Opiorphin
The body's own painkilling peptide from saliva — it doesn't act on opioid receptors itself, it protects the enkephalins that do. A research molecule, not a drug
Opiorphin is a tiny peptide — just five amino acids, Gln-Arg-Phe-Ser-Arg — that humans make in their saliva. It was discovered at the Institut Pasteur in 2006, and what makes it interesting is how it works. It is not an opioid and does not bind opioid receptors. Instead it blocks two enzymes, neprilysin and aminopeptidase N, that normally chew up the body's own opioid peptides, the enkephalins. By protecting the enkephalins from breakdown, opiorphin lets them build up and act longer — so it turns up the volume on the body's natural pain relief rather than adding an outside drug. In rats, injected opiorphin relieved acute mechanical pain about as powerfully as morphine, by activating endogenous mu- and delta-opioid pathways. Its rat equivalent, sialorphin, works the same way. Because it leans on the body's own system, it has drawn interest as a possible painkiller without the classic opioid downsides, and chemists have built more stable versions of it (such as STR-324). In people, opiorphin so far appears mainly as a saliva and tear marker that rises with pain. It is studied as a research peptide; 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
Opiorphin is a peptide the body makes in saliva; it has never been given to people as a treatment. The analgesia work is in animals, where synthetic peptide or its stable analog is given by injection or infusion at experimental amounts that do not carry over to people, and the human studies only measure natural opiorphin levels.
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What is it?
The body relieves pain partly with its own short opioid peptides, the enkephalins, which act on mu- and delta-opioid receptors. Their problem is that they are destroyed within seconds by surface enzymes — chiefly neprilysin (neutral endopeptidase) and aminopeptidase N. Opiorphin, discovered in human saliva in 2006, is a natural brake on those enzymes: a five-residue peptide (Gln-Arg-Phe-Ser-Arg) that inhibits both of them, so the enkephalins the body already makes last longer and signal more.
That indirect mechanism is the whole point. Opiorphin does not bind opioid receptors itself and is not an opioid. It is an enkephalinase inhibitor — it raises the tone of the body's own opioid system rather than flooding it with an external agonist. In the discovery study, opiorphin blocked both human neprilysin and human aminopeptidase N, and in a rat acute-mechanical-pain test (the pin-pain test) its pain-suppressing potency was as effective as morphine, an effect that depended on endogenous opioid transmission.
Its rat counterpart, sialorphin, works by the same route and reduces pain perception, which helped establish the mechanism across species. Because an enkephalinase inhibitor might relieve pain while avoiding some of the dependence and tolerance seen with direct opioid agonists, opiorphin became a lead for analgesic development. Its weakness is metabolic: the natural peptide is itself rapidly degraded, so chemists have made stabilized analogs — notably STR-324 — and delivery formulations to prolong its action.
In one preclinical neuropathic-pain model, continuous intravenous infusion of the stable analog STR-324 reduced mechanical allodynia and spontaneous pain behaviour and lowered pain-evoked spinal c-Fos, showing it acts through endogenous nociceptive pathways. A systematic review of opiorphin analogs catalogued the modifications used to improve stability while keeping the analgesic effect, and flagged the most promising candidates for further work.
In humans, opiorphin currently appears mainly as a biomarker rather than a treatment: observational studies find that salivary and tear opiorphin levels rise with painful conditions — dental pericoronitis, corneal injury — consistent with a pain-relief role, though these are correlational, not trials of giving opiorphin. Separately, research has linked opiorphin genes to prostate-cancer growth in laboratory models, a reminder that a molecule tied to growth and survival signalling is not automatically benign. Opiorphin is not approved anywhere, 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
Opiorphin is a human salivary pentapeptide that relieves pain indirectly: it inhibits the enzymes neprilysin and aminopeptidase N, which normally destroy the body's enkephalins, so endogenous enkephalins persist and activate mu- and delta-opioid receptors more strongly. It is not itself an opioid-receptor agonist.
Dual enkephalinase inhibition
Inhibits neprilysin (hNEP) and aminopeptidase N (hAP-N), the two main ectoenzymes that degrade enkephalins, protecting them from breakdown (PMID 17101991).
Endogenous opioid potentiation
With enkephalins preserved, mu- and delta-opioid signalling is amplified, producing analgesia as strong as morphine in a rat model without being an opioid itself (PMID 17101991).
Growth-signalling caveat
Opiorphin genes can promote tumour growth and angiogenesis in prostate-cancer models — a reason for caution about effects beyond analgesia (PMID 33593085).
Published Research
These are studies of opiorphin read from their PubMed records on November 7, 2026: the 2006 discovery paper establishing its structure, dual enzyme inhibition and morphine-comparable analgesia in rats; an animal neuropathic-pain study of the stabilized analog STR-324; a systematic review of opiorphin analogs; two human observational studies showing salivary and tear opiorphin rise with pain; and a laboratory study linking opiorphin genes to prostate-cancer growth. The human studies are observational biomarker work — opiorphin has not been given to people as a treatment.
Discovery: opiorphin inhibits enkephalin-degrading ectoenzymes and relieves pain in rats
A previously uncharacterised human salivary peptide, QRFSR, was identified and named opiorphin. It inhibited two enkephalin-catabolising ectoenzymes — human neprilysin and human aminopeptidase N — and, by potentiating endogenous opioid transmission, produced analgesia as effective as morphine in a rat acute-mechanical-pain test; its function parallels the rat peptide sialorphin (a discovery and characterisation study).
Opiorphin analog STR-324 reduces neuropathic pain behaviour (rats)
Continuous intravenous infusion of the stable opiorphin analog STR-324 over seven days significantly reduced mechanical allodynia and spontaneous pain-related behaviour in a rat spinal-nerve-ligation model of neuropathic pain, and lowered pain-evoked spinal c-Fos expression — evidence that it acts through endogenous nociceptive pathways (a preclinical result).
Opiorphin analogs and metabolic stability (systematic review)
A systematic review of opiorphin and its analogs catalogued the modifications used to improve the peptide's metabolic stability while preserving its potent, morphine-comparable analgesic effect (non-natural or D-amino-acid substitutions, side-chain changes, PEGylated-liposome delivery) and identified the most promising candidates — including STR-324 — for future research.
Tear opiorphin rises with ocular pain (human observational)
In people with ocular pain from a corneal foreign body, tear opiorphin levels were significantly higher than in pain-free controls, consistent with opiorphin being released as a pain-relief response in the densely innervated cornea — an observational biomarker association, not a trial of giving opiorphin.
Salivary opiorphin rises with acute dental pain (human observational)
In patients with acute pericoronitis, salivary opiorphin was significantly higher during painful disease than after the pain resolved following tooth extraction, supporting opiorphin as a potential salivary pain biomarker — an observational, correlational finding in a small sample, not an interventional study.
Opiorphin genes promote prostate-cancer growth in models
Prostate cancer was associated with overexpression of opiorphin genes; androgen-sensitive human prostate-cancer cells overexpressing an opiorphin gene formed tumours in castrated male mice (unlike parental cells) and modulated angiogenesis, steroid and hypoxia pathways — a laboratory signal that opiorphin signalling can promote tumour growth, relevant to safety, not a human outcome.
No Established Human Dose
Opiorphin is a peptide the body makes in saliva; it has never been given to people as a treatment. The analgesia work is in animals, where synthetic peptide or its stable analog is given by injection or infusion at experimental amounts that do not carry over to people, and the human studies only measure natural opiorphin levels. No regulator has approved any dose, and no published human dose exists, so no amount is printed here.
What this rests on: PMID 17101991, PMID 28806211, PMID 32482963.
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 Opiorphin 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 Opiorphin 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 Opiorphin, 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 Opiorphin stays intact once mixed.
How it is taken
Unknown: with no established human dose, there is no established way of taking Opiorphin. 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 natural peptide is rapidly degraded, motivating stabilized analogs (STR-324). After about five half-lives almost none is left.
When effects appear: unknown; no source on this page gives a time to effect for Opiorphin. Results reported in the studies are under Published Research.
Source: half-life: PMID 37933217.
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 opiorphin to people as a treatment; In animals its analgesia works through endogenous opioid pathways, so opioid-type effects (and the class concerns of tolerance/dependence) are a mechanistic consideration, though a goal of the approach is to reduce them versus direct opioids — an inference, not human data; Opiorphin genes promoted tumour growth, angiogenesis and a hypoxic-survival response in prostate-cancer models (PMID 33593085) — a laboratory safety signal worth weighing; Material sold online as 'opiorphin' 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 Opiorphin. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“Opiorphin is an endogenous 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 and its biology”).
Interactions
Unknown: a PubMed search for human interaction studies of Opiorphin (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 Opiorphin 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 approved-drug record for opiorphin or its analog STR-324 (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
Opiorphin is an endogenous 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 and its biology.
Contraindications & Cautions
Opiorphin has no approved use and no label. These points reflect its research status.
Legal Status
Opiorphin is an endogenous human peptide studied as a research compound; it is not a drug and is not approved in any country.
Frequently Asked Questions
?What is opiorphin?
A five-amino-acid peptide (Gln-Arg-Phe-Ser-Arg) the body makes in saliva, discovered in 2006. It relieves pain indirectly by blocking the enzymes that break down the body's own opioid peptides, the enkephalins.
?Is opiorphin an opioid?
No. It does not bind opioid receptors itself. It is an enkephalinase inhibitor — it protects enkephalins so they last longer, which amplifies the body's natural opioid analgesia (PMID 17101991).
?Is it as strong as morphine?
In a rat acute-pain test, injected opiorphin was as effective as morphine (PMID 17101991). That is an animal result; opiorphin has not been tested as a painkiller in people.
?Is it approved or available to buy?
No. Opiorphin is not a medicine, has no FDA application or label, and is approved nowhere. Material sold online as opiorphin is an unregulated research chemical. Grey Peptides lists no sellers and recommends no source; this page records the published science.
References
- [mechanism] Wisner A, et al. "Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways." Proc Natl Acad Sci U S A, 2006;103(47):17979-84. PMID: 17101991.
- [animal] Van Elstraete A, et al. "The Opiorphin Analog STR-324 Decreases Sensory Hypersensitivity in a Rat Model of Neuropathic Pain." Anesth Analg, 2018;126(6):2102-2111. PMID: 28806211.
- [review] Tome J, et al. "Enhancing Opiorphin's Metabolic Stability and Preserving its Potent Analgesic Effect: A Systematic Review." Curr Top Med Chem, 2024;24(1):74-88. PMID: 37933217.
- [clinical-trial] Ozdogan S, et al. "Tear Opiorphin Levels in Ocular Pain Caused by Corneal Foreign Body." Cornea, 2020;39(11):1377-1380. PMID: 32482963.
- [clinical-trial] Ertem SY, et al. "Evaluation of Salivary Opiorphin Levels in Acute Pericoronitis Related Pain." Niger J Clin Pract, 2025;28(3):378-384. PMID: 40214066.
- [animal] Mukherjee A, et al. "Role of opiorphin genes in prostate cancer growth and progression." Future Oncol, 2021;17(17):2209-2223. PMID: 33593085.
- [other] Opiorphin is the human salivary pentapeptide Gln-Arg-Phe-Ser-Arg (QRFSR), cleaved from the opiorphin prepropeptide (gene OPRPN, also called PROL1 / SMR3B). It was discovered and named by Wisner, Rougeot and colleagues at the Institut Pasteur in 2006, as described in the discovery paper carded on this page (read November 7, 2026). Its rat counterpart is the peptide sialorphin.
- [other] US FDA, Drugs@FDA and the openFDA label endpoint, searched November 7, 2026: no application and no label record for opiorphin or its analog STR-324. It is an endogenous human peptide studied in research, not a drug; FDA GSRS and ChEMBL hold no approved-drug record for it.
Sources & Citations
The six studies carded above were read from their PubMed records on November 7, 2026. Opiorphin's structure (QRFSR), its inhibition of neprilysin and aminopeptidase N, its morphine-comparable analgesia in rats, the STR-324 analog, the human salivary/tear biomarker associations, and the prostate-cancer-model link are from the discovery paper, review and studies carded here; the absence of US approval or an approved-drug record from Drugs@FDA, openFDA, FDA GSRS and ChEMBL was checked 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.