title: Topiramate in the treatment of migraine: a kainate (glutamate) receptor antagonist within the trigeminothalamic pathway.
abstract: 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 α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor activation.
  
  
  CONCLUSIONS
  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.
authors: Headache Group, University of California, San Francisco, 1701 Divisadero St, San Francisco, CA 94115, USA.
authors: Anna P
authors: AP
authors: Andreou
authors: Peter J
authors: PJ
authors: Goadsby
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004388:Dura Mater / Q000098:blood supply; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005145:Face / Q000294:innervation; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology; D007275:Injections, Intravenous; D007478:Iontophoresis; D008297:Male; D008881:Migraine Disorders; D059226:Nociceptive Pain / Q000503:physiopathology; D009619:Nociceptors / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects* / Q000503:physiopathology; D013787:Thalamic Nuclei / Q000187:drug effects* / Q000503:physiopathology; D000077236:Topiramate; D014276:Trigeminal Nerve / Q000187:drug effects* / Q000503:physiopathology
chemical_list: D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D005632:Fructose; D018698:Glutamic Acid; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D000077236:Topiramate