From the Department of Neuroscience (S.T.) and the Center for Neuroscience of Pain (N.S., M.S.), Jikei University School of Medicine, Tokyo, Japan; Department of Critical Care and Anesthesia, National Center for Child Health and Development, Tokyo, Japan (S.T.); Department of Palliative Medicine, Jikei University Hospital, Tokyo, Japan (N.S., M.S.); Department of Anesthesiology, Teikyo University Chiba Medical Center, Ichihara, Japan (Y.T); and the International Institute for Integrative Sleep Medicine (World Premier International Research Center Initiative), University of Tsukuba, Tsukuba, Japan (H.N., T.S., M.Y.).
Anesthesiology. 2018 May;128(5):992-1003. doi: 10.1097/ALN.0000000000002161.
Sleepiness and decrease in attention are dose-limiting side effects of opioids. The orexin/hypocretin system plays an important role in maintaining wakefulness. This study aimed to explore the potential of a nonpeptide orexin receptor agonist to alleviate morphine-induced sedative effects.
Morphine sedative effects were evaluated as changes in electroencephalogram (EEG), locomotor activity, and acoustic startle response in rats (n = 5 to 9 per group). Effects of intracerebroventricular orexin-A and systemic orexin type-2 receptor agonist, YNT-185, on EEG changes induced by morphine were examined. Furthermore, the authors examined effects of morphine administered with or without YNT-185 on locomotor activity and on acoustic startle response.
Morphine-induced, frequent, short epochs of increased power (total epoch duration: 0.5 [0.0 to 8.0] s/10 min during baseline vs. 74.0 [49.0 to 115.0] s/10 min during the post-morphine administration period; P = 0.012). EEG analyses revealed that morphine-induced, high-amplitude, slow activity (increase in spectral power of frequencies less than 15 Hz, baseline vs. postmorphine; P < 0.001). Orexin-A and YNT-185 attenuated these changes. Locomotor activity decreased after morphine (268 [103 to 889] ambulatory movement counts during baseline period [20 min] vs. 138 [7 to 434] counts during 40 to 59 min postadministration; P = 0.012), but did not change after morphine with YNT-185 (363 [121 to 636] vs. 864 [381 to 1092] counts, difference within morphine + YNT-185 group; P = 0.071). Startle response latency was longer after morphine (26 [20 to 28] ms) than after morphine with YNT-185 (17 [16 to 18] ms; P = 0.012).
Orexin-A and/or YNT-185 attenuated morphine-induced sedative effects assessed by EEG changes and behavioral measures in rats. The authors' results suggest that orexin-2 receptor activation alleviates morphine-induced sedative effects.
困倦和注意力下降是阿片类药物的剂量限制副作用。食欲素/下丘脑分泌素系统在维持清醒方面起着重要作用。本研究旨在探讨非肽类食欲素受体激动剂缓解吗啡引起的镇静作用的潜力。
通过脑电图（EEG）、运动活动和大鼠听觉惊跳反应评估吗啡的镇静作用（每组 5 至 9 只）。研究了脑室注射食欲素-A 和全身食欲素 2 型受体激动剂 YNT-185 对吗啡诱导的 EEG 变化的影响。此外，作者还研究了吗啡与 YNT-185 联合应用对运动活动和听觉惊跳反应的影响。
吗啡诱导的 EEG 频繁出现短暂的功率增加（总时段：基础期 0.5 [0.0 至 8.0] s/10 min，与给药后 74.0 [49.0 至 115.0] s/10 min 相比；P = 0.012）。EEG 分析表明，吗啡诱导的高振幅慢波活动（小于 15 Hz 的频谱功率增加，基础期与给药后相比；P < 0.001）。食欲素-A 和 YNT-185 减弱了这些变化。吗啡后运动活动减少（基线期 20 分钟内的活动计数为 268 [103 至 889]，给药后 40 至 59 分钟内为 138 [7 至 434]；P = 0.012），但与 YNT-185 联合吗啡后没有变化（363 [121 至 636] 与 864 [381 至 1092] 计数，联合吗啡+YNT-185 组内差异；P = 0.071）。听觉惊跳反应潜伏期在吗啡后延长（26 [20 至 28] ms），而在 YNT-185 后则缩短（17 [16 至 18] ms；P = 0.012）。
在大鼠中，食欲素-A 和/或 YNT-185 减弱了 EEG 变化和行为测量评估的吗啡引起的镇静作用。作者的结果表明，食欲素 2 型受体激活可缓解吗啡引起的镇静作用。
