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Nonpeptide Orexin-2 Receptor Agonist Attenuates Morphine-induced Sedative Effects in Rats
Satoshi Toyama1, Naohito Shimoyama, Yugo Tagaito
1From 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.).
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.
Insights
Orexin receptor activation can reduce opioid-induced sleepiness and attention deficits. This study shows orexin-2 receptor agonist YNT-185 alleviates morphine
Area of Science:
- Neuroscience
- Pharmacology
- Sleep Research
Background:
- Opioids cause dose-limiting side effects like sleepiness and reduced attention.
- The orexin/hypocretin system is crucial for maintaining wakefulness.
- Investigating novel strategies to counteract opioid-induced sedation is essential.
Purpose of the Study:
- To explore the potential of a nonpeptide orexin receptor agonist to alleviate morphine-induced sedative effects.
- To evaluate the efficacy of YNT-185, an orexin type-2 receptor agonist, in mitigating morphine's CNS depressant actions.
- To assess the impact of orexin system modulation on EEG and behavioral measures of sedation.
Main Methods:
- Sedative effects of morphine were assessed in rats using electroencephalogram (EEG), locomotor activity, and acoustic startle response.
- The effects of intracerebroventricular orexin-A and systemic YNT-185 on morphine-induced EEG changes were examined.
- Locomotor activity and acoustic startle response were measured in rats treated with morphine alone or in combination with YNT-185.
Main Results:
- Morphine induced significant EEG changes indicative of sedation, including increased slow-wave activity.
- YNT-185 and orexin-A attenuated morphine-induced EEG alterations.
- YNT-185 prevented the decrease in locomotor activity and shortened the startle response latency caused by morphine.
Conclusions:
- Orexin-A and YNT-185 demonstrated efficacy in attenuating morphine-induced sedative effects.
- Results suggest that orexin-2 receptor activation can counteract opioid-induced sedation.
- Targeting the orexin system may offer a therapeutic approach to manage opioid side effects.
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