟的机制。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。