Promotion of sleep by targeting the orexin system in rats, dogs and humans.
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.
Brisbare-Roch
Catherine
C
Research and Development, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Dingemanse
Jasper
J
Koberstein
Ralf
R
Hoever
Petra
P
Aissaoui
Hamed
H
Flores
Susan
S
Mueller
Celia
C
Nayler
Oliver
O
van Gerven
Joop
J
de Haas
Sanne L
SL
Hess
Patrick
P
Qiu
Changbin
C
Buchmann
Stephan
S
Scherz
Michael
M
Weller
Thomas
T
Fischli
Walter
W
Clozel
Martine
M
Jenck
François
F
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*
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