Friday, January 13, 2006
The triptan drugs used to treat migraine are widely regarded as vasoconstrictors: they shrink bloated blood vessels, relieving the irritation that contributes to migraine. To quote Walgreens on Imitrex, "This medicine is a cerebral vasoconstrictor used to relieve migraine headache attacks as they occur."
As luck would have it, they are not terribly specific. They also shrink blood vessels elsewhere, including the heart. So people with heart disease cannot use them. Ditto for peripheral artery disease and similar vascular problems. This bad side effect is shared by other migraine drugs like the ergot derivatives.
Enter donitriptan, a newer migraine drug under development. It seems to have little effect on blood vessels. Researchers are finding, though, that it still has major effects on the brain. In that paper about a study of rats, researchers found no regional blood flow changes anywhere in the body. Yet they found that the brain's oxygen use dramatically increased. (As measured in the jugular vein by decreased oxygen and increased carbon dioxide. Sumatriptan (Imitrex) has a similar metabolism increasing effect.) This bodes well for a new family of safer migraine drugs. They also found that the metabolism increase was cancelled by giving the rats a 5-HT1B/1D receptor antagonist. That localizes things to receptor subtypes that were already known to be important in migraine.
I want to know where the metabolism was happening. The neurons themselves are not really built to burn much energy, and doing so tends to kill them. If it was the neurons, we would expect triptan overdose and overuse to cause brain damage, along the lines of glutamate toxicity.
I'm guessing (pure speculation by a non-expert) that triptans affect the big support cells called astrocytes. They are the logistics system of the brain, delivering chemical supplies to delicate neurons, hauling away their waste, and constantly sweeping the environment so nothing unpleasant builds up. They are richly endowed with chemical transporters that take energy to run, and we know from studying spreading depression that they can survive huge gains and losses of certain chemicals. Perhaps 5-HT1B/1D stimulants force their transporters to run overtime, changing the equilibrium of one or more internal chemicals. This change would spill over into the neurons, to which they are directly connected, making them harder to trigger and quenching the abnormal sensitivity that causes migraine suffering.
Hmmm... It would be interesting to know what a 5-HT1B/1D antagonist drug does to migraineurs. If this theory is correct, small doses would reduce the migraine threshold, and largers doses would trigger an outright attack. Good luck finding volunteers for that study.
(This is based on my reading of the abstract, not the full paper.)