In the early 1970s, researchers hunting for a painkiller without morphine’s addiction risk asked why the brain had receptors that fit a poppy extract so precisely. In 1973 they reasoned the body must make its own matching molecule, and they isolated natural opioid peptides from pig brains, called enkephalins, then similar peptides from calf brains. The word endorphin, joining endogenous and morphine, followed. This episode explains how the pituitary gland makes endorphins by cutting a large precursor protein, pro-opiomelanocortin or POMC, with the enzymes PC1 and PC2, and how in 1976 scientists isolated alpha, beta and gamma endorphins from camel pituitary glands.

A 1977 study found beta-endorphin more potent than morphine, and naloxone blocked its effects. Alpha and gamma, shorter pieces of the same sequence, fold differently and do not bind opioid receptors at all, acting instead like a stimulant and a neuroleptic. In the body, beta-endorphin stops peripheral nerves from releasing substance P, and in the brain it suppresses GABA, releasing a flood of dopamine. Then the episode turns to the runner’s high: runners given a drug that blocked their opioid receptors still felt the high, and the evidence now points to endocannabinoids, which cross the blood-brain barrier far more easily.

• Why endorphin is named in part for Morpheus, the Greek god of dreams
• The nightclub bouncer analogy for how blocking GABA lets dopamine flow
• How the dual system may have let an injured early human keep running from a predator
• Triggers including inflamed tissue, electroacupuncture, deep meditation and hard laughter
• Endorphins as the pain shield during exercise while endocannabinoids deliver the euphoria