The Dual Orexin Receptor Antagonist Almorexant Induces Sleep and Decreases Orexin-Induced Locomotion by Blocking Orexin 2 Receptors
| العنوان: | The Dual Orexin Receptor Antagonist Almorexant Induces Sleep and Decreases Orexin-Induced Locomotion by Blocking Orexin 2 Receptors |
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| المؤلفون: | Dorothee Abramowski, Hugo Bürki, Edi Schuepbach, Daniel Hoyer, Thomas Dürst, Géraldine M. Mang, Christine E. Gee, Markus Fendt, Stefan Imobersteg |
| المصدر: | Sleep. 35:1625-1635 |
| بيانات النشر: | Oxford University Press (OUP), 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Male, Receptors, Neuropeptide, medicine.medical_specialty, Sleep induction, Rapid eye movement sleep, Receptors, G-Protein-Coupled, Mice, Orexin-A, Orexin Receptors, Physiology (medical), Internal medicine, Acetamides, mental disorders, Dual Orexin Receptor Antagonist Almorexant Induces Sleep, medicine, Animals, Sympathomimetics, Wakefulness, Receptor, Orexins, Chemistry, Neuropeptides, digestive, oral, and skin physiology, Intracellular Signaling Peptides and Proteins, Antagonist, Isoquinolines, Orexin receptor, Orexin, Mice, Inbred C57BL, Endocrinology, nervous system, Neurology (clinical), Almorexant, Sleep, Locomotion, hormones, hormone substitutes, and hormone antagonists, psychological phenomena and processes, medicine.drug |
| الوصف: | Study Objectives: Orexin peptides activate orexin 1 and orexin 2 receptors (OX1R and OX2R), regulate locomotion and sleep-wake. The dual OX1R/OX2R antagonist almorexant reduces activity and promotes sleep in multiple species, including man. The relative contributions of the two receptors in locomotion and sleep/wake regulation were investigated in mice. Design: Mice lacking orexin receptors were used to determine the contribution of OX1R and OX2R to orexin A-induced locomotion and to almorex- ant-induced sleep. Setting: N/A. Patients or Participants: C57BL/6J mice and OX1R +/+ , OX1R -/- , OX2R +/+ , OX2R -/- and OX1R -/- /OX2R -/- mice. Interventions: Intracerebroventricular orexin A; oral dosing of almorexant. Measurements and Results: Almorexant attenuated orexin A-induced locomotion. As in other species, almorexant dose-dependently increased rapid eye movement sleep (REM) and nonREM sleep in mice. Almorexant and orexin A were ineffective in OX1R -/- /OX2R -/- mice. Both orexin A- induced locomotion and sleep induction by almorexant were absent in OX2R -/- mice. Interestingly, almorexant did not induce cataplexy in wild-type mice under conditions where cataplexy was seen in mice lacking orexins and in OX1R -/- /OX2R -/- mice. Almorexant dissociates very slowly from OX2R as measured functionally and in radioligand binding. Under non equilibrium conditions in vitro, almorexant was a dual antagonist whereas at equilibrium, almorexant became OX2R selective. Conclusions: In vivo, almorexant specifically inhibits the actions of orexin A. The two known orexin receptors mediate sleep induction by almorex- ant and orexin A-induced locomotion. However, OX2R activation mediates locomotion induction by orexin A and antagonism of OX2R is sufficient to promote sleep in mice. |
| تدمد: | 1550-9109 0161-8105 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::eef137a6c467aff3bce1d6018756c32aTest https://doi.org/10.5665/sleep.2232Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....eef137a6c467aff3bce1d6018756c32a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15509109 01618105 |
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