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：
10670213
负责人：
Adrianne Genest Huxtable
金额：
$ 21.08万
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/10670213
关键词：
Accidents Acute Animal Model Apnea Autonomic nervous system Basic Science Birth Breathing Carbon Dioxide Caring Cells Central Nervous System 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 Reflex action 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 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 neural circuit neural network neurophysiology novel opioid exposure opioid overdose opioid use opioid use in pregnancy polysubstance use preBotzinger complex prenatal exposure 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.

项目摘要母体阿片类药物暴露后出生的新生儿禁欲综合征（NAS）的婴儿人数为动态上升，但围产期（母体 +新生儿）阿片类药物对神经的成熟的直接影响网络没有很好的特征。婴儿诊断为NAS暴露潜水员的婴儿负面结果，包括呼吸并发症的理解还不足。临床上，这些婴儿用外源治疗新生儿阿片类药物可以遏制戒断症状，但没有公认的标准临床给药制度和新生儿阿片类药物治疗的长期作用尚不清楚。该提议的目的是了解母体和新生儿阿片类药物暴露对成熟和改进的直接影响维持呼吸的重要呼吸控制网络。这个项目将利用一种新型的动物模型告知开发临床护理标准以治疗NAS。与其他动物模型不同概念的产妇阿片类药物，拟议的模型在呼吸网络活动开始时提供阿片类药物在子宫内，以靶向阿片类药物对网络成熟的直接影响。将测试两个特定的假设：1）产妇阿片类药物通过破坏两个之间的相互交流而导致新生儿呼吸的不稳定呼吸网络； 2）孕产妇阿片类药物后，新生儿的急性外源阿片类药物促进病理呼吸网络的成熟，潜在的新生儿呼吸障碍并削弱了对急性阿片类药物。我们最近发表的使用此模型显示的工作显示了增加的呼吸暂停（呼吸中的暂停）围产期阿片类药物后，新生儿的化学反射症（对呼吸刺激的反应）受损。此外，我们的初步数据表明，随着时间的流逝，用急性阿片类药物治疗NAS婴儿会增加呼吸暂停发作，突出显示增加呼吸衰竭脆弱性的窗户。我们的数据开始定位呼吸源围产期阿片类药物后的缺陷，我们假设这包括prebötzinger络合物的成熟受损（控制呼吸和高度阿片类药物敏感的基本神经网络）和沟通受损在Prebötzinger复合体和副呼吸组之间（第二，阿片类药物不敏感的呼吸道网络），独立于庞蒂恩网络。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使用创新的多学科方法才有可能。我们的实验方法包括：体内呼吸评估，体外神经生理学，允许直接进入孤立的神经网络控制呼吸和识别呼吸控制区域的阿片受体使用免疫组织化学。拟议研究的结果将大大提高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神经网络的直接影响至关重要，独立潜在的混杂变量（例如材料压力和多物质使用），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护理标准的必要第一步。