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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.).
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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