Hypocretin

Hypocretin, also known as orexin, refers to a pair of neuropeptides, hypocretin‑1 (orexin‑A) and hypocretin‑2 (orexin‑B), produced by a small group of neurons in the lateral hypothalamus. These neuropeptides bind to two G‑protein‑coupled receptors, OX1R and OX2R, and play a key role in regulating arousal, wakefulness, and appetite. Their discovery in 1998 highlighted a link between the hypothalamus and sleep‑wake control, leading to the identification of narcolepsy as a disorder associated with hypocretin deficiency.

In the central nervous system, hypocretin neurons project widely to regions involved in sleep regulation, reward, stress, and autonomic functions, including the locus coeruleus, raphe nuclei, and the ventral tegmental area. Activation of OX1R primarily influences reward and stress pathways, whereas OX2R is more involved in stabilizing wakefulness. Loss of hypocretin‑producing cells, measured as low cerebrospinal fluid hypocretin‑1 levels, is a hallmark of narcolepsy type 1 (formerly narcolepsy with cataplexy). Animal models lacking hypocretin signaling display fragmented sleep, reduced wake time, and altered energy balance.

Beyond sleep, hypocretin modulates feeding behavior and energy metabolism; intracerebroventricular administration stimulates food intake, while antagonism reduces appetite in rodents. The system also interacts with the hypothalamic‑pituitary‑adrenal axis, influencing stress responses. Pharmacologically, orexin receptor antagonists such as suvorexant are approved for insomnia, whereas therapeutic strategies to restore hypocretin signaling are under investigation for narcolepsy and other disorders. Research continues to explore hypocretin’s broader roles in neuropsychiatric conditions, metabolic disease, and neurodegeneration.