Age-dependent differences in opioid-induced respiratory depression

 描述(申请人提供)：阿片类药物是一种有效的止痛药，经常用于围术期疼痛控制。它们最危险的副作用是危及生命的呼吸抑制，这对幼儿构成了特别大的风险。除了众所周知的阿片类药物药代动力学发育差异外，这种敏感性也可能是由于呼吸中枢的不成熟所致。在围手术期环境中，呼吸暂停的风险增加 婴幼儿经常避免使用阿片类药物，而代之以效力较弱的非阿片类镇痛剂，这可能会导致应激反应和神经发育损伤的控制不良。当阿片类药物用于侵入性手术时，幼儿需要延长术后心肺监测以检测呼吸抑制，这具有重大的经济影响。因此，了解阿片类药物引起呼吸抑制的机制，特别是了解未成熟生物和成年生物之间的差异，具有重要的临床意义。以前的研究集中在阿片类药物对Prebötzinger复合体(Prebc)的影响，这是呼吸节律产生的一个重要领域。然而，这些研究中的许多使用了体外制剂、阿片类激动剂的临床超临床浓度或不允许精确定位研究药物效果的方法(例如，微透析)。只有一组在活体成年犬的研究完全驳斥了前BC的重要性，并定位了临床相关阿片浓度对桥臂旁核(PBN)的影响。目前还没有针对未成熟动物的体内研究发表。我们开发了一种独特的去大脑发育的活体兔子制剂，研究了临床阿片类药物浓度对脑干功能识别区域的影响，特别关注年龄相关性差异。该模型保留了生理反射和完整的神经元网络，允许局部核注射神经递质和Mu-阿片受体激动剂和拮抗剂，单个神经元记录和伴随的药物注射，以及以临床剂量率静脉注射阿片类药物。对幼兔和成年兔的前BC和PBN的初步研究表明：(A)临床剂量的OIRD在幼兔和成年兔中是由不同的区域介导的；(B)前BC不是OIRD的主要区域；(C)PBN在OIRD中起着重要作用。本研究的目的是明确PBN在幼年和成年动物临床OIRD中的作用及其与前BC的相互作用。我们将确定静脉注射阿片类药物引起的呼吸暂停在多大程度上可以在PBN中逆转。我们将确定前BC和PBN对呼吸频率控制的贡献，这可能是阿片类药物作用随年龄变化的原因。我们将进一步确定PBN的解剖投射和刺激PBN从而拮抗OIRD的神经递质。这一结果将有助于更好地定义OIRD的风险年龄组，并将有助于制定具体的治疗策略，以对抗阿片类镇痛剂的这种严重副作用。

 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.