Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida.
Center for Respiratory Research and Rehabilitation, University of Florida, Gainesville, Florida.
J Neurophysiol. 2022 Nov 1;128(5):1117-1132. doi: 10.1152/jn.00113.2022. Epub 2022 Oct 5.
Opioids suppress breathing through actions in the brainstem, including respiratory-related areas of the dorsolateral pons, which contain multiple phenotypes of respiratory patterned neurons. The discharge identity of dorsolateral pontine neurons that are impacted by opioids is unknown. To address this, single neuronal units were recorded in the dorsolateral pons of arterially perfused in situ rat preparations that were perfused with an apneic concentration of the opioid agonist fentanyl, followed by the opioid antagonist naloxone (NLX). Dorsolateral pontine neurons were categorized based on respiratory-associated discharge patterns, which were differentially affected by fentanyl. Inspiratory neurons and a subset of inspiratory/expiratory phase-spanning neurons were either silenced or had reduced firing frequency during fentanyl-induced apnea, which was reversed upon administration of naloxone. In contrast, the majority of expiratory neurons continued to fire tonically during fentanyl-induced apnea, albeit with reduced firing frequency. In addition, pontine late-inspiratory and postinspiratory neuronal activity were absent from apneustic-like breaths during the transition to fentanyl-induced apnea and the naloxone-mediated transition to recovery. Thus, opioid-induced deficits in respiratory patterning may occur due to reduced activity of pontine inspiratory neurons, whereas apnea occurs with loss of all phasic pontine activity and sustained tonic expiratory neuron activity. Opioids can suppress breathing via actions throughout the brainstem, including the dorsolateral pons. The respiratory phenotype of dorsolateral pontine neurons inhibited by opioids is unknown. Here, we describe the effect of the highly potent opioid fentanyl on the firing activity of these dorsolateral pontine neurons. Inspiratory neurons were largely silenced by fentanyl, whereas expiratory neurons were not. We provide a framework whereby this differential sensitivity to fentanyl can contribute to respiratory pattern deficits and apnea.
阿片类药物通过脑干中的作用抑制呼吸，包括含有多种呼吸模式神经元的脑桥背外侧呼吸相关区域。受阿片类药物影响的脑桥背外侧神经元的放电特征尚不清楚。为了解决这个问题，我们在动脉灌注原位大鼠脑桥背外侧记录了单个神经元单位，这些大鼠在阿片类激动剂芬太尼的呼吸暂停浓度下进行灌注，随后灌注阿片类拮抗剂纳洛酮（NLX）。根据呼吸相关放电模式对脑桥背外侧神经元进行分类，这些模式受芬太尼的影响而不同。吸气神经元和一部分吸气/呼气相跨越神经元在芬太尼引起的呼吸暂停期间被沉默或放电频率降低，纳洛酮给药后恢复。相比之下，大多数呼气神经元在芬太尼引起的呼吸暂停期间继续持续放电，尽管放电频率降低。此外，在从芬太尼引起的呼吸暂停过渡到纳洛酮介导的恢复期间，类似呼吸暂停的呼吸中没有脑桥晚期吸气和吸气后神经元活动。因此，呼吸模式的阿片类药物诱导缺陷可能是由于脑桥吸气神经元活动减少所致，而呼吸暂停是由于所有相位脑桥活动丧失和持续的呼气神经元紧张性活动所致。阿片类药物可以通过整个脑干中的作用抑制呼吸，包括脑桥背外侧。阿片类药物抑制的脑桥背外侧神经元的呼吸表型尚不清楚。在这里，我们描述了强效阿片类药物芬太尼对这些脑桥背外侧神经元放电活动的影响。芬太尼很大程度上沉默了吸气神经元，而呼气神经元不受影响。我们提供了一个框架，说明这种对芬太尼的不同敏感性如何导致呼吸模式缺陷和呼吸暂停。
