Endomorphin-2 (EM-2)
One of the body's own most selective painkillers for the mu-opioid receptor — a four-amino-acid peptide studied for analgesia. A research peptide, not a drug
Endomorphin-2 (EM-2) is one of a pair of tiny natural peptides — just four amino acids, Tyr-Pro-Phe-Phe — that are the most selective endogenous activators of the mu-opioid receptor known, the same receptor morphine acts on. Named in 1997 alongside its partner endomorphin-1, it produces powerful pain relief in animal studies when given into the brain or spinal cord. What makes endomorphin-2 scientifically interesting is how it differs from endomorphin-1: its analgesia recruits extra pathways — the release of dynorphin A (acting on kappa-opioid receptors) and Met-enkephalin (on delta-opioid receptors) — and it raises dopamine in the brain's reward centre by a mechanism that is not blocked by opioid antagonists at all, unlike endomorphin-1. A genuine mystery hangs over both peptides: despite decades of work, the gene and precursor protein they are cut from have never been firmly identified. Because peptides like endomorphin-2 are broken down quickly and cross the blood-brain barrier poorly, much of the research is on modified analogs built to last longer and penetrate the brain. Endomorphin-2 is studied as a research tool and an analgesic lead; it is not an approved medicine and has not been given to people as a treatment.
No established human dose Details ↓
Recommended Dosing
No established human dose
Endomorphin-2 is an endogenous peptide that has never been given to people as a treatment. The work is in animals and cells, where it is given directly into the brain or spinal fluid, or as engineered analogs, at experimental amounts that do not carry over to people.
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What is it?
The mu-opioid receptor is the target of morphine and the body's own pain-relief system. For years its known natural ligands were the enkephalins and beta-endorphin, which actually prefer other opioid receptors or bind mu less selectively. In 1997 two four-amino-acid peptides were isolated from brain and named endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2): the most selective endogenous mu-opioid agonists found, differing from each other by a single amino acid at position three.
Endomorphin-2 binds the mu-opioid receptor with high affinity and selectivity. In cell systems expressing the human mu receptor it behaves as a partial agonist with efficacy similar to morphine, and in isolated gut tissue (the guinea-pig ileum) it is a full agonist whose effects are blocked by mu-selective — but not delta- or kappa-selective — antagonists, confirming it works through the mu receptor.
Its headline effect is pain relief. Given into the brain's ventricles or the spinal fluid of mice, endomorphin-2 produces dose-dependent antinociception through mu receptors. But endomorphin-2 is not simply interchangeable with endomorphin-1: its analgesia carries extra components that endomorphin-1's does not — it triggers the release of dynorphin A, which acts on kappa-opioid receptors, and of Met-enkephalin, which acts on delta-opioid receptors, at spinal and supraspinal sites. This has led to the idea that distinct mu-receptor subtypes mediate the two peptides' effects.
The differences extend to reward circuitry. In freely moving rats, both endomorphins raise dopamine in the nucleus accumbens, but by opposite routes: endomorphin-1 does so through mu-opioid receptors (and is blocked by the opioid antagonist naloxone), whereas endomorphin-2's dopamine effect is NOT blocked by naloxone or a mu antagonist at all — a genuinely non-opioid mechanism. Because the native peptide is rapidly degraded and penetrates the brain poorly, much work focuses on engineered analogs; a glycosylated endomorphin-2, for instance, crossed into the brain better and produced potent central pain relief in mice even when injected peripherally.
Endomorphin-2 is an endogenous peptide studied as a research tool and an analgesic lead — a route toward painkillers that might separate analgesia from some opioid side effects. No published study has given endomorphin-2 to people as a treatment; the evidence is animal and cell work, it is approved nowhere, and material sold online under its name is an unregulated research chemical. Nothing here is a dose or a therapy; this page records what the published science says.
Mechanism of Action
Endomorphin-2 is the amidated tetrapeptide Tyr-Pro-Phe-Phe-NH2, a highly selective endogenous agonist of the mu-opioid receptor. Through it, endomorphin-2 produces antinociception — but with distinctive downstream recruitment of dynorphin and enkephalin and a non-opioid effect on reward-circuit dopamine that set it apart from endomorphin-1.
Selective mu-opioid agonism
Endomorphin-2 binds the mu-opioid receptor with high selectivity (partial agonist at the human receptor, full agonist in gut tissue), blocked by mu- but not delta-/kappa-antagonists (PMIDs 9617760, 9879730).
Antinociception with extra opioid recruitment
Central and spinal endomorphin-2 relieve pain in animals and additionally release dynorphin A (kappa) and Met-enkephalin (delta), unlike endomorphin-1 (PMID 12184724).
Non-opioid dopamine effect
Endomorphin-2 raises nucleus-accumbens dopamine by a mechanism not blocked by naloxone or a mu antagonist — distinct from endomorphin-1's mu-mediated effect (PMID 16034447).
Published Research
These are studies of endomorphin-2 read from their PubMed records on November 7, 2026: a human mu-opioid-receptor assay, a guinea-pig gut-tissue study confirming mu action, two reviews of the endomorphins' antinociceptive pharmacology, a rat study showing endomorphin-2 raises reward-circuit dopamine by a non-opioid route, and an engineered glycosylated analog with better brain penetration in mice. Endomorphin-2 has not been given to people as a treatment; the evidence is animal and cell work.
Endomorphin-2 is a partial agonist at the human mu-opioid receptor
In human mu-opioid-receptor-transfected cells, endomorphin-1 and endomorphin-2 stimulated G-protein activation (35S-GTPgammaS binding) as partial agonists, with efficacy similar to morphine. This confirmed the endomorphins act on the human mu receptor with morphine-like activity — a receptor-pharmacology result.
Endomorphin-2 activates mu receptors in guinea-pig gut neurons
In guinea-pig ileum preparations, endomorphin-2 (and endomorphin-1) inhibited electrically evoked contractions as full agonists; the effect was shifted by a mu-selective antagonist but not by delta- or kappa-selective antagonists, showing endomorphin-2 acts selectively through mu-opioid receptors on excitatory myenteric neurons (an ex-vivo tissue result).
Antinociceptive properties of endomorphin-2 in the mouse (review)
A review of endomorphin-1 and endomorphin-2 analgesia in mice: given into the brain ventricles or spinal fluid, both produce dose-dependent, mu-mediated antinociception. Endomorphin-2's effect additionally recruits the release of dynorphin A (kappa) and Met-enkephalin (delta), unlike endomorphin-1 — evidence the review reads as pointing to distinct mu-receptor subtypes.
Pharmacology of the selective endogenous mu agonists endomorphin-1 and -2
A comprehensive review: the endomorphins are unevenly distributed in the brain, stored in neurons and axon terminals, released on depolarisation, degraded by endopeptidases, and bind mu receptors with high affinity and selectivity. Their most prominent action is antinociception (central and peripheral); endomorphin-2 also causes vasodilatation via endothelial nitric oxide. Framed as potent antinociceptive and vasodilator agents.
Endomorphin-2 raises reward-circuit dopamine by a non-opioid route
In freely moving rats, intra-accumbens endomorphin-2 and endomorphin-1 both raised nucleus-accumbens dopamine dose-dependently, but by different mechanisms: endomorphin-1's effect was blocked by the mu antagonist CTOP and by naloxone, while endomorphin-2's was NOT blocked by either — a genuinely non-opioid mechanism distinguishing the two peptides (a preclinical result).
A glycosylated endomorphin-2 analog gives central analgesia after peripheral dosing
A glycosylated analog of endomorphin-2 (a glucose moiety on a position-3 tyrosine) showed improved blood-brain-barrier permeability and enhanced antinociception in mice after peripheral administration, suggesting glycosylation as a route to make this rapidly degraded, poorly brain-penetrant peptide into a usable analgesic lead (a preclinical medicinal-chemistry result).
No Established Human Dose
Endomorphin-2 is an endogenous peptide that has never been given to people as a treatment. The work is in animals and cells, where it is given directly into the brain or spinal fluid, or as engineered analogs, at experimental amounts that do not carry over to people. No regulator has approved any dose, and no published human dose exists, so no amount is printed here.
What this rests on: PMID 12184724, PMID 16034447, PMID 24220171.
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-2 (EM-2) 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-2 (EM-2) 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-2 (EM-2), 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-2 (EM-2) stays intact once mixed.
How it is taken
Unknown: with no established human dose, there is no established way of taking Endomorphin-2 (EM-2). What the human studies gave and how is set out under No Established Human Dose.
What to expect, and when
How long it stays in the body: a half-life of very short; the native peptide is rapidly degraded by peptidases. After about five half-lives almost none is left.
When effects appear: unknown; no source on this page gives a time to effect for Endomorphin-2 (EM-2). Results reported in the studies are under Published Research.
Source: half-life: PMID 24220171.
Side effects, and when to stop or get help
From the Side Effects section: No human adverse-event data exist: no published study has administered endomorphin-2 to people; As a mu-opioid-receptor agonist it is in the same pharmacological class as morphine, so opioid-type effects (sedation, respiratory depression, tolerance, dependence) would be the expected risks of any mu agonist — a class inference, not human data for this peptide; In animals it produces antinociception and affects gut, reward and cardiovascular (nitric-oxide) pathways (PMIDs 11337033, 16034447) — preclinical signals, not a human safety profile; Material sold online as 'endomorphin-2' is an unregulated research chemical of unverified content. Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Endomorphin-2 (EM-2). Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“Endomorphin-2 is a research peptide that has not been given to people as a drug, so there is no human safety profile; the points below reflect that research status”).
Interactions
Unknown: a PubMed search for human interaction studies of Endomorphin-2 (EM-2) (reviewed 2026-11-07) 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-2 (EM-2) 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. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Research Chemical (Not a drug: Drugs@FDA and the openFDA label endpoint hold no record, and FDA GSRS and ChEMBL hold no drug record for endomorphin-2 (searched November 7, 2026)). Sport: Not on the 2026 List.
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-2 is a research peptide that has not been given to people as a drug, so there is no human safety profile; the points below reflect that research status.
Contraindications & Cautions
Endomorphin-2 has no approved use and no label. These points reflect its research status.
Legal Status
Endomorphin-2 is an endogenous opioid peptide studied as a research compound; it is not a drug and is not approved in any country.
Frequently Asked Questions
?What is endomorphin-2?
An endogenous four-amino-acid peptide (Tyr-Pro-Phe-Phe-NH2) that, with endomorphin-1, is one of the two most selective natural agonists of the mu-opioid receptor — the receptor morphine acts on.
?What does it do?
In animals it produces potent pain relief through mu-opioid receptors (PMID 12184724). It differs from endomorphin-1 by additionally releasing dynorphin and Met-enkephalin, and by raising reward-circuit dopamine through a non-opioid mechanism (PMID 16034447).
?How is it different from endomorphin-1?
They differ by one amino acid (position 3: Phe in endomorphin-2, Trp in endomorphin-1) and in their downstream pharmacology — endomorphin-2 recruits extra kappa/delta opioid pathways in analgesia and has a non-opioid dopamine effect. The precursor gene for both has never been firmly identified.
?Is it approved or available to buy?
No. Endomorphin-2 is not a medicine, has no FDA application or label, and is approved nowhere. Material sold online as endomorphin-2 is an unregulated research chemical. Grey Peptides lists no sellers and recommends no source; this page records the published science.
References
- [mechanism] 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.
- [animal] Tonini M, et al. "Endomorphin-1 and endomorphin-2 activate mu-opioid receptors in myenteric neurons of the guinea-pig small intestine." Naunyn Schmiedebergs Arch Pharmacol, 1998;358(6):686-9. PMID: 9879730.
- [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.
- [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.
- [animal] Okutsu H, et al. "Endomorphin-2 and endomorphin-1 promote the extracellular amount of accumbal dopamine via nonopioid and mu-opioid receptors, respectively." Neuropsychopharmacology, 2006;31(2):375-83. PMID: 16034447.
- [animal] Fichna J, et al. "Novel glycosylated endomorphin-2 analog produces potent centrally-mediated antinociception in mice after peripheral administration." Bioorg Med Chem Lett, 2013;23(24):6673-6. PMID: 24220171.
- [other] Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) were identified and named as endogenous mu-opioid-receptor agonists by Zadina and colleagues in 1997; unusually for a neuropeptide, the biosynthetic precursor protein and gene for the endomorphins have never been firmly identified, so there is no single UniProt gene entry for endomorphin-2. Its identity and pharmacology rest on the isolation and receptor studies carded on this page (read November 7, 2026).
- [other] US FDA, Drugs@FDA and the openFDA label endpoint, searched November 7, 2026: no application and no label record for endomorphin-2. It is an endogenous opioid peptide studied as a research tool and analgesic lead, not a registered drug; FDA GSRS and ChEMBL hold no drug record for it.
Sources & Citations
The six studies carded above were read from their PubMed records on November 7, 2026. Endomorphin-2's identity (Tyr-Pro-Phe-Phe-NH2), its selective mu-opioid agonism, its antinociceptive action and its distinctive dynorphin/enkephalin and non-opioid dopamine effects are from the receptor studies, reviews and animal studies carded here; the absence of a firmly identified precursor gene, and of US approval or a drug record from Drugs@FDA, openFDA, FDA GSRS and ChEMBL, were noted the same day. 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.