Blockade of Orexin-1 Receptors Attenuates Orexin-2 Receptor Antagonism-Induced Sleep Promotion in the Rat

Abstract

Orexins are peptides produced by lateral hypothalamic neurons that exert a prominent role in the maintenance of wakefulness by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptor located in wake-active structures. Pharmacological blockade of both receptors by the dual OX1/2R antagonist (2R)-2-[(1S)-6,7-dimethoxy-1-{2-[4-(trifluoromethyl)phenyl]ethyl}-3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylethanamide (almorexant) has been shown to promote sleep in animals and humans during their active period. However, the selective distribution of OX1R and OX2R in distinct neuronal circuits may result in a differential impact of these receptors in sleep-wake modulation. The respective role of OX1R and OX2R on sleep in correlation with monoamine release was evaluated in rats treated with selective antagonists alone or in combination. When administered in either phase of the light/dark cycle, the OX2R antagonist 1-(2,4-dibromophenyl)-3-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea (JNJ-10397049) decreased the latency for persistent sleep and increased nonrapid eye movement and rapid eye movement sleep time. Almorexant produced less hypnotic activity, whereas the OX1R antagonist 1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea (SB-408124) had no effect. Microdialysis studies showed that either OX2R or OX1/2R antagonism decreased extracellular histamine concentration in the lateral hypothalamus, whereas both OX1R and OX1/2R antagonists increased dopamine release in the prefrontal cortex. Finally, coadministration of the OX1R with the OX2R antagonist greatly attenuated the sleep-promoting effects of the OX2R antagonist. These results indicate that blockade of OX2R is sufficient to initiate and prolong sleep, consistent with the hypothesis of a deactivation of the histaminergic system. In addition, it is suggested that simultaneous inhibition of OX1R attenuates the sleep-promoting effects mediated by selective OX2R blockade, possibly correlated with dopaminergic neurotransmission.

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

“…Finally, the compounds were tested at the defined doses in the BE model. OX 1 R and OX 2 R antagonists are reported in the literature to be involved in the control of sleep, in particular to induce hypnotic effects (Di Fabio et al, 2011;Gozzi et al, 2011;Dugovic et al, 2009). In a preclinical hypnotic sleep model in male rats, the results obtained demonstrated that the dual OX 1 /OX 2 R antagonist, SB-649868, induced a robust hypnotic effect, both on the ability to induce and to maintain sleep, reaching a statistically significant effect at 3 mg/kg.…”

“…Moreover, the simultaneous antagonism of both OX 1 R and OX 2 R or the selective inhibition of OX 2 R results in the induction of a strong hypnotic effect (Brisbare-Roch et al, 2007;Dugovic et al, 2009;Di Fabio et al, 2011).…”

“…Therefore, this study was aimed at investigating the effect of the dual OX 1 /OX 2 R antagonist SB-649868 (N-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide) (Di Fabio et al, 2011), the selective OX 1 R antagonist GSK1059865 (5-bromo-N-[(2S,5S)-1-(3-fluoro-2-methoxybenzoyl)-5-methylpiperidin-2-yl]methyl-pyridin-2-amine) (Gozzi et al, 2011), and the selective OX 2 R antagonist JNJ-10397049 (N-(2,4-dibromophenyl) (McAtee et al, 2004;Dugovic et al, 2009) in the BE model described by Cifani et al (2009), in which BE episodes for HPF is evoked in female rats by cycles of food restriction/re-feeding and acute stress. The three antagonists were first evaluated in vitro in rat recombinant OX 1 R and OX 2 R to determine their potency and to confirm their selectivity for the two receptor subtypes.…”

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

“…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

“…Notably, almorexant was well tolerated with no signs of cataplexy, suggesting that acute, short-lived, intermittent temporary blockade of orexin receptors will not result in a narcolepsy-like phenotype(40). Recently, repeated administration of an OXR-2 selective antagonist, JNJ-10397049, was shown to decrease the latency for persistent sleep and increased NREM sleep time more potently than did the dual antagonist, almorexant (41), while, an OXR-1 selective antagonist SB-408124 had no effect on sleep parameters. Rather, the OXR-1 antagonist attenuated the sleep-promoting effects of the OXR-2 antagonist when simultaneously administered, possibly by increasing dopamine release in the prefrontal cortex.…”