The Dual Orexin Receptor Antagonist Almorexant Induces Sleep and Decreases Orexin-Induced Locomotion by Blocking Orexin 2 Receptors (original) (raw)

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1Novartis Institutes for BioMedical Research, Basel, Switzerland

2University of Lausanne, Lausanne, Switzerland

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1Novartis Institutes for BioMedical Research, Basel, Switzerland

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1Novartis Institutes for BioMedical Research, Basel, Switzerland

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1Novartis Institutes for BioMedical Research, Basel, Switzerland

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1Novartis Institutes for BioMedical Research, Basel, Switzerland

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1Novartis Institutes for BioMedical Research, Basel, Switzerland

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1Novartis Institutes for BioMedical Research, Basel, Switzerland

3Department of Pharmacology, School of Medicine, The University of Melbourne, Parkville, Victoria, Australia

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1Novartis Institutes for BioMedical Research, Basel, Switzerland

4Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

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1Novartis Institutes for BioMedical Research, Basel, Switzerland

5Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

DISCLOSURE STATEMENT

This study was performed at and funded by the Novartis Institutes for BioMedical Research, the research arm of Novartis AG. Ms. Mang received a student stipend from Novartis while working on this study for her Master's degree. All other authors are/were employed by NIBR, received their salaries from and potentially own stock in the company.

*Address correspondence to: Christine E. Gee, PhD, Institute for Synaptic Physiology, Center for Molecular Neurobiology (ZMNH), Falkenried 94, D-20251 Germany; Tel: +49 (0)40 81989193; E-mail: christine.gee@zmnh.uni-hamburg.de

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Received:

01 January 2012

Revision received:

01 June 2012

Published:

01 December 2012

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Géraldine M. Mang, Thomas Dürst, Hugo Bürki, Stefan Imobersteg, Dorothee Abramowski, Edi Schuepbach, Daniel Hoyer, Markus Fendt, Christine E. Gee, The Dual Orexin Receptor Antagonist Almorexant Induces Sleep and Decreases Orexin-Induced Locomotion by Blocking Orexin 2 Receptors, Sleep, Volume 35, Issue 12, 1 December 2012, Pages 1625–1635, https://doi.org/10.5665/sleep.2232
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Abstract

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 almorexant-induced sleep.

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 almorexant 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.

© 2012 Associated Professional Sleep Societies, LLC.

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