Endorphins: The Body's Natural Painkillers

Why can an injured athlete sometimes keep playing without feeling the pain until later? Why does a hard run leave some people feeling calm and elated? Part of the answer lies in endorphins, small proteins made by your own body that act on the same receptors as morphine. Their discovery in the 1970s revealed that the brain has its own built-in pain-control system, and it transformed our understanding of pain, stress and addiction.

The name

“Endorphin” is short for endogenous morphine: “endogenous” means made inside the body, and morphine is the powerful painkiller extracted from the opium poppy. The name captures the key idea: these are the body’s own opioids.

The discovery

By the early 1970s, scientists knew that opium-derived drugs like morphine were extraordinarily effective at relieving pain, and that they worked at very low doses, suggesting they acted on specific receptors, proteins shaped to bind them.

• In 1973, three research groups independently showed that the brain contains opioid receptors: Candace Pert and Solomon Snyder in the USA, Eric Simon, and Lars Terenius in Sweden.
• This raised an obvious question: why would the brain have receptors for a chemical from a poppy? Surely it must make its own molecules that fit them.
• In 1975, John Hughes and Hans Kosterlitz in Aberdeen, Scotland, isolated two small peptides from pig brains that acted like morphine. They called them enkephalins (from the Greek for “in the head”).
• Soon afterwards, larger opioid peptides, the endorphins, were identified, most importantly β-endorphin.

What endorphins are, chemically

Unlike morphine, which is an alkaloid (a nitrogen-containing ring compound made by plants), the body’s opioids are peptides: short chains of amino acids (see the peptide bond).

Opioid peptide	Length	Notes
Met-enkephalin	5 amino acids	Tyr-Gly-Gly-Phe-Met
Leu-enkephalin	5 amino acids	Tyr-Gly-Gly-Phe-Leu
β-endorphin	31 amino acids	Begins with the Met-enkephalin sequence; long-lasting and potent
Dynorphins	about 8–17 amino acids	Begin with the Leu-enkephalin sequence

Notice the shared start: Tyr-Gly-Gly-Phe. The tyrosine at the beginning, with its phenol ring and free amino group, is essential for binding to opioid receptors. Morphine has a similar arrangement: a phenol-containing ring and a basic nitrogen held a similar distance apart. That structural resemblance is why a plant molecule and a human peptide fit the same receptor (see amino acids).

How they’re made

Opioid peptides are cut from larger precursor proteins. β-Endorphin comes from a large protein called pro-opiomelanocortin (POMC), which is also cut to produce other hormones, including ACTH (which stimulates cortisol release) and a hormone that stimulates skin pigment cells. That’s one reason endorphins are released alongside the stress hormone system.

How endorphins work

Endorphins bind to opioid receptors, mainly the μ (mu), δ (delta) and κ (kappa) types. These receptors are linked to G proteins. When activated, they:

• reduce the release of pain-signalling neurotransmitters, such as substance P and glutamate, from nerve endings;
• make nerve cells less excitable, by opening potassium channels and closing calcium channels.

The result is that pain signals travelling from the body up the spinal cord to the brain are dampened. Endorphins can also affect mood and reward by influencing dopamine release in the brain’s reward pathways (see dopamine).

Because they’re peptides, endorphins are eventually broken down by peptidase enzymes, which limits how long their effects last.

When the body releases endorphins

• Pain and injury: part of the body’s emergency response, allowing escape or survival despite injury.
• Stress: released with ACTH from the pituitary gland.
• Prolonged or intense exercise.
• Laughter, social bonding, music and physical touch are thought to trigger opioid release, though these effects are harder to measure.
• Childbirth: endorphin levels rise during labour.
• Acupuncture and placebo effects: some placebo pain relief can be blocked by naloxone (see below), suggesting that expectation itself can trigger the release of opioid peptides.

The “runner’s high”: what’s really going on

Many runners describe a feeling of calm euphoria and reduced pain after long runs. For decades, this was attributed to endorphins. The evidence is mixed:

• Endorphin levels in the blood do rise during long exercise.
• But β-endorphin is a large peptide that doesn’t cross the blood–brain barrier easily, so blood levels don’t necessarily reflect brain levels.
• Brain-imaging studies have found opioid release in the brain after long runs, supporting a role for endorphins in mood.
• Research also points to endocannabinoids, lipid messengers that act on the same receptors as cannabis and that do cross into the brain. In some studies, blocking opioid receptors didn’t stop the runner’s high, but blocking cannabinoid receptors did.

The current view is that the runner’s high is probably produced by several systems together, with endocannabinoids playing a major part and endorphins contributing to pain relief.

Endorphins, opioid drugs and addiction

Opioid drugs, including morphine, heroin, codeine, oxycodone and fentanyl, act on the same μ-opioid receptors as endorphins, but much more strongly and for longer. They’re highly effective painkillers, but:

• the body adapts to repeated opioid use by reducing its response, leading to tolerance (needing more for the same effect);
• stopping suddenly causes withdrawal;
• activating opioid receptors in the brainstem suppresses breathing, which is how opioid overdoses kill.

Naloxone is an opioid antagonist: it binds tightly to opioid receptors without activating them, displacing opioid drugs. It can rapidly reverse an overdose and is widely carried by emergency services. In research, naloxone is used to test whether an effect depends on endorphins: if naloxone blocks the effect, opioid peptides are probably involved.

For how other painkillers work, see how painkillers work.

How scientists study endorphins

Measuring endorphins is harder than it sounds. Blood samples show peptides circulating in the body, but they don’t reveal what’s happening inside the brain, because β-endorphin crosses the blood–brain barrier poorly. Researchers therefore use indirect methods. PET scanning with a radioactive drug that binds opioid receptors can show how much of the receptor is occupied: if the body releases more endorphins, less of the radioactive tracer can bind. Experiments with naloxone test whether blocking opioid receptors removes an effect, such as placebo pain relief. Both approaches have limits, which is one reason claims about endorphins in everyday life should be treated with some caution.

Common misconceptions

• “Endorphins are hormones that make you happy.” They’re mainly pain-modulating peptides; mood effects are real but more complex.
• “The runner’s high is just endorphins.” Endocannabinoids appear to play a major role too.
• “You can get addicted to your own endorphins.” Natural endorphin release is brief and regulated, very different from the intense, prolonged receptor activation caused by opioid drugs.

Key takeaways

• Endorphins (“endogenous morphine”) are the body’s own opioid peptides, discovered in the mid-1970s after opioid receptors were found in the brain.
• They include enkephalins (5 amino acids) and β-endorphin (31 amino acids), all beginning with Tyr-Gly-Gly-Phe; β-endorphin is cut from POMC.
• They bind μ, δ and κ opioid receptors, reducing the release of pain-signalling neurotransmitters.
• They’re released in pain, stress and exercise; the runner’s high likely involves endocannabinoids as well.
• Opioid drugs act on the same receptors more powerfully; naloxone blocks them. For the wider picture, see neurotransmitters.