1. Promotion of sleep by targeting the orexin system in rats, dogs and humans
- Author
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Thomas Weller, Hamed Aissaoui, Francois Jenck, Patrick Hess, Susan Flores, Ralf Koberstein, Petra Hoever, Catherine Brisbare-Roch, Jasper Dingemanse, Michael Scherz, Joop M. A. van Gerven, Oliver Nayler, Sanne de Haas, Stephan Buchmann, Walter Fischli, Martine Clozel, Changbin Qiu, and Celia Mueller
- Subjects
Male ,Receptors, Neuropeptide ,medicine.medical_specialty ,Hypothalamus, Posterior ,Cataplexy ,Sleep, REM ,General Biochemistry, Genetics and Molecular Biology ,Receptors, G-Protein-Coupled ,Dogs ,Sex Factors ,Orexin Receptors ,Tetrahydroisoquinolines ,Internal medicine ,Acetamides ,mental disorders ,medicine ,Animals ,Humans ,Orexins ,business.industry ,Neuropeptides ,Suvorexant ,Intracellular Signaling Peptides and Proteins ,Electroencephalography ,General Medicine ,Isoquinolines ,medicine.disease ,Orexin receptor ,Rats ,Orexin ,Endocrinology ,Female ,Wakefulness ,medicine.symptom ,Almorexant ,business ,psychological phenomena and processes ,Somnolence ,Signal Transduction ,Narcolepsy ,medicine.drug - 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.
- Published
- 2007
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