Topiramate in the treatment of migraine: A kainate (glutamate) receptor antagonist within the trigeminothalamic pathway

Background: The development of new agents for the preventive treatment of migraine is the greatest unmet need in the therapeutics of primary headaches. Topiramate, an anticonvulsant drug, is an effective anti-migraine preventive whose mechanism of action is not fully elucidated. Since glutamate plays a major role in migraine pathophysiology, the potential action of topiramate through glutamatergic mechanisms is of considerable interest. Methods: Recordings of neurons in the trigeminocervical complex (TCC) and the ventroposteromedial thalamic nucleus (VPM) of anesthetized rats were made using electrophysiological techniques. The effects of intravenous or microiontophorezed topiramate on trigeminovascular activation of second- and third-order neurons in the trigeminothalamic pathway were characterized. The potential interactions of topiramate with the ionotropic glutamate receptors were studied using microiontophoresis. Results: Both intravenous and microiontophorized topiramate significantly inhibited trigeminovascular activity in the TCC and VPM. In both nuclei microiontophoretic application of topiramate significantly attenuated kainate receptor-evoked firing but had no effect on N-methyl-D-aspartic acid or alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor activation. Conclusion: The data demonstrate for the first time that topiramate modulates trigeminovascular transmission within the trigeminothalamic pathway with the kainate receptor being a potential target. Understanding the mechanism of action of topiramate may help in the design of new medications for migraine prevention, with the data pointing to glutamate-kainate receptors as a fruitful target to pursue.