HCRTR2 (hypocretin receptor 2) is a G-protein coupled receptor that binds the neuropeptides orexin-A and orexin-B, coupling with both Gq/11 and Gi/o heterotrimeric G-proteins to initiate downstream signaling cascades 1. The receptor plays a critical role in sleep-wake regulation, with HCRTR2 being strongly linked to sleep-wake control compared to HCRTR1 which is more associated with motivation and reward functions 1. Loss of orexin-producing neurons leads to narcolepsy, and OX2R knockout mice display clear narcolepsy-like phenotypes including fragmented sleep-wake cycles 2. The receptor is expressed in the hypothalamus and its activation increases wakefulness, as demonstrated by selective HCRTR2 agonists that promote wake states in wild-type but not OX2R knockout mice 2. HCRTR2 genetic variants have been investigated in cluster headache, a severe neurovascular disorder with circadian patterns, though results across populations have been inconsistent 345. The receptor system represents a therapeutic target, with HCRTR2 antagonists approved for insomnia treatment and agonists showing potential for treating excessive daytime sleepiness 1. Additionally, HCRTR2 variants have been associated with daytime napping behavior in genome-wide studies 6.