Nature Medicine | Spoonful of Medicine

New animal model of migraine headaches creates the aura of pain in mice

ratheadache.jpg Developing new drugs to treat pain is, well, a pain. In clinical trials, researchers typically test experimental pain medicines by asking people to rate the level of pain they experience on a scale of one-to-ten. Clearly, such an approach isn’t possible in preclinical animal models, so researchers have developed a number of proxy measures. Some investigators hope to judge pain in mice and rats based on facial expressions, while others are gauging the frequency with which rodents turn towards relief. But all these approaches have their limitations (see our 2010 news feature “Animalgesic effects”).

Instead of trying to prove that animals are experiencing pain, some researchers are turning towards modeling the molecular mechanisms associated with human pain with the hope that halting those pathways will result in more comfort. Indeed, that’s the approach taken by Giorgio Casari and his colleagues from the San Raffaele Scientific Institute in Milan, Italy, who reported a new mouse model for migraine headaches last week in PLoS Genetics.


The Italian team focused on one of three genes implicated in a rare, heritable form of migraine called familial hemiplegic migraine (FHM), characterized by an aura 15-20 minutes before the migraine attack. This aura, caused by a wave of cellular depolarization across the brain called a cortical spreading depression (CSD), triggers visual light and dark spots and even feeling loss over half of the patient’s body. The researchers inserted a mutated human version of the Atp1a2 gene — a genetic marker for FHM that encodes a subunit of a sodium-potassium ATP pump involved in ion transport in the brain — into mice, and, using electrodes, observed that the CSD was more easily induced and propagated more quickly in these models than normal mice.

Based on electrophysiological measurements, Casari hypothesizes that the mutation prevents neurotransmitters from being cleared from their receptors, thereby creating a “more excitable neural network” that manifests as migraines. Casari says his model should be applicable beyond FHM, but not everyone is convinced of its broad utility. The idea that all migraines are caused by such neural hyperexcitability is gaining traction in the field. But, says Michael Oshinsky, a neurologist at Thomas Jefferson University in Philadelphia, “the evidence is not convincing yet.”

Image: Eric Collins

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