Peptides can be a right pain (Image: Henrik Sorensen/Getty)

It can start with flashing lights, a tingling sensation and a feeling of unease, followed by excruciating pain. Migraines can be triggered by lack of food or too much stress but their underlying cause has remained a mystery. Now researchers have found that a migraine may be triggered by a protein deep in the brain that stimulates the neurons controlling facial sensations.

The discovery creates a potential new target for safer migraine medicines and adds weight to the theory that neurons, not blood vessels, are responsible for migraine attacks.


“Where a migraine starts is a key question,” says Debbie Hay at the University of Auckland in New Zealand. “There has been a great deal of debate around the mechanisms of migraine. If we can pin this down, we may have better chances of preventing it.”

To investigate, Simon Akerman at New York University and Peter Goadsby at Kings College London, UK, studied two neuropeptides released by neurons thought to play a role in the pain associated with migraine.

These protein-like molecules, called VIP and PACAP, first raised suspicion after they were found to be elevated in blood drained from the brains of people having a migraine attack. When researchers administered these peptides to volunteers, they found that they could cause a headache or migraine about two hours later.

Both peptides widen blood vessels, which was thought to be significant in migraine. In fact, the only drugs specifically developed for migraine that are in use today – triptans – were designed to shrink blood vessels in the brain. As a result, they cannot be used by people with cardiovascular disorders.

The root of the problem

Akerman and Goadsby studied the effects of VIP and PACAP on a set of neurons that innervate the head and face, which are known to trigger a headache. The pair measured the electrical activity of these neurons in anaesthetised rats and studied blood vessels in the rodents’ brain to identify when they dilated or constricted.

Some rats were then given PACAP, while others were treated with VIP. Only PACAP caused the neurons to increase their activity – about an hour and a half after it was administered. This suggests that the peptide is responsible for kick-starting a migraine, says Akerman.

To block the effect, Akerman and Goadsby used molecules that block the receptors that PACAP binds to. The drugs made no difference when they were given to the rats intravenously, but when they were injected directly into the brain, the neurons responsible for a headache no longer surged with activity. “These receptors could genuinely represent a new therapeutic target for migraine,” says Akerman.

“It appears that these receptors are indeed important, and this is definitely vital to helping us understand migraine and for developing new treatments,” says Hay, who wasn’t involved with the work. “The receptors are a new and exciting target for migraine.”

In need of relief

New therapies are desperately needed. Triptans don’t work for half the people who try them, says Akerman. At any rate, their development was based on a misunderstanding of how migraine works.

In their study, Akermand and Goadsby found that both VIP and PACAP caused blood vessels to dilate, but that this effect only lasted for about 10 minutes. And in the case of PACAP, the widening of blood vessels did not happen at the same time as the overactivity of neurons. In other words, the dilation of blood vessels doesn’t seem to have anything to do with migraine.

Although triptans are prescribed as vasoconstrictors – drugs that shrink blood vessels – other research suggests that they also block the release of peptides like PACAP from neurons. Why this is only effective in half the people who take the drug is still a mystery.

What’s clear, is that vasoconstriction does not help migraine, says Akerman. “Triptans are effective, but for the wrong reasons.”

Journal reference: Science Translational Medicine DOI: 10.1126/scitranslmed.aaa7557

Read: “Not just a headache: How migraine changes your brain“