Scientists identified two small five-amino-acid peptides in the brain — met-enkephalin and leu-enkephalin — that naturally activate opioid receptors, proving the brain makes its own morphine-like painkillers.
5 amino acidsThe brain's natural painkillers turned out to be remarkably small — just five amino acids long — yet they bind the same receptors as complex plant molecules like morphine, fundamentally changing our understanding of pain and addiction.
What the researchers found
The researchers identified enkephalin as consisting of two related pentapeptides (five-amino-acid chains): met-enkephalin (Tyr-Gly-Gly-Phe-Met) and leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). These peptides differ only in their final amino acid — methionine versus leucine. Both act as natural ligands (binding molecules) for opioid receptors in the brain, meaning they are the body's endogenous counterparts to plant-derived opiates like morphine.
The identification was confirmed by sequencing the natural peptides using the dansyl-Edman procedure and mass spectrometry, then chemically synthesizing both sequences and showing they matched the biological activity of the natural extracts.
Why it matters
This is one of the most important papers in neuroscience history. Before this discovery, scientists knew the brain had receptors for opiates but couldn't explain why — since plants make morphine, not humans. Finding that the brain produces its own opioid peptides explained why we have opioid receptors in the first place and launched the entire field of endogenous opioid research. It fundamentally changed our understanding of pain, addiction, mood regulation, and the brain's reward system.
How the study worked
The researchers extracted enkephalin from pig brain tissue, then used two complementary analytical techniques — the dansyl-Edman degradation procedure (which reads amino acid sequences one letter at a time) and mass spectrometry — to determine the exact amino acid sequences. They then chemically synthesized both peptides in the laboratory and compared the synthetic versions to the natural brain extracts to confirm identical structure and biological activity.
What this study cannot tell us
The abstract is notably brief, as was common for Nature papers in 1975. The initial characterization was limited to identifying the sequences and confirming opioid receptor binding. The broader physiological roles of enkephalins — including their involvement in pain modulation, mood, gut function, and immune regulation — would only be elucidated in subsequent decades of research. The work used pig brain tissue, though enkephalins were later confirmed across mammalian species including humans.
How to read the evidence
This is a foundational discovery paper — primary experimental research published in Nature that identified a new class of biological molecules. As a structural identification study, it established a fact rather than testing a hypothesis, and has been confirmed and extended by thousands of subsequent studies.
When this study was published
Published in 1975, this is a 50-year-old landmark paper. While the basic discovery is well-established history, the enkephalin system remains an active area of research with ongoing relevance to pain management, addiction science, and peptide drug development.
The bigger picture
This discovery opened the floodgates for endogenous opioid research. Within years, scientists found endorphins, dynorphins, and other opioid peptides — revealing an entire natural pain-modulation system in the brain. This knowledge has shaped our understanding of pain management, opioid addiction, and the neuroscience of pleasure and reward. It also provided the foundation for developing peptide-based pain medications and understanding why opioid drugs are both effective and addictive.
Questions still open
- How do met-enkephalin and leu-enkephalin differ functionally despite their nearly identical structures?
- Can the enkephalin system be therapeutically targeted to manage pain without the addiction risks of exogenous opioids?
- What other endogenous opioid peptides exist in the brain, and how do they interact with enkephalins?
Common questions
What are enkephalins and why was their discovery so important?
What's the difference between enkephalins and endorphins?
Read the original research
Identification of two related pentapeptides from the brain with potent opiate agonist activity.
Nature, 258(5536), 577-80
Citation
Hughes, J; Smith, T W; Kosterlitz, H W; Fothergill, L A; Morgan, B A; Morris, H R. (1975). Identification of two related pentapeptides from the brain with potent opiate agonist activity.. Nature, 258(5536), 577-80.