μ opioid receptor activation hyperpolarizes respiratory-controlling Kolliker-Fuse neurons and suppresses post-inspiratory drive
μ opioid receptor activation hyperpolarizes respiratory-controlling Kolliker-Fuse neurons and suppresses post-inspiratory drive
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DOI：
10.1113/jp270822
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发表时间：
2015-10-01
影响因子：
5.5
通讯作者：
Williams, John T.
中科院分区：
文献类型：
--
作者：
Levitt, Erica S.;Abdala, Ana P.;Williams, John T.
阿片类药物引起的呼吸影响包括误吸和吞咽困难，提示上呼吸道受损。脑桥Kolliker-Ehrmann核（KF）控制上气道通畅并调节呼吸，特别是吸气/呼气相变。鉴于KF在协调呼吸模式中的重要性，在系统和细胞水平上研究了该核中μ阿片受体激活的机制。在麻醉的、迷走神经完整的大鼠中，向KF中注射阿片激动剂DAMGO或[Met（5）]脑啡肽（ME）降低呼吸频率和振幅。μ阿片激动剂DAMGO直接应用于大鼠原位动脉灌注工作心-脑干制备物的KF中，导致强烈的呼吸暂停（由于吸气后驱动丧失而延长的低幅度吸气），其被阿片拮抗剂纳洛酮迅速逆转。在脑切片制剂中，KF神经元上的μ阿片受体的激活使不同的神经元群体（61%）超极化。正如预期的那样，阿片类药物诱导的超极化降低了神经元对电流注射或局部应用谷氨酸的兴奋性。在电压钳记录的阿片激动剂ME产生的外向电流是浓度依赖性的，在钾平衡电位逆转，并被氯化钡，G蛋白偶联的内向整流钾（GIRK）电导的特征。临床上使用的药物吗啡在KF神经元中产生外向电流，其效力与蓝斑脑切片制备中吗啡介导的电流相似。因此，由μ阿片激动剂超极化的KF神经元群体可能是阿片诱导的吸气后损失和诱导呼吸暂停的介质。
Opioid-induced respiratory effects include aspiration and difficulty swallowing, suggesting impairment of the upper airways. The pontine Kolliker-Fuse nucleus (KF) controls upper airway patency and regulates respiration, in particular the inspiratory/expiratory phase transition. Given the importance of the KF in coordinating respiratory pattern, the mechanisms of mu opioid receptor activation in this nucleus were investigated at the systems and cellular level. In anaesthetized, vagi-intact rats, injection of opioid agonists DAMGO or [Met(5)] enkephalin (ME) into the KF reduced respiratory frequency and amplitude. The mu opioid agonist DAMGO applied directly into the KF of the in situ arterially perfused working heart-brainstem preparation of rat resulted in robust apneusis (lengthened low amplitude inspiration due to loss of post-inspiratory drive) that was rapidly reversed by the opioid antagonist naloxone. In brain slice preparations, activation of mu opioid receptors on KF neurons hyperpolarized a distinct population (61%) of neurons. As expected, the opioid-induced hyperpolarization reduced the excitability of the neuron in response to either current injection or local application of glutamate. In voltage-clamp recordings the outward current produced by the opioid agonist ME was concentration dependent, reversed at the potassium equilibrium potential and was blocked by BaCl2, characteristics of a G protein-coupled inwardly rectifying potassium (GIRK) conductance. The clinically used drug morphine produced an outward current in KF neurons with similar potency to morphine-mediated currents in locus coeruleus brain slice preparations. Thus, the population of KF neurons that are hyperpolarized by mu opioid agonists are likely mediators of the opioid-induced loss of post-inspiration and induction of apneusis.