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.

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

“…ALM and other HcrtR antagonists effectively induce sleep (Brisbare-Roch et al, 2007;Cox et al, 2010) but cause less impairment in memory tasks (Dietrich and Jenck, 2010;Morairty et al, 2014) or motor function in rodents (Ramirez et al, 2013;Steiner et al, 2011), dogs (Tannenbaum et al, 2014), and non-human primates (Uslaner et al, 2013) than do traditional hypnotics. Although some degree of impairment may occur at high doses in humans (Hoever et al, 2010(Hoever et al, , 2012Jacobson et al, 2014), HcrtR antagonists are expected to exhibit a favorable safety profile compared with ZOL and other hypnotics, though years of post-market surveillance will be needed to confirm this hypothesis.…”

“…Although BzRAs are effective for the induction of sleep, they can have detrimental effects on cognitive performance (Huang et al, 2010;Uslaner et al, 2013;Wesensten et al, 1996), resulting in the need for hypnotics with an improved cognitive profile. Because of the involvement of the Hcrt system in sleep and arousal, Hcrt receptor (HcrtR) antagonists have been extensively investigated for the treatment of insomnia (Brisbare-Roch et al, 2007;Dugovic et al, 2009;Morairty et al, 2014;Roecker and Coleman, 2008;Uslaner et al, 2013;Winrow et al, 2011) and are thought to promote sleep through selective disfacilitation of wake-promoting systems.…”

Orexin deficiency and narcolepsy

“…Almorexant was reported to shorten time spent awake and enables and maintains sleep in rats, dogs, and humans (37,38). Almorexant significantly improved the primary parameter of sleep efficiency (time spent sleeping while confined to bed during an eight hour period at night) in a dose-dependent manner.…”

Overview of orexin/hypocretin system

“…Indeed, Almorexant (ACT078573, Actelion Pharmaceuticals Ltd.), an orally available antagonist of both receptors, has been reported to increase subjective and objective electrophysiological signs of sleep in humans (Brisbare-Roch et al, 2007).…”