Orexin

Orexin, also known as hypocretin, is a neuropeptide produced in the hypothalamus, specifically by a relatively small group of neurons concentrated in the lateral hypothalamus. Orexins play a crucial role in regulating arousal, wakefulness, and appetite. There are two main types of orexin peptides, orexin-A (hypocretin-1) and orexin-B (hypocretin-2), which bind to two G protein-coupled receptors, orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R), respectively. While orexin-A binds with similar affinity to both receptors, orexin-B demonstrates a higher affinity for OX2R.

The orexin system's involvement in sleep-wake regulation is particularly significant. Orexin neurons project widely throughout the brain, influencing regions involved in alertness, such as the locus coeruleus (norepinephrine), the tuberomammillary nucleus (histamine), and the dorsal raphe nucleus (serotonin). Through these projections, orexin promotes wakefulness and suppresses sleep.

Dysfunction of the orexin system is strongly implicated in narcolepsy. In most cases of narcolepsy with cataplexy (sudden muscle weakness triggered by strong emotions), there is a significant loss of orexin-producing neurons in the hypothalamus, leading to reduced levels of orexin in the cerebrospinal fluid. This deficiency results in excessive daytime sleepiness, fragmented nighttime sleep, and cataplexy. Mutations in the orexin receptor 2 (OX2R) gene have also been linked to narcolepsy in some populations.

Beyond sleep and wakefulness, orexin is also involved in regulating appetite, reward-seeking behavior, and energy homeostasis. Orexin neurons are sensitive to changes in glucose levels and are stimulated by hunger and inhibited by satiety. They project to brain regions involved in reward processing, such as the ventral tegmental area (VTA), suggesting a role in motivation and addiction. The orexin system contributes to the coordination of feeding behavior, arousal, and energy expenditure.

Research into orexin continues to explore its diverse functions and potential therapeutic applications. Orexin receptor agonists are being investigated as potential treatments for sleep disorders, while orexin receptor antagonists are being explored as potential treatments for insomnia and anxiety.