orexintargeting

Orexintargeting refers to medical and research approaches that modulate the orexin, or hypocretin, neuropeptide system in the brain to influence arousal, appetite, reward, and stress responses. The orexin system comprises two neuropeptides, orexin A and orexin B, produced in the lateral hypothalamus, and two G protein–coupled receptors, OX1R and OX2R, that are distributed throughout the brain. Orexin signaling promotes wakefulness and goal-directed behaviors and links energy balance with arousal, making it a target for several disorders.

Therapeutic strategies fall into agonism or antagonism of orexin receptors. Orexin receptor antagonists block orexin signaling and have become an established treatment option for insomnia. The first approved dual orexin receptor antagonists, suvorexant, lemborexant, and daridorexant, reduce sleep onset and maintenance without producing typical sedatives. They are taken orally and carry risks such as daytime sedation, impaired driving performance, and next-day residual effects, particularly in older adults or those with comorbidities.

In contrast, orexin receptor agonists—agents that stimulate orexin signaling—are primarily in preclinical and early clinical development for disorders characterized by excessive sleepiness, notably narcolepsy type 1. Selective agonists for OX1R or OX2R, or dual agonists, are being explored in hopes of restoring wakefulness without triggering adverse arousal-related effects.

Beyond sleep, orexin-targeting has potential applications in obesity, addiction, and mood disorders due to orexin's role in feeding, reward, and stress pathways. However, the systemic nature of orexin signaling poses challenges for safety and tolerability, and more research is needed to establish long-term outcomes.

Overall, orexintargeting encompasses pharmacological and research approaches aimed at manipulating the orexin system to treat sleep and metabolic conditions and to understand its broader roles in behavior and physiology.