The discovery: when scientists found the brain’s own opioid signals
The problem: opioid effects were known, but the natural signal was not
By the early 1970s, researchers understood that drugs such as morphine acted on specialised opioid receptors. The major unanswered question was simple: why would the body have receptors for an external drug?
The solution came from searching for naturally produced molecules that could fit those receptors.
In 1975, John Hughes, Hans Kosterlitz and colleagues published the landmark identification of two related pentapeptides, met-enkephalin and leu-enkephalin, isolated from brain tissue and shown to possess opiate-like activity. Their Nature paper described enkephalin as a natural ligand for opiate receptors and identified the sequences of both peptides.
The name enkephalin comes from the Greek phrase en kephalos, meaning “in the head”. It reflects the original discovery of these molecules in brain tissue.
The discovery changed opioid biology. Researchers were no longer studying only plant-derived drugs or synthetic medicines. They could now examine the body’s own opioid “maintenance system”: a network involved in pain control, emotional processing and stress adaptation.
Key point: Leu-enkephalin is not an artificial imitation of opioid biology. It is part of the biology.
For the primary discovery paper, see Hughes et al., Nature, 1975.
One amino acid separates leu-enkephalin from met-enkephalin
The problem: two nearly identical peptides can look interchangeable
Leu-enkephalin and met-enkephalin share the first four amino acids:
Tyr-Gly-Gly-Phe-
The difference is at position five:
| Feature | Leu-enkephalin | Met-enkephalin |
|---|---|---|
| Full sequence | Tyr-Gly-Gly-Phe-Leu | Tyr-Gly-Gly-Phe-Met |
| Position 5 | Leucine | Methionine |
| Peptide length | Five amino acids | Five amino acids |
| Main research profile | Relatively more δ-opioid preference | More balanced μ/δ activity |
| Native duration | Very short | Very short |
Leucine and methionine are both hydrophobic amino acids, but their side chains are not identical. Leucine is a branched hydrocarbon, while methionine contains sulphur. Think of the two peptides as matching keys with the same first four teeth but a slightly different final tooth.
That small structural change can alter:
- How the peptide fits within the opioid receptor binding pocket
- The balance between δ-opioid receptor and μ-opioid receptor activity
- How enzymes recognise and cleave the peptide
- The shape and duration of downstream signalling
Leu-enkephalin is generally described as having a stronger relative preference for δ-opioid receptors, while met-enkephalin tends to show a more balanced μ/δ profile. These are relative pharmacological tendencies, not absolute categories. Receptor behaviour depends on the assay, tissue, concentration and experimental conditions.
The position-five change also influences degradation, but you should not interpret this as meaning one native peptide lasts dramatically longer in every situation. Both are broken down rapidly in biological fluids. Their measured duration depends on the research model, enzyme environment and route of exposure.
Short summary: One residue can change receptor preference, enzyme recognition and signalling, but both native enkephalins remain short-lived.
For a direct companion resource, see the Met-Enkephalin 10 mg page.
