What it is
The enkephalins are two peptides of five amino acids each — the body's own opioids. In 1975 John Hughes, Hans Kosterlitz and colleagues reported that "enkephalin", a natural ligand for opiate receptors, is in fact two pentapeptides (Nature 258:577, PMID 1207728):
| Name | Sequence | Formula | Molecular weight |
|---|---|---|---|
| Met-enkephalin | Tyr-Gly-Gly-Phe-Met (YGGFM) | C27H35N5O7S | 573.7 |
| Leu-enkephalin | Tyr-Gly-Gly-Phe-Leu (YGGFL) | C28H37N5O7 | 555.6 |
Formulas and weights: PubChem CIDs 443363 and 461776. The two differ only in the last amino acid, and that last letter gives each its name. They established the sequence by the dansyl-Edman method and mass spectrometry, then synthesised both peptides and compared them with the natural material — the standard of proof for a new peptide at the time.
Where they come from
The body does not build enkephalins one at a time. It makes long precursor proteins and cuts the short peptides out:
- Proenkephalin (267 residues, UniProt P01210) holds four copies of Met-enkephalin, two extended versions (Met-enkephalin-Arg-Gly-Leu and Met-enkephalin-Arg-Phe) and one Leu-enkephalin — six Met sequences to one Leu, which is why Met-enkephalin is the more abundant of the two.
- Prodynorphin (254 residues, UniProt P01213) carries the Leu-enkephalin sequence at the start of longer peptides — alpha-neoendorphin, dynorphin A and rimorphin — so Leu-enkephalin has two possible sources.
Every one of these opioid peptides begins with Tyr-Gly-Gly-Phe (our reading of the two UniProt entries). Each copy is flanked by pairs of basic amino acids (Lys-Arg, Lys-Lys or Arg-Arg), the usual cutting signal in hormone precursors (our reading of P01210).
What they do
UniProt summarises the enkephalins as neuropeptides that "compete with and mimic the effects of opiate drugs" and play a role in "pain perception and responses to stress" (P01210). Its annotations go further for some of proenkephalin's other products: Met-enkephalin-Arg-Phe is described as a strong ligand of the mu opioid receptor, and BAM22, another fragment, as a peptide that can trigger itch through a non-opioid receptor, MRGPRX1. Those statements rest mainly on laboratory and animal work.
What is not established in people: that raising enkephalins, by any product, relieves pain or stress. The physiology was worked out in tissue and animals; the human trial record (below) is small and early-phase.
The human record
- ClinicalTrials.gov lists 15 studies naming an enkephalin as an intervention, 8 of them Met-enkephalin (2026-10-26). None has led to an approved product.
- "Opioid growth factor": Met-enkephalin is studied in cancer under that name — 13 PubMed titles pair the two terms. Its most recent published trial, a phase I dose-escalation in 14 people with unresectable liver cancer, gave doses up to 300 µg/kg by vein with no grade 3 toxicity (Kimchi et al., Cancer Invest 2025, PMID 40196893; NCT00706576). A phase I study is designed to find a tolerable dose; it does not show that a treatment works.
Where it stands
- Not an approved medicine in the US. The enkephalins are measured in research, not prescribed.
- Research record: PubMed indexes 16,538 records under the MeSH heading Enkephalins and 21,971 mentioning enkephalin* anywhere (2026-10-26).
Related reading
Another of the body's own neuropeptides with a pain role is substance P, which carries pain signals rather than damping them. Precursor-and-cut biology is shared with ACTH, cut from proopiomelanocortin — the same precursor that yields beta-endorphin. How a chain is numbered from its tyrosine end is explained in the peptide chain.