Abstract
Orexins (also known as hypocretins) play critical roles in the regulation of sleep/wakefulness states by activating two G-protein coupled receptors (GPCRs), orexin 1 (OX1R) and orexin 2 receptors (OX2R). In order to understand the differential contribution of both receptors in regulating sleep/wakefulness states we compared the pharmacological effects of a newly developed OX2R antagonist (2-SORA), Compound 1 m (C1 m), with those of a dual orexin receptor antagonist (DORA), suvorexant, in C57BL/6J mice. After oral administration in the dark period, both C1m and suvorexant decreased wakefulness time with similar efficacy in a dose-dependent manner. While C1m primarily increased total non-rapid eye movement (NREM) sleep time without affecting episode durations and with minimal effects on REM sleep, suvorexant increased both total NREM and REM sleep time and episode durations with predominant effects on REM sleep. Fos-immunostaining showed that both compounds affected the activities of arousal-related neurons with different patterns. The number of Fos-IR noradrenergic neurons in the locus coeruleus was lower in the suvorexant group as compared with the control and C1m-treated groups. In contrast, the numbers of Fos-IR neurons in histaminergic neurons in the tuberomamillary nucleus and serotonergic neurons in the dorsal raphe were reduced to a similar extent in the suvorexant and C1m groups as compared with the vehicle-treated group. Together, these results suggest that an orexin-mediated suppression of REM sleep via potential activation of OX1Rs in the locus coeruleus may possibly contribute to the differential effects on sleep/wakefulness exerted by a DORA as compared to a 2-SORA.
Highlights
A series of studies have suggested that loss of hypothalamic neurons producing orexin causes narcolepsy in humans and other mammalian species, showing that orexin plays an extremely important role in the regulation of sleep/wakefulness states, especially in the maintenance of wakefulness (Sakurai and Mieda, 2011)
The decrease of wakefulnes was accompanied by a dose-dependent increase of non-rapid eye movement (NREM) sleep time (Figure 1B, Figure S1B), which was significant during the 6 h after administration [F(3, 26) = 8.54, p < 0.01 for 30 mg/kg, p < 0.001 for 90 mg/kg] (Figure 1B)
No significant difference in total REM sleep time was observed between the Compound 1m (C1m) and vehicle groups, there was a weak tendency for C1m to increase total REM sleep tine (Figure 1C, Figure S1C)
Summary
A series of studies have suggested that loss of hypothalamic neurons producing orexin (orexin neurons) causes narcolepsy in humans and other mammalian species, showing that orexin plays an extremely important role in the regulation of sleep/wakefulness states, especially in the maintenance of wakefulness (Sakurai and Mieda, 2011). Several orexin receptor antagonists with different pharmacological characteristics are under development as generation sleep-inducing drugs. A dual orexin receptor antagonist (DORA), almorexant (ACT078573), blocks both OX1R and OX2R with similar potency (IC50 16 and 15 nM, respectively). Almorexant was reported to shorten the time spent awake and maintain sleep in rats, dogs, and humans (Brisbare-Roch et al, 2007; Hoever et al, 2010). Almorexant significantly improved the primary parameter of sleep efficiency in humans (time spent sleeping while confined to bed during an 8 h period at night) in a dose-dependent manner. Almorexant was well tolerated with no sign of cataplexy, suggesting that acute, short-lived, intermittent temporary blockade of orexin receptors will not result in a narcolepsy-like phenotype (Neubauer, 2010)
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