Orexin-B (Hypocretin-2)

Orexin-B (also called hypocretin-2) is a 28-amino acid neuropeptide produced exclusively by neurons in the lateral hypothalamic area (LHA). It is one of two orexin peptides — the other being Orexin-A (33 amino acids, also documented in this database). Both peptides are derived from the same 130-amino acid precursor protein, prepro-orexin.

Orexin-B was discovered simultaneously by two groups in 1998: Sakurai et al. (Cell, named orexin from the Greek "orexis" = appetite) and de Lecea et al. (PNAS, named hypocretin from hypothalamus + secretin-like structure). The peptides activate two G-protein-coupled receptors: OX1R and OX2R.

**Receptor selectivity:** - **OX1R (orexin receptor 1)**: Prefers Orexin-A; Gq-coupled; mediates some reward and stress circuits - **OX2R (orexin receptor 2)**: Binds both Orexin-A and Orexin-B with similar affinity; Gq- and Gi-coupled; critical for wakefulness maintenance

Orexin-B's pharmacological distinction from Orexin-A is its relatively higher OX2R selectivity, which is the primary receptor mediating wakefulness (based on pharmacological and genetic studies).

**Narcolepsy and orexin deficiency:** The critical importance of orexin research came from the discovery that narcolepsy type 1 is caused by loss of orexin neurons (due to autoimmune destruction in most patients). This results in: cataplexy (sudden loss of muscle tone triggered by emotion), excessive daytime sleepiness, sleep paralysis, and hypnagogic hallucinations. Orexin/hypocretin deficiency in CSF is a diagnostic criterion for narcolepsy type 1.

**Therapeutic implications:** - Insomnia treatment: Dual orexin receptor antagonists (DORAs) — suvorexant (Belsomra), lemborexant (Dayvigo), daridorexant (Quviviq) — block orexin signaling to allow sleep onset and maintenance - Narcolepsy treatment: OX2R agonists (TAK-994, Takeda) are in Phase II trials to replace lost orexin signaling in narcolepsy type 1 - Other research: Addiction (orexin modulates drug reward and reinstatement), anxiety (OX1R in fear circuits), and metabolic research (orexins regulate energy expenditure)