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A migraine seems to include a domino effect. The trigeminal ganglion and nucleus caudalis are clusters of neurons that receive pain signals from different parts of the body.

Courtesy: Beth Israel Deaconess Medical Center.

Migraines are distressingly common. An estimated 25 million Americans, mainly women, suffer them. Newer drugs help many people, but too often migraines remain debilitating, fearful, and a plain pain in the neck.

Literally. Extreme skin sensitivity has now joined the list of strange migraine symptoms. The softest brushing with a soft brush can be blindingly painful -- as if the sensory nerves hear a doorbell ringing, and react by summoning a SWAT team.

According to new research, skin sensitivity appears among the majority of migraine sufferers. But the sensitivity may be more than just a bizarre symptom -- it also seems to substantiate a new theory about the cause of migraines that could eventually produce new drugs to neutralize the fearsome headaches.

A domino theory of the nerves
The little-discussed skin pain seems to be a reality for many migraine sufferers. In May, Rami Burstein, who studies pain at Beth Israel Deaconess Medical Center in Boston, along with colleagues, published a study showing that 79 percent of 44 migraine patients had extreme skin sensitivity.

Rami Burstein uses a brush to check skin sensitivity. Courtesy: Beth Israel Deaconess Medical Center

"People tell us they can't brush their hair, wear earrings or eyeglasses, or shave their beards because it's so painful," says Burstein, who is also associate professor of neurobiology at Harvard Medical School. The pressure of a single strand of hair, he says, can feel like a jab with a white-hot knife. Burstein thinks that a series of neuronal clusters -- in the sensory ganglions, the brainstem and the thalamus -- become sensitized in a kind of domino effect. If the sensitized cluster, a group of nerve cells that acts like the hub of a computer network, happens to be connected to the skin, the result can be skin sensitivity.

Imagine a neighborhood where a loud all-night party at house A frays nerves at house B, whose sleep-starved occupants respond by bellowing at some kids innocently playing tag outside house C. In this case, the over-sensitization caused by the party is a trauma that's passed down the line. Once the problem at house A gets bad enough, it won't help to just shut down the party, because the people in house B are already irritated from listening to endless hours of mindless music. To stop the domino effect, house B must also be calmed down.

On the alert
This mundane metaphor helps explain what Burstein thinks is occurring in the brain. Instead of starting with a loud party, however, the problem starts with the release of inflammatory proteins from the dura, which envelops the brain, and from blood vessels and nerve endings in the brain.

The release of these proteins oversensitizes the trigeminal ganglion, located above the palate, which receives signals about conditions inside the skull. When oversensitized, the ganglion interprets normal pressure inside the skull as the throbbing pain of migraine. Because the trigeminal ganglion seems to cause the primary pain of migraine, it is the target of current migraine drugs, which block serotonin receptors in sensory neurons connected to the dura. The drugs are often effective, but only if taken immediately after the headache begins.

The oversensitized trigeminal ganglion may, in turn, send signals to the nucleus caudalis, at the top of the spinal cord. Unlike the trigeminal ganglion, this group of nerves is connected to the skin, particularly near the eye, where Burstein found the most dramatic skin sensitivity in migraine sufferers.

In rats, Burstein found that once the trigeminal ganglion has activated the nucleus caudalis for an hour, the nucleus caudalis remains overwrought even if the trigeminal ganglion is calmed by drugs -- as existing migraine treatments often do. The rat experiments also indicated that hyper-sensitive neurons in the nucleus caudalis interpret soft touches on the skin as pain.

If Burstein's theory holds water, the nucleus caudalis and other nerve centers should provide more targets for anti-migraine drugs. Although the current migraine drugs often work if taken quickly after the headache's onset, that is impossible for people who don't have meds handy or get the headaches while asleep.

"This could explain why current anti-migraine therapies, which work on the primary cluster, are only effective if taken during the firsts hour after an attack has begun," Burstein says. "So this study says to drug companies, 'Hey, you missed an important part of the anti-migraine drug industry -- you have to target the secondary neurons.'"

The study may also provide palliative relief against the out-of-control feeling that may accompany migraine, Burstein adds. "This study provides for the first time a scientific explanation -- a neural basis -- for neurological symptoms that often accompany migraine attacks. Until now, patients were unwilling to talk about these symptoms because they were afraid" of being labeled "crazy." Instead, he says, skin sensitivity has a clear origin in the hypervigilance of oversensitized nerve cells.

-- David Tenenbaum

Bibliography
Burstein, R., Yarnitsky, D., Goor-Aryeh, I., Ransil, B.J. and Bajwa, Z., (2000) An Association Between Migraine and Cutaneous Allodynia, Ann. Neurol. 47 (5) 614-624

Burstein, R., Cutrer, F.M. and Yarnitsky, D., (2000) The Development of Cutaneous Allodynia During a Migraine Attack: Clinical Evidence for the Sequential Recruitment of Spinal and Supraspinal Nociceptive Neurons in Migraine, Brain, 123(8), 1703-1709.