What it is
Orexin is two neuropeptides, both cut from one 131-residue precursor called prepro-orexin (UniProt O43612):
| Peptide | Length | Structure |
|---|---|---|
| Orexin-A (hypocretin-1) | 33 | QPLPDCCRQKTCSCRLYELLHGAGNHAAGILTL; two disulfide bonds, a pyroglutamate cap at the start, an amidated end |
| Orexin-B (hypocretin-2) | 28 | RSGPPGLQGRLQRLLQASGNHAAGILTM; a straight chain with an amidated end |
The 1998 PNAS paper found them restricted to nerve cells of the dorsal and lateral hypothalamus, whose fibres project widely — to the brainstem and thalamus among other targets.
Two names, one discovery
Two laboratories found the peptides in 1998, weeks apart. De Lecea and colleagues called them hypocretins — "hypo" from the hypothalamus and "cretin" from secretin, the gut hormone the paper notes they resemble (PNAS, 6 January, PMID 9419374). Sakurai and colleagues called them orexins, from the Greek for appetite, because they increased feeding in rats (Cell, 20 February, PMID 9491897). The receptors carry the orexin name (OX1R, OX2R); the genes carry the hypocretin name (HCRT, HCRTR1, HCRTR2).
What it does
UniProt's annotation describes the orexins as regulators of food intake and sleep–wakefulness. Orexin-A binds both receptors; orexin-B prefers OX2R (UniProt O43613, O43614). The firmest human evidence came from what happens when the system is missing:
- 2000, Peyron and colleagues: a global loss of hypocretins in all six narcolepsy brains examined; screening 74 patients found one precursor-gene mutation, in a single early-onset case, so the loss is usually not inherited (Nature Medicine, PMID 10973318).
- 2000, Thannickal and colleagues: an 85–95% reduction in the number of hypocretin neurons, while the intermixed MCH neurons were not reduced — a loss specific to these cells (Neuron, PMID 11055430).
The authors concluded that most human narcolepsy is associated with a deficient hypocretin system. The appetite role the peptides were named for rests mainly on animal work.
The drugs: blockers, not peptides
No medicine gives orexin to anyone. The approved drugs block its receptors, and all three are small molecules:
| Drug | Brand | Approved | Application |
|---|---|---|---|
| Suvorexant | Belsomra | 2014-08-13 | NDA204569 |
| Lemborexant | Dayvigo | 2019-12-20 | NDA212028 |
| Daridorexant | Quviviq | 2022-01-07 | NDA214985 |
Belsomra's label states the logic plainly: orexin signalling "plays a role in wakefulness", and blocking orexin A and B from their receptors "is thought to suppress wake drive."
Where it stands
openFDA's Drugs@FDA returns no application with orexin as the active ingredient (2026-10-03). PubMed returns 8,098 records for orexin or hypocretin, 194 tagged as randomised controlled trials — nearly all testing the receptor blockers.
Related reading
Orexin sits beside the other hypothalamic and gut signals in this library — ghrelin for hunger and oxytocin, another peptide made in the hypothalamus. For peptides discussed for sleep, see peptides for sleep and DSIP.