Satoshi Toyama1, Naohito Shimoyama, Yugo Tagaito, Hiroshi Nagase, Tsuyoshi Saitoh, Masashi Yanagisawa, Megumi Shimoyama. 1. 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.).
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
BACKGROUND: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. METHODS: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. RESULTS: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). CONCLUSIONS: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.
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