Age-dependent differences in opioid-induced respiratory depression

阿片类药物引起的呼吸抑制存在年龄依赖性差异

• 批准号: 8963016
• 负责人: Astrid G Stucke
• 金额: $ 24.89万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963016
• 关键词: Adult; Adverse effects; Affect; Age; Agonist; Analgesics; Anatomy; Apnea; Area; Bathing; Brain Stem; Breathing; Canis familiaris; Clinical; Complex; Data; Dependence; Development; Dorsal; Dose; Dose-Rate; Drug Kinetics; Electrodes; Excitatory Amino Acid Antagonists; Generations; Glutamate Agonist; In Vitro; Individual; Infant; Infusion procedures; Injection of therapeutic agent; Injury; Intravenous; Label; Laboratories; Lead; Life; Location; Mediating; Mental Depression; Methods; Microdialysis; Microinjections; Modeling; Monitor; Morphine; Naloxone; Narcotic Antagonists; Neonatal; Neurons; Neurotransmitters; Nuclear; Operative Surgical Procedures; Opioid; Opioid Analgesics; Opioid Rotation; Organism; Oryctolagus cuniculus; Pain; Pain management; Patients; Pattern; Perioperative; Pharmaceutical Preparations; Physiological; Play; Pontine structure; Postoperative Period; Predisposition; Preparation; Procedures; Publishing; Reflex action; Research; Respiratory Center; Risk; Role; Site; Staging; Testing; Therapeutic; Ventilatory Depression; age group; age related; biological adaptation to stress; clinical effect; clinically relevant; density; economic implication; immature animal; improved; in vivo; interest; intravenous injection; juvenile animal; mature animal; mu opioid receptors; neurotransmitter agonist; novel; parabrachial nucleus; public health relevance; receptor; receptor expression; remifentanil; respiratory; response; spatial relationship; young adult

 DESCRIPTION (provided by applicant): Opioids are potent analgesics that are frequently used for perioperative pain control. Their most dangerous side effect is life threatening respiratory depression, which poses a particular risk in young infants. In addition to well-known developmental differences in opioid pharmacokinetics, this susceptibility may also be due to immaturity of the respiratory center. In the perioperative setting, the increased risk for apnea in young infants often results in avoidance of opioids and substitution with less potent non-opioid analgesics, which may lead to a poorly controlled stress response and neurodevelopmental injury. Whenever opioids are used for invasive procedures, young infants require extended postoperative cardiorespiratory monitoring to detect respiratory depression, which has significant economic implications. It is thus of great clinical relevance to elicit the mechanisms f opioid-induced respiratory depression (OIRD) and especially to understand the differences between immature and adult organisms. Previous research has focused on opioid effects on the preBötzinger Complex (preBC), which is an important area of respiratory rhythm generation. Many of these studies, however, employed in vitro preparations, supraclinical concentrations of opioid agonists or methods that did not allow for precise localization of the study drug effect (e.g., microdialysis). Only one set of studies in in vivo adult dogs completely refuted the importance of the preBC and localized the effect of clinically relevant opioid concentrations to the parabrachial nucleus (PBN) in the pons. No in vivo studies have yet been published for immature animals. We have developed a unique decerebrate developmental in vivo rabbit preparation that investigates the effects of clinical opioid concentrations on functionally identifed areas in the brainstem with particular focus on age-dependent differences. The model has preserved physiological reflexes and intact neuronal networks and allows for localized nuclear injections of neurotransmitter and mu-opioid receptor agonists and antagonists, single neuron recordings and concomitant drug injections and for intravenous opioid infusions at clinical dose-rates. Preliminary studies in the preBC and PBN of young and adult rabbits have provided ample data indicating that (a) OIRD at clinical doses is mediated by different areas in young and adult rabbits, (b) the preBC is not the main area for OIRD, and (c) the PBN plays an important role in OIRD. The objective of the proposed study is to define the role of the PBN and its interplay with the preBC in clinical OIRD for young and adult animals. We will establish the degree to which bradypnea from intravenous opioids can be reversed in the PBN. We will determine the contributions of preBC and PBN to respiratory rate control, which are likely responsible for the age-dependent differences in opioid effect. We will further identify the anatomical projections of the PBN and neurotransmitters that stimulate the PBN and can thus antagonize OIRD. The results will allow better definition of the age group at risk for OIRD and will aid the development of specific therapeutic strategies to counteract this serious side effect of opioid analgesics.

 描述（由申请人提供）：阿片类药物是强效镇痛药，常用于围手术期疼痛控制。它们最危险的副作用是危及生命的呼吸抑制，这对幼儿构成特别的风险。除了众所周知的阿片药代动力学的发育差异外，这种易感性也可能是由于呼吸中枢的不成熟。在围手术期，呼吸暂停的风险增加， 幼儿经常避免使用阿片类药物，代之以效力较低的非阿片类镇痛药，这可能导致应激反应控制不良和神经发育损伤。每当阿片类药物用于侵入性手术时，婴幼儿需要延长术后心肺监测以检测呼吸抑制，这具有显著的经济意义。因此，这是非常重要的临床意义，以引出阿片类药物诱导的呼吸抑制（OIRD）的机制，特别是了解未成熟和成年生物体之间的差异。以前的研究集中在阿片类药物对前Bötzinger复合体（preBC）的影响，这是呼吸节律产生的重要领域。然而，这些研究中的许多采用了体外制剂、阿片类激动剂的临床上浓度或不允许研究药物作用的精确定位的方法（例如，微透析）。只有一组成年犬的体内研究完全否定了前BC的重要性，并将临床相关阿片类药物浓度的影响局限于脑桥的臂旁核（PBN）。尚未发表未成熟动物的体内研究。我们已经开发了一种独特的去大脑发育在体内兔制备，研究临床阿片类药物浓度对脑干功能鉴定区域的影响，特别关注年龄依赖性差异。该模型保留了生理反射和完整的神经元网络，并允许神经递质和μ-阿片受体激动剂和拮抗剂的局部核注射，单神经元记录和伴随药物注射，以及临床剂量率的静脉内阿片类药物输注。对幼兔和成年兔的前BC和PBN的初步研究提供了充足的数据，表明（a）临床剂量下的OIRD由幼兔和成年兔的不同区域介导，（B）前BC不是OIRD的主要区域，（c）PBN在OIRD中起重要作用。拟定研究的目的是确定PBN的作用及其与preBC在幼龄和成年动物临床OIRD中的相互作用。我们将确定静脉注射阿片类药物引起的呼吸缓慢在PBN中可以逆转的程度。我们将确定preBC和PBN对呼吸频率控制的贡献，这可能是阿片类药物作用的年龄依赖性差异的原因。我们将进一步确定PBN的解剖投影和刺激PBN的神经递质，从而拮抗OIRD。研究结果将允许更好地定义OIRD风险的年龄组，并将有助于制定具体的治疗策略，以抵消阿片类镇痛药的这种严重副作用。