title: Promotion of sleep by targeting the orexin system in rats, dogs and humans.
abstract: Orexins 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 OX(1) and OX(2) 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 GABA(A) 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.
authors.affiliation: Research and Development, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Brisbare-Roch
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
authors.forename: Ralf
authors.initials: R
authors.lastname: Koberstein
authors.forename: Petra
authors.initials: P
authors.lastname: Hoever
authors.forename: Hamed
authors.initials: H
authors.lastname: Aissaoui
authors.forename: Susan
authors.initials: S
authors.lastname: Flores
authors.forename: Celia
authors.initials: C
authors.lastname: Mueller
authors.forename: Oliver
authors.initials: O
authors.lastname: Nayler
authors.forename: Joop
authors.initials: J
authors.lastname: van Gerven
authors.forename: Sanne L
authors.initials: SL
authors.lastname: de Haas
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Changbin
authors.initials: C
authors.lastname: Qiu
authors.forename: Stephan
authors.initials: S
authors.lastname: Buchmann
authors.forename: Michael
authors.initials: M
authors.lastname: Scherz
authors.forename: Thomas
authors.initials: T
authors.lastname: Weller
authors.forename: Walter
authors.initials: W
authors.lastname: Fischli
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
authors.forename: François
authors.initials: F
authors.lastname: Jenck
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007034:Hypothalamus, Posterior / Q000187:drug effects* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology; D007546:Isoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009479:Neuropeptides / Q000378:metabolism* / Q000502:physiology; D064446:Orexin Receptors; D000068797:Orexins; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D012895:Sleep, REM / Q000187:drug effects*; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000081:Acetamides; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D044005:Tetrahydroisoquinolines; C519150:almorexant