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Article abstract

Nature Medicine 13, 150 - 155 (2007)

Published online: 28 January 2007 | doi:10.1038/nm1544

Promotion of sleep by targeting the orexin system in rats, dogs and humans

Catherine Brisbare-Roch1, Jasper Dingemanse1, Ralf Koberstein1, Petra Hoever1, Hamed Aissaoui1, Susan Flores1, Celia Mueller1, Oliver Nayler1, Joop van Gerven2, Sanne L de Haas2, Patrick Hess1, Changbin Qiu3, Stephan Buchmann1, Michael Scherz1, Thomas Weller1, Walter Fischli1, Martine Clozel1 & François Jenck1

AbstractOrexins are hypothalamic peptides that play an important role in maintaining wakefulness in mammals. Permanent deficit in orexinergic function is a pathophysiological hallmark of rodent, canine and human narcolepsy. Here we report that in rats, dogs and humans, somnolence is induced by pharmacological blockade of both orexin OX1 and OX2 receptors. When administered orally during the active period of the circadian cycle, a dual antagonist increased, in rats, electrophysiological indices of both non-REM and, particularly, REM sleep, in contrast to GABAA receptor modulators; in dogs, it caused somnolence and increased surrogate markers of REM sleep; and in humans, it caused subjective and objective electrophysiological signs of sleep. No signs of cataplexy were observed, in contrast to the rodent, dog or human narcolepsy syndromes. These results open new perspectives for investigating the role of endogenous orexins in sleep-wake regulation.

1. Research and Development, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
2. Centre for Human Drug Research, Zernikedreef 10, 2333 CL Leiden, The Netherlands.
3. Shanghai Institute of Materia Medica, Actelion Joint Laboratories, Institute for Biological Sciences of the Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, 555 Zu Chong Zhi Road, Shanghai 201203, China.

Correspondence to: François Jenck1 e-mail: francois.jenck@actelion.com