The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors.

STUDY OBJECTIVES: Orexin peptides activate orexin 1 and orexin 2 receptors (OX(1)R and OX(2)R), regulate locomotion and sleep-wake. The dual OX(1)R/OX(2)R antagonist almorexant reduces activity and promotes sleep in multiple species, including man. The relative contributions of the two receptors in locomotion and sleep/wake regulation were investigated in mice.

DESIGN: Mice lacking orexin receptors were used to determine the contribution of OX(1)R and OX(2)R to orexin A-induced locomotion and to almorexant-induced sleep.

SETTING: N/A.

PATIENTS OR PARTICIPANTS: C57BL/6J mice and OX(1)R(+/+), OX(1)R(-/-), OX(2)R(+/+), OX(2)R(-/-) and OX(1)R(-/-)/OX(2)R(-/-) mice.

INTERVENTIONS: Intracerebroventricular orexin A; oral dosing of almorexant.

MEASUREMENTS AND RESULTS: Almorexant attenuated orexin A-induced locomotion. As in other species, almorexant dose-dependently increased rapid eye movement sleep (REM) and nonREM sleep in mice. Almorexant and orexin A were ineffective in OX(1)R(-/-)/OX(2)R(-/-) mice. Both orexin A-induced locomotion and sleep induction by almorexant were absent in OX(2)R(-/-) mice. Interestingly, almorexant did not induce cataplexy in wild-type mice under conditions where cataplexy was seen in mice lacking orexins and in OX(1)R(-/-)/OX(2)R(-/-) mice. Almorexant dissociates very slowly from OX(2)R as measured functionally and in radioligand binding. Under non equilibrium conditions in vitro, almorexant was a dual antagonist whereas at equilibrium, almorexant became OX(2)R selective.

CONCLUSIONS: In vivo, almorexant specifically inhibits the actions of orexin A. The two known orexin receptors mediate sleep induction by almorexant and orexin A-induced locomotion. However, OX(2)R activation mediates locomotion induction by orexin A and antagonism of OX(2)R is sufficient to promote sleep in mice.