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Pig Brains and Mouse Tissue: How the Brain’s Own Opioid Peptides Were Found
If morphine works by fitting into a receptor, why does the body have such a receptor at all? Nobody grows morphine in the brain. In the early 1970s that question pushed several laboratories toward a remarkable idea: the brain must make its own morphine-like molecules.
Key takeaways
- Opiate receptors were demonstrated in brain tissue in 1973 by groups led by Solomon Snyder (with Candace Pert), Eric Simon and Lars Terenius.
- In Aberdeen, John Hughes and Hans Kosterlitz searched pig brain for a natural substance that acted on the same receptors.
- In 1975 they reported two short peptides, now called Met-enkephalin and Leu-enkephalin, each five amino acids long.
- The name comes from the Greek for “in the head”.
- The discovery opened the study of endorphins and the whole field of neuropeptides, and credit for it remains debated.
A receptor with no obvious reason to exist
By the early 1970s, pharmacologists knew that opiates like morphine bind to specific sites in the nervous system. In 1973, researchers at Johns Hopkins, including Solomon Snyder and graduate student Candace Pert, showed that radioactive opiates stuck to brain tissue in a way that matched their potency. Eric Simon in New York and Lars Terenius in Sweden reported similar findings.
That raised an obvious question. Evolution did not build a receptor for a poppy extract. Something made inside the body must be the natural key.
Bioassays and pig brain
In Aberdeen, Hans Kosterlitz and John Hughes used a clever tool. Strips of guinea pig intestine and mouse vas deferens twitch when electrically stimulated, and opiates quiet the twitching. The effect is blocked by naloxone, a drug that blocks opiate receptors. That made a sensitive test: any extract that quieted the twitch and was reversed by naloxone probably contained an opiate-like factor.
They prepared extracts from pig brain and separated them into fractions, running the bioassay on each. The activity followed a small peptide. In 1975 the team, including chemists who worked out the structure, reported two related compounds that differed only in the last amino acid: methionine in one and leucine in the other. They named them enkephalins.
Five amino acids
The sequence begins Tyr-Gly-Gly-Phe, followed by Met or Leu. That tiny amount of information is enough to bind the receptor, and the tyrosine at the front is critical. Enkephalins are broken down in minutes by enzymes that clip off the front amino acid, which is a classic example of why short peptides can be fleeting. We discuss that problem in half-life engineering.
Larger relatives followed quickly. Beta-endorphin, a 31-amino-acid peptide, was identified in the pituitary the same year. The idea of “endogenous morphine” gave endorphins their name.
Who gets the credit
The discovery is a good example of how credit in science can become tangled. The 1978 Lasker Award recognized Hughes, Kosterlitz and Snyder. Candace Pert, who had done much of the experimental work on the receptor, was not named, and she criticized the omission publicly for the rest of her career. Historians of science still discuss the case as an example of how graduate students and junior researchers can be overlooked.
What the lab can take from it
- A bioassay with a built-in blocker, like naloxone, is a powerful way to prove a mechanism.
- Short peptides are often rapidly degraded, so identity and timing matter.
- Binding to tissue and function are different questions, which is why researchers run both binding assays and functional tests.
- Receptors can signal in more than one way, a theme explored in biased agonism.
The bottom line
The enkephalin story is about asking why a receptor exists. The answer, a family of small peptides made in the brain itself, changed pharmacology. For an everyday example of a neuropeptide studied in research settings, see our DSIP overview and the sleep history in the sleep substance hunters story.
Related reading
- Half-life engineering
- The sleep substance hunters
- Biased agonism explained
- Browse the full Research Library
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For laboratory research use only. Not for human or veterinary use, and not intended to diagnose, treat, cure or prevent any condition. This article is educational and is not medical advice.