So much is happening all at once during a migraine that it has been hard to pinpoint what sets off the trigeminal nerve. Some scientists are focusing on a wave of electrical activity that spreads across the brain just before a migraine and triggers the aura—the shimmering light show experienced by 1 in 5 migraine patients. Others wonder wheth-er there is some kind of migraine generator buried deep within the brain stem. Even when researchers think they know the order in which different parts of the brain turn on during an attack, they can't always be sure if one section is initiating an action or anticipating the need to respond.

What seems clear, however, is that the brain of a migraineur (as sufferers are called) is primed to overreact to all sorts of stimuli that most people can easily tolerate. "The brain receives input from a wide variety of triggers—stress, hormones, falling barometric pressure, food, drink, sleep disturbances," says Dr. David Buchholz, a neurologist at the Johns Hopkins University School of Medicine in Baltimore, Md. "Each of us has his own stack of triggers and his own personal threshold at which the migraine mechanism activates. The higher the trigger level climbs above the threshold, the more fully activated the migraine system—and the more pain."

In this view, people who are prone to migraine have a low threshold for activating the trigeminal nerve. Those who suffer only an occasional tension-type headache have a much higher threshold. Persistent treatment of acute attacks and prevention of additional ones may reset the brain's threshold point at a higher level.

Researchers are exploring the possibility that migraine sufferers are not just hypersensitive to various triggers but that their brains have lost some of their natural ability to suppress pain signals. To find out more, scientists are studying a part of the brain called the periaqueductal gray matter, which, says Dr. Welch in Kansas City, "switches off the pain response so that you can focus on the fight to survive. It's the reason why if you have a cut that you don't remember getting, it doesn't start to hurt until you actually look at it."

Each time a migraine occurs, Welch and others have found, the periaqueductal gray matter fills with oxygen, which triggers chemical reactions that deposit iron in that section of the brain. As the iron builds up, the brain's ability to block out pain decreases. That may explain why many migraineurs become more sensitive to pain with each episode.

If overly sensitive nerve cells are the problem, it makes sense to try to calm them down— and that's exactly what the first drug tailored to block an oncoming migraine was designed to do. Approved in the U.S. in 1993, sumatriptan mimics the action of a neurotransmitter called serotonin, which plays many roles in the brain, including regulation of mood and pain. In the case of migraines, the drug prevents nerve endings in the dura from releasing their stimulatory proteins. No proteins, no pain.

Sumatriptan's success launched a new class of drugs called triptans that provide most migraineurs substantial relief. Like the painkillers before them, the triptans deliver their best results when taken early in an attack. Unfortunately, their effect is often temporary (drug companies are working on longer-lasting versions). Also, the drugs can trigger certain cardiovascular side effects, which means they should not be used by patients who have an increased risk of heart attack or stroke.

Still, triptans have dramatically changed the lives of millions of migraine sufferers and opened up promising areas of research. Scientists have discovered that triptans, besides affecting serotonin pathways, also directly block one of the stimulatory proteins released by the nerve endings in the dura. New compounds that target this protein, dubbed cgrp, are being tested in Europe. One big problem, says Lars Edvinsson of Lund University in Sweden, "is that the drug can be given only intravenously. We need a cgrp blocker that works as a tablet."

Pain relief isn't the only reason to stop a migraine before it goes too far. When the illness goes untreated, there is some evidence "of a mechanism in the central nervous system that makes traditional medications less useful," says Dr. Michael Moskowitz, a neurologist at Harvard Medical School in Boston. How that resistance develops is the subject of intense investigation.

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