Kyotorphin
Tyrosine joined to arginine: an analgesic dipeptide found in the brain in 1979, studied in animals and measured in human cerebrospinal fluid
Kyotorphin is the dipeptide L-tyrosyl-L-arginine, isolated from cow brain in 1979. Injected into the brains of rodents it relieves pain, mostly by making nerve endings release met-enkephalin, one of the body's own opioids. It is made by an enzyme from its two amino acids, stored in nerve endings and broken down rapidly by aminopeptidases. In people it has only been measured, in spinal fluid, where levels were lower in persistent pain and in Alzheimer's disease. It has never been given to people as a treatment.
No established human dose Details ↓
Recommended Dosing
No established human dose
Kyotorphin has never been given to a person in any study read. The human evidence is two measurements of the body's own kyotorphin in cerebrospinal fluid, lower in people with persistent pain and in people with Alzheimer's disease.
What is it?
Kyotorphin is about as small as a peptide can be: two amino acids, tyrosine and arginine, joined by one peptide bond. It was isolated from cow brain in 1979 as a natural pain-relieving substance. Unlike the enkephalins and endorphins, it does not bind opioid receptors itself. Instead it seems to act on a receptor of its own and to make nerve endings release met-enkephalin, which then produces opioid analgesia.
The evidence that it works as a signalling molecule in the brain comes from rats. It is concentrated in the midbrain, pons, medulla and dorsal spinal cord, the regions where morphine injections and electrical stimulation relieve pain best. It sits in nerve-ending fractions, nerve endings take it up and release it again when depolarised in a calcium-dependent way, and a specific enzyme in those endings builds it from tyrosine and arginine, using the cell's energy carrier. A 2018 study proposed that this enzyme is tyrosyl-tRNA synthetase, the enzyme that normally loads tyrosine onto its transfer RNA. Radiolabelled kyotorphin binds rat brain membranes at high and low affinity sites coupled to the Gi protein, and the dipeptide leucine-arginine blocks it.
Its effects depend on where it is given. Injected into the brain or spinal fluid of rodents it relieves pain, an effect naloxone or the delta-opioid blocker naltrindole reverses and that depends on descending noradrenaline and serotonin pathways in the spinal cord. Given into the paw it blocked pain from bradykinin without involving opioids, yet at far smaller amounts it caused pain by releasing substance P from nerve endings. In rat heart muscle it damped the response to adrenaline-like drugs.
The main obstacle is that it barely survives. Brain and blood enzymes cut it in two rapidly, and blocking those enzymes with bestatin made it nearly five times more potent in mice. The transporter PEPT2 also clears it from the spinal fluid; mice lacking PEPT2 needed a fifth of the usual amount for the same pain relief. Because it also crosses the blood-brain barrier poorly, most recent work has gone into modified versions, such as an amidated form and an ibuprofen conjugate, which are different molecules and are not covered here.
In people, kyotorphin has only been measured. A Japanese study found it in normal human cerebrospinal fluid and at lower levels in patients with persistent pain. A 2013 study found lower levels in the spinal fluid of people with Alzheimer's disease, inversely related to phosphorylated tau, and suggested it as a possible marker. Rat studies followed, in which kyotorphin given into the brain partly protected against a chemically induced Alzheimer-like model. No study has given kyotorphin to a person, and it is not a medicine anywhere.
Mechanism of Action
Kyotorphin acts in the brain and spinal cord mainly by releasing met-enkephalin from nerve endings; it does not bind opioid receptors itself, and outside the central nervous system it has separate, non-opioid effects.
Enkephalin release
It makes nerve endings release met-enkephalin, so its pain relief is reversed by naloxone and, in the spinal cord, by the delta-opioid blocker naltrindole.
Its own receptor
Rat brain membranes hold high- and low-affinity kyotorphin binding sites coupled to the Gi protein; leucine-arginine blocks them.
Fast breakdown
Aminopeptidases in brain and blood cut it rapidly, and the transporter PEPT2 removes it from spinal fluid; blocking either strengthens its effect.
Peripheral effects
In the mouse paw it blocked bradykinin pain without opioids at higher amounts and caused pain through substance P release at very small amounts.
Published Research
These are studies of kyotorphin itself, read from their PubMed abstracts: two measurements in human cerebrospinal fluid, laboratory work with human enzymes and cells and with rat brain tissue, animal studies of pain and behaviour, and reviews. Synthetic derivatives such as amidated kyotorphin, and studies that gave its precursor L-arginine, are listed under References only.
Lower in the spinal fluid of Alzheimer's patients
Cerebrospinal fluid from 25 people with Alzheimer's disease and 13 age-matched controls was tested for kyotorphin and phosphorylated tau. The ratio of the two differed significantly between the groups, and in the patients kyotorphin fell as phosphorylated tau rose. The authors proposed it as a possible marker of neurodegeneration.
Measured in human spinal fluid, lower in persistent pain
A Japanese study found kyotorphin in normal human cerebrospinal fluid at about 1.2 pmol per ml and at about 0.24 pmol per ml in patients with persistent pain, supporting a role as a natural pain modulator in the human brain.
Broken down by human dipeptidases
Dipeptidases purified from human kidney, pancreas and liver hydrolysed kyotorphin, and the blood pressure drug captopril blocked all four competitively, which the authors suggested might explain some captopril side effects.
Stimulates an opioid peptide transporter in human nerve cells
In a human neuronal cell line, kyotorphin raised the activity of a sodium- and chloride-coupled transporter for opioid peptides about 2.5-fold, mainly by raising its affinity; D-kyotorphin had little effect. Kyotorphin is itself carried by the brain peptide transporter PEPT2.
Tyrosyl-tRNA synthetase can make it
Recombinant human tyrosyl-tRNA synthetase built kyotorphin from tyrosine and arginine with an energy source. Knocking the enzyme down in rat PC12 cells lowered kyotorphin but not other tyrosine dipeptides, and in mice the enzyme's levels across brain regions tracked kyotorphin production after arginine was given.
A synthetase in rat nerve endings
An enzyme in the soluble fraction of rat brain nerve endings joined tyrosine and arginine into kyotorphin, an energy-using reaction that also needed magnesium. Its distribution across brain regions matched kyotorphin levels, and it made three to four times more kyotorphin than processing of precursor proteins did.
Taken up and released by nerve endings
Rat brain nerve-ending preparations took up synthetic kyotorphin by an energy-dependent, temperature-dependent process and released it on depolarisation with high potassium in a calcium-dependent way, as expected of a neurotransmitter.
A receptor coupled to Gi
Labelled kyotorphin bound rat brain membranes at high- and low-affinity sites. Kyotorphin switched on G-protein activity and a lipid-cleaving enzyme through the Gi protein, effects lost after pertussis toxin and restored by adding back Gi, and leucine-arginine blocked binding without acting itself.
Concentrated in the brain's pain pathway
Measured by liquid chromatography in rat brain and spinal cord, kyotorphin was highest in the midbrain, pons and medulla and the dorsal spinal cord, the sites most sensitive to morphine and to stimulation-induced analgesia.
Acts on single pain-pathway neurons like the enkephalins
Applied directly to single neurons, kyotorphin mostly quietened lamina V-type neurons of the rabbit spinal dorsal horn and excited neurons of the rat medulla's nucleus reticularis paragigantocellularis; naloxone blocked both effects.
Bestatin protects it and strengthens analgesia
Rat brain homogenates and an aminopeptidase purified from monkey brain broke kyotorphin down rapidly. Bestatin blocked this, and given with kyotorphin into the cisterna it strengthened analgesia about 4.8-fold in an effect naloxone abolished.
Rapid breakdown in rodent brain and serum
Kyotorphin was hydrolysed quickly by rat and mouse brain and serum enzymes, more by brain than serum, while its D-arginine form was not. Bestatin inhibited the hydrolysis and raised kyotorphin's analgesic potency in the brain about 4.8 times.
PEPT2 limits its pain relief
Mice lacking the peptide transporter PEPT2 cleared kyotorphin from spinal fluid more slowly and needed about a fifth of the usual amount for the same analgesia after injection into the brain ventricles, while the response to D-kyotorphin did not differ.
Spinal analgesia through delta-opioid receptors
Given into the spinal fluid of mice, kyotorphin relieved pain in a tail-pinch test. Leucine-arginine and the delta-opioid blocker naltrindole reversed it, other opioid blockers did not, and kyotorphin did not bind spinal opioid receptors itself.
Needs descending noradrenaline and serotonin pathways
Spinal kyotorphin's pain relief in mice was abolished by blocking adrenoceptors or serotonin receptors and by depleting noradrenaline or serotonin, like that of a delta-opioid agonist.
Non-opioid pain relief in the paw
Injected into the mouse paw, kyotorphin reduced pain responses to bradykinin in a dose-dependent way. Leucine-arginine and pertussis toxin reversed this but naloxone did not, so enkephalin release was not needed at this site.
Very small amounts cause pain through substance P
At tiny amounts in the paw, kyotorphin caused pain responses in mice. Substance P receptor blockers, capsaicin pretreatment and deletion of the substance P gene all abolished them, pointing to substance P release from nerve endings.
Behaviour and memory in rats
Single injections into the brain ventricles relieved pain in rats, but repeated dosing lost that effect. Only the highest amount reduced anxiety-like behaviour and movement, and none changed recognition memory or protein oxidation.
Partial protection in a rat Alzheimer model
Rats given streptozotocin into the brain develop an Alzheimer-like state. Fourteen days of kyotorphin into the ventricles normalised anxiety, restored object recognition memory and reduced protein and nerve cell loss in some regions, but did not fix spatial memory or oxidative damage.
Damps adrenaline-like effects on heart muscle
Screening over 400 peptides on rat papillary muscle found that kyotorphin, though it did not change contraction itself, blocked the rise in contraction caused by isoprenaline. Leucine-arginine and naloxone reversed this, suggesting it releases opioids in the heart.
A sensitive method for measuring it in brain
Two fluorescence-based liquid chromatography methods measured kyotorphin in rat brain tissue at about 60 to 100 pmol per gram in cortex, striatum and hypothalamus.
Forty years of kyotorphin research
A review by the discovering group summarises its uneven brain distribution along the pain pathway, its storage in nerve endings, its synthetase and possible release from calpastatin by calpain, its Gi-coupled receptor and leucine-arginine antagonist, its breakdown and PEPT2 clearance, and its release of met-enkephalin.
Pharmacological potential and derivatives
A review notes that kyotorphin is concentrated in cortex, that its receptor has not been identified at the gene level, and that poor brain entry and rapid breakdown led to more fat-soluble and stable derivatives, including ibuprofen conjugates, with proposed roles as an Alzheimer's marker.
Physiology, precursor and clinical angle
A Japanese review covers kyotorphin's synthesis, distribution, release, uptake and breakdown, describes L-arginine as its precursor and outlines giving L-arginine for chronic pain.
No Established Human Dose
Kyotorphin has never been given to a person in any study read. The human evidence is two measurements of the body's own kyotorphin in cerebrospinal fluid, lower in people with persistent pain and in people with Alzheimer's disease. Every study that gave it was in animals, injected into the brain, spinal fluid or paw, or in cells and tissue. The one human infusion study in this literature gave L-arginine, its precursor, not kyotorphin. There is no human dose to state.
What this rests on: PMID 1766121, PMID 24198785.
Educational information, not medical advice. The doses on this page come from approved labels, published studies and, where no study exists, amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no label and no published test that says what forms or vial sizes Kyotorphin is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
Unknown: no human dose of Kyotorphin has been established (see No Established Human Dose below), so there is no amount to work out. The reconstitution calculator does the arithmetic for any vial, water and dose.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store Kyotorphin, before or after mixing. The mixing guide sets out the general rules, with their sources: keep a mixed vial in the fridge, and use it promptly, as the bacteriostatic water label says of any drug dissolved in it. The 28 days often quoted is the limit for an opened multiple-dose vial from a manufacturer, an outer limit set for sterility, not a time a mixed solution has been shown to keep. Nobody has published how long Kyotorphin stays intact once mixed.
How it is taken
Unknown: with no established human dose, there is no established way of taking Kyotorphin. What the human studies gave and how is set out under No Established Human Dose.
What to expect, and when
Unknown: no cited half-life and no label or trial duration on this page says how long Kyotorphin lasts or how long it was given. Results reported in the studies are under Published Research.
Side effects, and when to stop or get help
From the Side Effects section: Pain responses at very small amounts injected into the paw of mice, through substance P release (PMID 10366753); Reduced movement and anxiety-like behaviour at the highest amount given into rat brain (PMID 33932008); Loss of the pain-relieving effect with repeated dosing in rats (PMID 33932008); Blunted heart muscle response to adrenaline-like stimulation in rat tissue (PMID 16325776). Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Kyotorphin. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“No person has been given kyotorphin, so there are no human side effect data”).
Interactions
Unknown: a PubMed search for human interaction studies of Kyotorphin (reviewed 2026-10-28) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of Kyotorphin products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder; it checks the measured mass against Kyotorphin's expected mass, 337.4 Da, from this entry's molecular data. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Research Chemical (Not a medicine: an endogenous dipeptide). Sport: Prohibited (S0 catch-all).
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
No person has been given kyotorphin, so there are no human side effect data. These are effects seen in animals.
Contraindications & Cautions
No product label exists. These cautions follow from the evidence.
Legal Status
Kyotorphin is a research compound; it is not approved as a medicine anywhere in the sources read.
Frequently Asked Questions
?What is kyotorphin?
A dipeptide, tyrosine joined to arginine, found in the brain in 1979. In rodents it relieves pain when injected into the brain or spinal fluid, mainly by releasing met-enkephalin.
?Is kyotorphin an opioid?
Not directly. It does not bind opioid receptors itself; it makes nerve endings release met-enkephalin, which does. That is why naloxone blocks its pain relief in the brain but not in the paw.
?Has kyotorphin been tested in people?
Only measured. Studies found it in human cerebrospinal fluid, lower in persistent pain and in Alzheimer's disease. No study has given it to a person.
?Why is kyotorphin not used as a painkiller?
It is broken down rapidly by enzymes in blood and brain and crosses the blood-brain barrier poorly, so researchers have moved to modified derivatives, which are different molecules.
?Where does kyotorphin come from in the body?
An enzyme in nerve endings joins tyrosine and arginine, spending cellular energy; a 2018 study proposed that tyrosyl-tRNA synthetase does this. It may also be cut from the protein calpastatin.
?Is kyotorphin related to carnosine?
Only in being a natural dipeptide. Carnosine is beta-alanine with histidine and has different roles in muscle and brain.
References
- [pubmed] Santos SM, et al. "Neuropeptide Kyotorphin (Tyrosyl-Arginine) has Decreased Levels in the Cerebro-Spinal Fluid of Alzheimer's Disease Patients: Potential Diagnostic and Pharmacological Implications." Front Aging Neurosci, 2013;5:68. PMID: 24198785.
- [pubmed] Nishimura K, et al. "[Kyotorphin like substance in human cerebrospinal fluid of patients with persistent pain]." Masui, 1991;40(11):1686-90. PMID: 1766121.
- [pubmed] Ito Y, et al. "Inhibition of hydrolytic activities of human dipeptidases toward leukotriene D4 and kyotorphin by captopril." Clin Exp Hypertens A, 1987;9(2-3):681-5. PMID: 3301087.
- [pubmed] Thakkar SV, et al. "Stimulation of Na+/Cl--coupled opioid peptide transport system in SK-N-SH cells by L-kyotorphin, an endogenous substrate for H+-coupled peptide transporter PEPT2." Drug Metab Pharmacokinet, 2008;23(4):254-62. PMID: 18762712.
- [pubmed] Tsukahara T, et al. "Tyrosyl-tRNA synthetase: A potential kyotorphin synthetase in mammals." Peptides, 2018;101:60-68. PMID: 29289698.
- [pubmed] Ueda H, et al. "Kyotorphin (tyrosine-arginine) synthetase in rat brain synaptosomes." J Biol Chem, 1987;262(17):8165-73. PMID: 3597366.
- [pubmed] Ueda H, et al. "Uptake and release of kyotorphin in rat brain synaptosomes." Life Sci, 1986;38(26):2405-11. PMID: 3724363.
- [pubmed] Ueda H, et al. "The kyotorphin (tyrosine-arginine) receptor and a selective reconstitution with purified Gi, measured with GTPase and phospholipase C assays." J Biol Chem, 1989;264(7):3732-41. PMID: 2537290.
- [pubmed] Ueda H, et al. "Regional distribution of a novel analgesic dipeptide kyotorphin (Tyr-Arg) in the rat brain and spinal cord." Brain Res, 1980;198(2):460-4. PMID: 7407611.
- [pubmed] Satoh M, et al. "Effects of tyrosyl-arginine (kyotorphin), a new opioid dipeptide, on single neurons in the spinal dorsal horn of rabbits and the nucleus reticularis paragigantocellularis of rats." Neurosci Lett, 1980;16(3):319-22. PMID: 7052447.
- [pubmed] Ueda H, et al. "Degradation of kyotorphin by a purified membrane-bound-aminopeptidase from monkey brain: potentiation of kyotorphin-induced analgesia by a highly effective inhibitor, bestatin." Life Sci, 1985;36(19):1865-71. PMID: 3990513.
- [pubmed] Matsubayashi K, et al. "Hydrolytic deactivation of kyotorphin by the rodent brain homogenates and sera." J Pharmacobiodyn, 1984;7(7):479-84. PMID: 6541692.
- [pubmed] Jiang H, et al. "Enhanced antinociceptive response to intracerebroventricular kyotorphin in Pept2 null mice." J Neurochem, 2009;109(5):1536-43. PMID: 19383084.
- [pubmed] Ochi T, et al. "Blockade of the antinociceptive effect of spinally administered kyotorphin by naltrindole in mice." Neurosci Lett, 2002;322(2):95-8. PMID: 11958852.
- [pubmed] Ochi T, et al. "The spinal antinociceptive effect of kyotorphin in mice: involvement of the descending noradrenergic and serotonergic systems." Neurosci Lett, 2002;329(2):193-6. PMID: 12165410.
- [pubmed] Inoue M, et al. "Peripheral non-opioid analgesic effects of kyotorphin in mice." Neurosci Lett, 1997;236(1):60-2. PMID: 9404952.
- [pubmed] Inoue M, et al. "Low dose of kyotorphin (tyrosine-arginine) induces nociceptive responses through a substance P release from nociceptor endings." Brain Res Mol Brain Res, 1999;69(2):302-5. PMID: 10366753.
- [pubmed] Angelova H, et al. "Effects of the antinociceptive dipeptide L-tyrosine-L-arginine (kyotorphin) on the motivation, anxiety, and memory in rats." Folia Med (Plovdiv), 2021;63(2):189-196. PMID: 33932008.
- [pubmed] Angelova H, et al. "Moderate protective effect of Kyotorphin against the late consequences of intracerebroventricular streptozotocin model of Alzheimer's disease." Amino Acids, 2019;51(10-12):1501-1513. PMID: 31520285.
- [pubmed] Li Y, et al. "Kyotorphin has a novel action on rat cardiac muscle." Biochem Biophys Res Commun, 2006;339(3):805-9. PMID: 16325776.
- [pubmed] Kai M, et al. "High-performance liquid chromatographic separation of kyotorphin, a basic Tyr-Arg dipeptide, in rat brain tissue and quantification using fluorimetric detection." J Chromatogr B Biomed Sci Appl, 1997;688(2):205-12. PMID: 9061457.
- [review] Ueda H. "Review of Kyotorphin Research: A Mysterious Opioid Analgesic Dipeptide and Its Molecular, Physiological, and Pharmacological Characteristics." Front Med Technol, 2021;3:662697. PMID: 35047919.
- [review] Perazzo J, et al. "Pharmacological Potential of the Endogenous Dipeptide Kyotorphin and Selected Derivatives." Front Pharmacol, 2016;7:530. PMID: 28127286.
- [review] Takagi H. "[Physiological and pharmacological actions of a neuroactive dipeptide, kyotorphin, and its precursor, L-arginine, and clinical application]." Nihon Yakurigaku Zasshi, 1990;96(3):85-96. PMID: 2272541.
- [pubmed] Harima A, et al. "Analgesic effect of L-arginine in patients with persistent pain." Eur Neuropsychopharmacol, 1991;1(4):529-33. PMID: 1822318.
- [pubmed] Perazzo J, et al. "Neuropeptide Kyotorphin Impacts on Lipopolysaccharide-Induced Glucocorticoid-Mediated Inflammatory Response. A Molecular Link to Nociception, Neuroprotection, and Anti-Inflammatory Action." ACS Chem Neurosci, 2017;8(8):1663-1667. PMID: 28472878.
- [other] PubChem CID 123804, Kyotorphin: formula C15H23N5O4, molecular weight 337.37. Read October 28, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/123804
Sources & Citations
Every study on this page was read from its PubMed record on October 28 or 29, 2026. Regulatory status comes from Drugs@FDA and the EMA medicines list. Searches recorded on October 28, 2026: PubMed kyotorphin[tiab] 210 records; ClinicalTrials.gov, Drugs@FDA and the EMA list 0. Grey Peptides sells nothing and links to no vendor.
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. Talk to a licensed clinician about your own situation.