OX2R-selective orexin agonism is sufficient to ameliorate cataplexy and sleep/wake fragmentation without inducing drug-seeking behavior in mouse model of narcolepsy

Abstract

Acquired loss of hypothalamic orexin (hypocretin)-producing neurons causes the chronic sleep disorder narcolepsy-cataplexy. Orexin replacement therapy using orexin receptor agonists is expected as a mechanistic treatment for narcolepsy. Orexins act on two receptor subtypes, OX1R and OX2R, the latter being more strongly implicated in sleep/wake regulation. However, it has been unclear whether the activation of only OX2R, or both OX1R and OX2R, is required to replace the endogenous orexin functions in the brain. In the present study, we examined whether the selective activation of OX2R is sufficient to rescue the phenotype of cataplexy and sleep/wake fragmentation in orexin knockout mice. Intracerebroventricular [Ala11, D-Leu15]-orexin-B, a peptidic OX2R-selective agonist, selectively activated OX2R-expressing histaminergic neurons in vivo, whereas intracerebroventricular orexin-A, an OX1R/OX2R non-selective agonist, additionally activated OX1R-positive noradrenergic neurons in vivo. Administration of [Ala11, D-Leu15]-orexin-B extended wake time, reduced state transition frequency between wake and NREM sleep, and reduced the number of cataplexy-like episodes, to the same degree as compared with orexin-A. Furthermore, intracerebroventricular orexin-A but not [Ala11, D-Leu15]-orexin-B induced drug-seeking behaviors in a dose-dependent manner in wild-type mice, suggesting that OX2R-selective agonism has a lower propensity for reinforcing/drug-seeking effects. Collectively, these findings provide a proof-of-concept for safer mechanistic treatment of narcolepsy-cataplexy through OX2R-selective agonism.

Targeting Orexin Receptors for the Treatment of Insomnia: From Physiological Mechanisms to Current Clinical Evidence and Recommendations

“… 19 Other preclinical studies indicate that although OX2R play the more prominent role in the orexin modulation of wake-sleep states, OX1R are also relevant to the physiological control of REM sleep and vigilance-state related muscle tone and to the promotion of arousal. 42 , 44 , 45 Nevertheless, recent work demonstrated that pharmacological OX2R agonism is sufficient to ameliorate cataplexy and sleep/wake fragmentation in orexin KO mice 46 and in orexin-neuron deficient orexin-ataxin 3 mice. 47 This discrepancy awaits clarification.…”

Rôle du système limbique dans le déclenchement des cataplexies dans la narcolepsie de type 1

“…En effet, l'administration systémique d'hypocrétine chez le chien narcoleptique [38], l'injection intra-cérébro-ventriculaire d'hypocrétine chez des souris Orexine/Ataxine 3 [39], la mise en place de greffons de neurones à hypocrétine chez des souris Orexine/Ataxine3 [40], ou encore l'infusion intrathécale d'hypocrétine chez des souris Orex-KO [41] suppriment les cataplexies. Les injections intrapéritonéales ou intra-cérébro-ventriculaires d'agonistes non-peptidergiques des récepteurs 2 à hypocrétine (YNT-185 et AL-OXB) permet également une réduction des cataplexies chez les souris Orex-KO et Orexine/Ataxine3 [42,43]. Le lien physiopathologique entre l'hypocrétine et la cataplexie est donc bien établi.…”

Design and synthesis of orexin 1 receptor-selective agonists

“…Moreover, 8 was obtained from the hydrogenation of amide 10. The other cinnamoyl derivatives (11)(12)(13)(14)(15)(16)(17)(18)(19)(20) were synthesized in the same manner as 10, using the corresponding amines. The solid-state structure of 18 was determined unequivocally using single-crystal X-ray diffraction analysis (for details, see the Supporting Information).…”

“…35 Moreover, our group has recently reported that the OX2R-selective peptide AL-OXB does not show any preference in a conditioned place-preference (CPP) test. 14 However, the direct involvement of receptor-selective activation in the reward system has not yet been investigated using selective smallmolecule agonists. Thus, we first performed a CPP test using the OX1R-selective agonist (R)-18, OX2Rselective agonist (S)-2, and OX1R/OX2R dual agonist (R)-2 to clarify the involvement of OX1R-selective activation in the reward system.…”

“…[5][6][7][8][9] Accordingly, OX2R agonists are attracting attention as potential therapeutic agents for narcolepsy. [5][6][7][8] In contrast, although dysfunction of the orexin/OX1R system has not been implicated in the development of narcolepsy symptoms, several genetic and pharmacological studies have revealed that the orexin/OX1R system is involved in the regulation of sleep-wakefulness, 8,10,11 feeding behavior, 1,12 reward seeking, 4,13,14 analgesia, [15][16][17] energy homeostasis, 18,19 emotion, [20][21][22][23] and the autonomic nervous system. 24,25 Despite the importance of the physiological roles of OX1R, its contribution to disease pathogenesis is not fully understood yet.…”