ADVERTISEMENT
CURRENT ISSUE
APRIL 2014
KINDLE EDITION


SLEEP Seeking New Editor

The APSS is seeking qualified candidates for editor-in-chief of SLEEP



SEARCH JOURNAL ARCHIVES


SEARCH PUBMED


MANUSCRIPT SUBMISSIONS


SUBSCRIBE TO SLEEP

CONTINUING MEDICAL EDUCATION


ADVERTISE WITH US


ABOUT SLEEP

ABSTRACT SUPPLEMENTS


ACCEPTED PAPERS
Bookmark and Share         RSS Feed

VOLUME 35, ISSUE 12

DUAL OREXIN RECEPTOR ANTAGONIST ALMOREXANT INDUCES SLEEP
The Dual Orexin Receptor Antagonist Almorexant Induces Sleep and Decreases Orexin-Induced Locomotion by Blocking Orexin 2 Receptors

http://dx.doi.org/10.5665/sleep.2232

Géraldine M. Mang, MSc1,2; Thomas Dürst1; Hugo Bürki1; Stefan Imobersteg1; Dorothee Abramowski1; Edi Schuepbach1; Daniel Hoyer, PhD1,3; Markus Fendt, PhD1,4; Christine E. Gee, PhD1,5

1Novartis Institutes for BioMedical Research, Basel, Switzerland; 2University of Lausanne, Lausanne, Switzerland; 3Department of Pharmacology, School of Medicine, The University of Melbourne, Parkville, Victoria, Australia; 4Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany; 5Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany



  Expand  Table of Contents    
Text size:  

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.

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 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.

Citation:

Mang GM; Dürst T; Bürki H; Imobersteg S; Abramowski D; Schuepbach E; Hoyer D; Fendt M; Gee CE. The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors. SLEEP 2012;35(12):1625-1635.

Expand  Table of Contents
ADVERTISEMENT
Classifieds View SLEEP 2011 Poster Presentations Online