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Evidence: LowPeptideResearch ChemicalHypothalamic neuropeptideNot a drugPrefers the OX2 receptor

Orexin-B

The second orexin, a 28-amino-acid peptide from the lateral hypothalamus that acts mainly through the OX2 receptor

Orexin-B was discovered in 1998 alongside orexin-A, cut from the same precursor. It binds both orexin receptors but favours OX2. It has never been developed as a medicine, and the human evidence is limited to measurements and tissue studies.

At a Glance Read Research →
Overview

What is it?

Orexin-B and orexin-A were identified together in 1998 by Sakurai and colleagues. Both are cut from one precursor, prepro-orexin, made by neurons in and around the lateral and posterior hypothalamus, and both bind two previously orphan receptors. In that first report, giving the peptides into rat brains stimulated feeding, and the precursor's message rose with fasting. Orexin-B is also called hypocretin-2.

Most of what is known about orexin-B comes from animal and tissue work. In rat spinal cord slices it excited neurons that handle pain and temperature. In rat midbrain slices it increased glutamate transmission onto dopamine neurons through OX2 receptors, suggesting a role in motivation distinct from orexin-A's. A 2024 study found it protected dopamine neurons in a Parkinson's disease model.

Human evidence is limited to measurements and tissue. In 36 obese and 16 lean women, plasma orexin-A was lower in obesity, but orexin-B did not differ. In human fat tissue, both orexins acted on functional orexin receptors and changed genes involved in fat storage and breakdown. A 2018 study found an orexin-B and OX2 receptor pathway protected heart muscle in rat models, and in people with heart failure, lower OX2 receptor expression in the heart went with worse symptoms.

No medicine is orexin-B itself. Selective OX2 receptor agonists are in development for narcolepsy, but orexin-B as a peptide remains a research tool, with no human dosing study on PubMed.

Structured data

At a Glance

Every value in this table is printed from the Grey Peptides dataset, the same record the compound explorer and comparison tool read, so the three can never disagree.

ClassOrexin-B is the second orexin peptide, co-expressed with Orexin-A from the same precursor, with preferential activity at the OX2 receptor that dominates wakefulness maintenance.
SequenceRSGPPGLQGRLQRLLQASGNHAAGILTM-amide
FormulaC130H209N43O36
Molecular weight2937.4 g/mol
Half-lifenot reported in the sources read
Typical doseN/A N/A (N/A, endogenous)
US statusResearch Chemical
Evidence levelLow
Last reviewed2026-10-16
Evidence

Published Research

These studies were read from their PubMed abstracts: measurements in people, laboratory work on human tissue and rat neurons, and animal studies of the peptide's effects in pain, lung injury, aneurysm, Parkinson's and heart models. The large literature reached through the shared name hypocretin-2 is mostly about the saporin neurotoxin conjugate or about drugs blocking the OX2 receptor, and is not cited here.

Human2005

Plasma levels in obese women

In 36 obese and 16 lean women, plasma orexin-A was lower in obesity while orexin-B did not change; NPY, leptin and insulin were higher.

PMID: 16135994
Human2018

The heart: OX2 receptors and heart failure

An orexin-B/OX2 receptor pathway was cardioprotective in rat models, and in patients with heart failure lower OX2 receptor expression correlated with worse NYHA class.

PMID: 30467191
In Vitro2006

Human adipose tissue

Functional orexin receptors were found in human fat; orexin-A and -B reduced hormone-sensitive lipase mRNA in omental tissue and altered adipogenic gene expression.

PMID: 17065396
In Vitro2002

Spinal pain-processing neurons

In rat spinal cord slices, hypocretin-2 excited certain superficial dorsal horn neurons, consistent with a role in pain and temperature sense.

PMID: 11790816
In Vitro2008

Dopamine neurons of the VTA

In rat midbrain slices, orexin-B increased glutamatergic transmission to ventral tegmental area neurons via OX2 receptors and PKC and reduced spike-timing long-term potentiation.

PMID: 18793323
Animal2024

A Parkinson's disease model

Orexin-B protected dopaminergic neurons from MPTP neurotoxicity, with reduced ERK phosphorylation in cell and animal models.

PMID: 38787465
Animal2024

Nerve-injury pain in rats

In rats with a chronic constriction injury of the sciatic nerve, orexin B eased neuropathic pain by damping microglial activation and the inflammatory response in the spinal cord, acting through JNK and NF-kB signalling.

PMID: 39255695
Animal2025

Lung injury in sepsis

In sepsis-induced acute lung injury, orexin B improved the permeability of lung microvascular endothelial cells, protecting the pulmonary endothelial barrier through ROCK2.

PMID: 39623599
Animal2026

Cerebral aneurysms

Orexin B protected against the formation of cerebral aneurysms through anti-inflammatory mechanisms that depend on the OX2 receptor and suppress SP-1, which the authors propose as a treatment target.

PMID: 42257697
In Vitro2002

Selective action in a brainstem relay

In rat nucleus tractus solitarius neurons, hypocretin 2 strengthened excitatory but not inhibitory synapses, including viscerosensory inputs, which the authors read as a role in modulating autonomic sensory signalling.

PMID: 12435409
Animal2003

Where the peptide is found in limbic brain

Orexin-B-containing neurons were identified in limbic structures, and the authors suggest a specific subset within the amygdaloid complex forms part of circuits coordinating homeostatic and behavioural responses.

PMID: 12650973
Animal2002

It travels with orexin-A

In the cat, hypocretin-1 and hypocretin-2 were found together both in hypothalamic cell bodies and in brainstem fibres and terminals, so if both are released together their different effects must depend on which receptors the target cells carry.

PMID: 12182950
Animal2023

In the testis

Orexin B and the OX2 receptor were found in mouse testis, with stage-specific staining in adults, which the authors suggest points to a role in sperm production and steroid synthesis.

PMID: 36841281
Safety

Side Effects & Contraindications

Reported Side Effects

No human dosing studies exist.

● No human safety data: orexin-B has not been given to people in any trial on PubMed

Contraindications & Cautions

A research peptide.

● Not approved for any use and not studied in humans as a treatment
● Tested athletes — see the Sport (WADA) row below
Questions

Frequently Asked Questions

?What is orexin-B?

A 28-amino-acid neuropeptide made in the hypothalamus, discovered in 1998 together with orexin-A, that acts mainly on the OX2 receptor.

?How is it different from orexin-A?

Both come from the same precursor, but orexin-A binds both receptors strongly while orexin-B prefers OX2; in rat brain slices they had different effects on dopamine neurons.

?Is it used as a medicine?

No. Selective OX2 receptor agonists are being developed for narcolepsy, but orexin-B itself has not been given to people as a treatment.

?Has it been tested in people?

Only measured: plasma orexin-B did not differ between obese and lean women, and human fat and heart tissue express its receptors. No human dosing study is on PubMed.

Bibliography

References

  1. [pubmed] Baranowska B, et al. "Plasma orexin A, orexin B, leptin, neuropeptide Y (NPY) and insulin in obese women." Neuro Endocrinol Lett, 2005;26(4):293-6. PMID: 16135994.
  2. [pubmed] Patel VH, et al. "Functional cardiac orexin receptors: role of orexin-B/orexin 2 receptor in myocardial protection." Clin Sci (Lond), 2018;132(24):2547-2564. PMID: 30467191.
  3. [pubmed] Digby JE, et al. "Orexin receptor expression in human adipose tissue: effects of orexin-A and orexin-B." J Endocrinol, 2006;191(1):129-36. PMID: 17065396.
  4. [pubmed] Grudt TJ, et al. "Hypocretin-2 (orexin-B) modulation of superficial dorsal horn activity in rat." J Physiol, 2002;538(Pt 2):517-25. PMID: 11790816.
  5. [pubmed] Borgland SL, et al. "Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons." Eur J Neurosci, 2008;28(8):1545-56. PMID: 18793323.
  6. [pubmed] Ma X, et al. "Orexin B protects dopaminergic neurons from 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity associated with reduced extracellular signal-regulated kinase phosphorylation." Mol Biol Rep, 2024;51(1):669. PMID: 38787465.
  7. [pubmed] Mieda M. "The roles of orexins in sleep/wake regulation." Neurosci Res, 2017;118:56-65. PMID: 28526554.
  8. [pubmed] Mitsuma T, et al. "Radioimmunoassay for hypocretin-2." Endocr Regul, 2000;34(1):23-7. PMID: 10808249.
  9. [pubmed] Imperatore R, et al. "Role of Orexin-B/Orexin 2 receptor in myocardial protection." Clin Sci (Lond), 2019;133(7):853-857. PMID: 30948623.
  10. [pubmed] Sakurai T, et al. "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior." Cell, 1998;92(4):573-85. PMID: 9491897.
  11. [pubmed] Zhu Z, et al. "The protective effects of orexin B in neuropathic pain by suppressing inflammatory response." Neuropeptides, 2024;108:102458. PMID: 39255695.
  12. [pubmed] Wang Y, et al. "orexin B alleviates sepsis-associated lung injury through the attenuation of pulmonary endothelial barrier dysfunction by regulating the rho-associated coiled-coil containing protein kinase 2/zonula occludens-1 (ROCK2/ZO-1) axis." Biotechnol Appl Biochem, 2025;72(4):883-896. PMID: 39623599.
  13. [pubmed] Chen L, et al. "Orexin B Reduces Cerebral Aneurysms Through Inhibition of SP-1." CNS Neurosci Ther, 2026;32(6):e70958. PMID: 42257697.
  14. [pubmed] Smith BN, et al. "Selective enhancement of excitatory synaptic activity in the rat nucleus tractus solitarius by hypocretin 2." Neuroscience, 2002;115(3):707-14. PMID: 12435409.
  15. [pubmed] Ciriello J, et al. "Identification of neurons containing orexin-B (hypocretin-2) immunoreactivity in limbic structures." Brain Res, 2003;967(1-2):123-31. PMID: 12650973.
  16. [pubmed] Zhang JH, et al. "Co-localization of hypocretin-1 and hypocretin-2 in the cat hypothalamus and brainstem." Peptides, 2002;23(8):1479-83. PMID: 12182950.
  17. [pubmed] Yadav A, et al. "Localization and expression of Orexin B (OXB) and its type 2 receptor (OX2R) in mouse testis during postnatal development." Peptides, 2023;164:170979. PMID: 36841281.
  18. [pubmed] España RA, et al. "Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action." Neuroscience, 2001;106(4):699-715. PMID: 11682157.
  19. [pubmed] Smolinska N, et al. "Adiponectin, orexin A and orexin B concentrations in the serum and uterine luminal fluid during early pregnancy of pigs." Anim Reprod Sci, 2017;178:1-8. PMID: 28089263.
  20. [pubmed] Rotondo M, et al. "Circular Dichroism Study of Orexin B under Oxidative Stress Conditions." Molecules, 2023;28(2). PMID: 36677542.
  21. [pubmed] Dale NC, et al. "Orexin receptor 2 (OX(2)R) exhibits ligand-dependent spatio-temporal pharmacology through Gα(i):β-arrestin dynamics in response to Orexin-A and Orexin-B." Biochem Pharmacol, 2026;243(Pt 2):117517. PMID: 41203035.

Sources & Citations

Studies were read from their PubMed records (October 6, 2026).

Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Consult a licensed healthcare provider before making health decisions.

Last reviewed: 2026-10-16