Endomorphin-1
The four-amino-acid opioid peptide that binds the same receptor as morphine, where it has been found in people, and what animal studies show
Endomorphin-1 is a tetrapeptide amide, Tyr-Pro-Trp-Phe-NH2, that binds the mu-opioid receptor, the main target of morphine, more selectively than any other natural substance known when it was found. It has been isolated from human brain cortex and measured in human blood and immune cells. Given into the brain or spinal fluid of mice and rats it relieves pain through mu receptors, and in rats it slowed breathing less than morphine-like drugs at pain-relieving doses. It breaks down fast and crosses into the brain poorly, so research has moved to modified analogues. No study has given endomorphin-1 to a person.
No established human dose Details ↓
Recommended Dosing
No established human dose
No dose exists for endomorphin-1 in people. The human studies here measure it in blood, immune cells and brain tissue or test it on donated human tissue in the laboratory; every study that gave it to a living body used mice or rats, by injection into the brain, spinal fluid, paw or vein.
What is it?
Endomorphin-1 is one of two short peptides, with endomorphin-2, proposed in 1997 as the body's own ligands for the mu-opioid receptor, the receptor that morphine and most opioid painkillers act on. Its four amino acids are tyrosine, proline, tryptophan and phenylalanine, with the end capped as an amide. Researchers first found it in cow brain and soon purified it from human brain cortex, where it was more abundant than in cow brain and fully active.
In cell systems carrying the human mu receptor, endomorphin-1 acts as a partial agonist with an efficacy similar to morphine's. It inhibited nerve-driven contractions of human vas deferens tissue through opioid receptors, and it reduced noradrenaline release from nerves in human blood vessels. A 2020 study found that it favours one of the receptor's signalling routes (cAMP) over another, a property called biased agonism that drug designers look for.
Most of what endomorphin-1 does in a living body comes from rodents. Injected into the brain ventricles or spinal fluid of mice it produced dose-dependent pain relief through mu receptors, partly by switching on descending noradrenaline and serotonin pathways. It relieved nerve-injury pain in mice more than an equal amount of morphine. In conscious rats given it into a vein, it relieved pain at a threshold similar to other mu agonists but depressed breathing only at higher doses and did not lower blood pressure. In rats it also limited heart damage after a blocked coronary artery, and injected into one part of the basal ganglia it caused abnormal mouth movements.
Human data are measurements. Plasma endomorphin-1 was lower in people with diabetes than in healthy volunteers and fell after a meal in both groups. In type 2 diabetes it was higher before a Western-style meal than before an Eastern-style one. It was found in blood immune cells of healthy people, and in rats with arthritis it rose in the spleen, thymus and inflamed joints. A puzzle remains: a search of the human proteome found no precursor protein that could produce it in the usual way.
Endomorphin-1 itself is unlikely to become a drug. It is broken down by enzymes and crosses the blood-brain barrier poorly, and reviews describe chemical strategies to make it more stable and brain-penetrant. Many analogues have been tested in animals; those are separate molecules, so their results are listed under References only. Related opioid peptides with their own entries include the enkephalins, beta-endorphin and dermorphin.
Mechanism of Action
Endomorphin-1 is a highly selective agonist of the mu-opioid receptor; in animals its pain relief runs through spinal and brain pathways, and in the body it is broken down quickly.
Descending pain control
In mice it switches on noradrenaline and serotonin pathways that act on the spinal cord to block pain signals (PMID 12184724).
Blood vessels and heart
It reduces noradrenaline release from vascular nerves and widens vessels through nitric oxide; in rats it limited heart damage after reperfusion (PMIDs 10375796, 11337033, 39576477).
Biased signalling
It favours the cAMP route over G-protein activation at the human mu receptor, a profile linked to fewer side effects (PMID 32112361).
Published Research
These are studies of endomorphin-1 read from their PubMed abstracts: its isolation from human brain and measurements in human blood and cells, laboratory work on human tissues and receptors, animal studies of pain, breathing, movement and the heart, and three reviews. Studies of modified endomorphin-1 analogues are listed under References only.
Isolated from human brain cortex
Endomorphin-1 and endomorphin-2, first isolated from cow brain, were purified from the fronto-parietal cortex of human brain by solid-phase extraction and HPLC and tracked with a specific radioimmunoassay. The human peptides were fully active and present in much larger amounts than in cow frontal cortex.
Lower in people with diabetes
In 38 patients with diabetes and 22 healthy volunteers given a standard breakfast, plasma endomorphin-1 was lower in the patients both fasting (48 vs 73 pg/mL) and 2 hours after the meal (40 vs 63 pg/mL). Levels fell after eating in both groups by a similar amount, which the authors link to changes in blood glucose.
Meal style and endomorphin-1 in type 2 diabetes
In 57 patients with type 2 diabetes tested with an Eastern-style meal and a high-fat, high-protein Western-style meal, endomorphin-1, C-peptide, GLP-1 and ghrelin were all higher before the Western meal. The Western meal also produced a larger C-peptide rise and higher blood glucose afterwards.
Present in human immune cells
Radioimmunoassays detected endomorphin-1 in blood lymphocytes from three healthy people (13 to 303 pg per 100 million cells). In rats with adjuvant arthritis it was raised in the spleen and thymus and detectable in five of eight inflamed joint linings, but not in joints of healthy rats.
A partial agonist at the human mu receptor
In fibroblasts carrying the human mu-opioid receptor, endomorphin-1 and endomorphin-2 activated G proteins only partly compared with the full agonist DAMGO, with an efficacy similar to morphine's.
Biased signalling at the mu receptor
In three cell lines carrying the human mu receptor, endomorphin-1 and endomorphin-2 preferentially drove cAMP signalling, while dynorphin-B preferred G-protein (GTPgammaS) signalling. Blocking RGS4 or knocking down adenylyl cyclase 6 did not change the endomorphins' bias.
Relaxing human vas deferens
In electrically stimulated strips of human vas deferens, endomorphin-1 inhibited the twitch contractions by about 82% at most, with or without peptidase inhibitors, and naloxone blocked the effect, showing opioid receptors that dampen nerve-driven contraction in this tissue.
Less noradrenaline from human vascular nerves
Endomorphin-1 and -2 did not release nitric oxide from human blood cells or vessel lining and did not bind the mu3 opiate receptor subtype, but they did reduce stimulated noradrenaline release from sympathetic nerves in human vessels, which the authors propose as the route to their blood-pressure-lowering effect.
No known precursor in the human proteome
Searching the human proteome found 12 proteins containing the endomorphin-1 sequence, but none followed by the glycine needed for the end amide, and no endomorphin-2 candidate met all processing criteria either. An endomorphin-2 antibody also recognised four unrelated mouse brain proteins, so earlier tissue-staining results need re-reading.
Pain relief in mice, reviewed
This minireview describes endomorphin-1 and -2 given into the brain ventricles or spinal fluid of mice: both produced dose-dependent pain relief in the tail-flick test through mu receptors, with release of noradrenaline and serotonin acting in the spinal cord. Endomorphin-2 had extra components through dynorphin and Met-enkephalin that endomorphin-1 lacked.
Different routes for the two endomorphins
Given intrathecally to mice, both endomorphins relieved pain within a minute. Pretreatment with 3-methoxynaltrexone, nor-binaltorphimine or naltrindole weakened endomorphin-2's effect but not endomorphin-1's, which suggests the two act through different mu receptor subtypes and that only endomorphin-2 releases dynorphin and Met-enkephalin.
Nerve-injury pain in mice
In the spared nerve injury model, endomorphin-1 and -2 given into the brain ventricles raised paw withdrawal thresholds more than an equal amount of morphine, on both the injured and uninjured side. Injected into the paw they also worked, through mu1 and mu2 receptor subtypes, but given under the skin they did not.
Breathing and blood pressure in rats
In conscious rats given intravenous endomorphin-1, endomorphin-2, DAMGO or morphine, the pain-relief threshold was similar for the three peptides. Endomorphin-1 depressed breathing only at higher doses and stimulated it more afterwards, and it slowed the heart without lowering blood pressure, which the authors offer as a basis for safer analgesics.
Abnormal movements from the globus pallidus
Injected into both sides of the globus pallidus in rats, endomorphin-1 caused dose-dependent abnormal mouth and face movements that lasted the full hour of observation. Naloxone and a mu-selective blocker prevented it, and three hours of exposure in cells did not desensitise the mu receptor.
Smaller heart attacks in rats
Given into a vein 5 minutes before blood flow returned to a blocked coronary artery, endomorphin-1 reduced infarct size by 33% in rats. In isolated hearts it improved pumping during reperfusion and lowered the release of creatine kinase, a marker of heart muscle damage.
Pharmacology of the two endomorphins
This review describes the endomorphins as unevenly distributed in the brain, stored in neurons and nerve endings, released by depolarisation, broken down by peptidases and bound tightly and specifically by mu receptors. Their clearest effect is pain relief from central and peripheral sites, and they widen blood vessels by releasing nitric oxide from vessel lining.
Getting endomorphins into the brain
Opioid alkaloids carry side effects and some pain resists them, so modified endomorphins are being designed. This review covers peptidomimetics that resist breakdown and strategies to improve their entry into the central nervous system, which raised pain relief in animal tests.
No Established Human Dose
No dose exists for endomorphin-1 in people. The human studies here measure it in blood, immune cells and brain tissue or test it on donated human tissue in the laboratory; every study that gave it to a living body used mice or rats, by injection into the brain, spinal fluid, paw or vein. No trial in people was found on PubMed or ClinicalTrials.gov, and no product is approved.
What this rests on: PMID 20022398, PMID 22340163, PMID 9437727.
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 Endomorphin-1 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 Endomorphin-1 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 Endomorphin-1, 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 Endomorphin-1 stays intact once mixed.
How it is taken
Unknown: with no established human dose, there is no established way of taking Endomorphin-1. 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 Endomorphin-1 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: Depressed breathing at higher intravenous doses in rats, though less than other mu agonists at pain-relieving doses (PMID 10988119); Slowed heart rate in conscious rats; in anaesthetised rats it lowered both heart rate and blood pressure (PMID 10988119); Sustained abnormal mouth and face movements when injected into the rat globus pallidus (PMID 11404430); As a mu-opioid agonist it acts on the same receptor as morphine; dependence has not been studied in people. Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Endomorphin-1. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“Endomorphin-1 has not been given to people, so these are effects seen in animals”).
Interactions
Unknown: a PubMed search for human interaction studies of Endomorphin-1 (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 Endomorphin-1 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 Endomorphin-1's expected mass, 610.7 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: a research peptide). 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
Endomorphin-1 has not been given to people, so these are effects seen in animals.
Contraindications & Cautions
There is no product label. These cautions follow from the evidence.
Legal Status
Endomorphin-1 is a research peptide; it is not approved as a medicine anywhere in the sources read.
Frequently Asked Questions
?What is endomorphin-1?
A four-amino-acid peptide amide, Tyr-Pro-Trp-Phe-NH2, proposed as one of the body's own ligands for the mu-opioid receptor, the receptor morphine acts on. It was isolated from cow and then human brain.
?Is endomorphin-1 a painkiller?
In mice and rats, yes: injected into the brain, spinal fluid or paw it relieved pain through mu receptors, in one nerve-injury model more than an equal amount of morphine. It has never been tested for pain in people.
?Is it safer than morphine?
Rat studies hint at a better profile, with less breathing depression at pain-relieving doses, but nothing has been tested in humans, and it acts on the same receptor as morphine.
?Where is endomorphin-1 found in people?
In brain cortex, in blood plasma, where it was lower in diabetes, and in blood immune cells. How the body makes it is unclear, since no precursor protein has been identified.
?Why has it not become a drug?
It is broken down quickly and crosses into the brain poorly. Research has moved to modified analogues designed to last longer and reach the brain, which are separate molecules.
?What is its half-life?
No half-life in people or animals was found in the abstracts read; reviews describe it as rapidly broken down by peptidases.
References
- [other] PubChem CID 5311080, Endomorphin 1: formula C34H38N6O5, molecular weight 610.7. Read October 28, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/5311080
- [clinical-trial] Hackler L, et al. "Isolation of relatively large amounts of endomorphin-1 and endomorphin-2 from human brain cortex." Peptides, 1997;18(10):1635-9. PMID: 9437727.
- [clinical-trial] Xia FZ, et al. "Peripheral endomorphin-1 levels are suppressed in diabetic patients." Diabetes Res Clin Pract, 2010;87(2):200-3. PMID: 20022398.
- [clinical-trial] Chen Y, et al. "Short reaction of C-peptide, glucagon-like peptide-1, ghrelin and endomorphin-1 for different style diet in type 2 diabetic patients." Chin Med J (Engl), 2011;124(21):3485-9. PMID: 22340163.
- [clinical-trial] Jessop DS, et al. "Opioid peptides endomorphin-1 and endomorphin-2 in the immune system in humans and in a rodent model of inflammation." Ann N Y Acad Sci, 2002;966:456-63. PMID: 12114304.
- [pubmed] Hosohata K, et al. "Endomorphin-1 and endomorphin-2 are partial agonists at the human mu-opioid receptor." Eur J Pharmacol, 1998;346(1):111-4. PMID: 9617760.
- [pubmed] LaVigne J, et al. "The endomorphin-1/2 and dynorphin-B peptides display biased agonism at the mu opioid receptor." Pharmacol Rep, 2020;72(2):465-471. PMID: 32112361.
- [pubmed] Bigoni R, et al. "Effects of nociceptin and endomorphin 1 on the electrically stimulated human vas deferens." Br J Clin Pharmacol, 2001;51(4):355-8. PMID: 11318773.
- [pubmed] Rialas CM, et al. "Endomorphin-1 and -2 inhibit human vascular sympathetic norepinephrine release: lack of interaction with mu 3 opiate receptor subtype." Zhongguo Yao Li Xue Bao, 1998;19(5):403-7. PMID: 10375796.
- [pubmed] Terskiy A, et al. "Search of the human proteome for endomorphin-1 and endomorphin-2 precursor proteins." Life Sci, 2007;81(23-24):1593-601. PMID: 17964607.
- [review] Tseng LF. "The antinociceptive properties of endomorphin-1 and endomorphin-2 in the mouse." Jpn J Pharmacol, 2002;89(3):216-20. PMID: 12184724.
- [pubmed] Sakurada S, et al. "Differential antinociceptive effects induced by intrathecally-administered endomorphin-1 and endomorphin-2 in mice." Jpn J Pharmacol, 2002;89(3):221-3. PMID: 12184725.
- [pubmed] Wang CL, et al. "Antiallodynic Effects of Endomorphin-1 and Endomorphin-2 in the Spared Nerve Injury Model of Neuropathic Pain in Mice." Anesth Analg, 2017;125(6):2123-2133. PMID: 28787346.
- [pubmed] Czapla MA, et al. "Differential cardiorespiratory effects of endomorphin 1, endomorphin 2, DAMGO, and morphine." Am J Respir Crit Care Med, 2000;162(3 Pt 1):994-9. PMID: 10988119.
- [pubmed] Mehta A, et al. "Endomorphin-1: induction of motor behavior and lack of receptor desensitization." J Neurosci, 2001;21(12):4436-42. PMID: 11404430.
- [pubmed] Gorbunov AS, et al. "Cardioprotective Effect of Selective μ(2)-Opioid Receptor Agonist Endomorphin-1 in Cardiac Reperfusion In Vivo and In Vitro." Bull Exp Biol Med, 2024;178(1):86-90. PMID: 39576477.
- [review] Horvath G. "Endomorphin-1 and endomorphin-2: pharmacology of the selective endogenous mu-opioid receptor agonists." Pharmacol Ther, 2000;88(3):437-63. PMID: 11337033.
- [review] De Marco R, et al. "Strategies to Improve Bioavailability and In Vivo Efficacy of the Endogenous Opioid Peptides Endomorphin-1 and Endomorphin-2." Curr Top Med Chem, 2015;16(2):141-55. PMID: 26279081.
- [pubmed] Wu Y, et al. "Original endomorphin-1 analogues exhibit good analgesic effects." Bioorg Med Chem Lett, 2017;27(7):1557-1560. PMID: 28256374.
Sources & Citations
Every study on this page was read from its PubMed record on October 29, 2026. Status comes from Drugs@FDA (openFDA), the EMA medicines list and ClinicalTrials.gov, searched October 28, 2026. 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.