GABAA receptor modulation of trigeminovascular nociceptive neurotransmission by midazolam is antagonized by flumazenil.
Studies of the pharmacology of trigeminocervical neurons with input from intracranial pain-producing structures have enhanced the understanding of the basic neurobiology of primary headache, such as migraine. Clinical observations of the treatment of migraine with medicines acting at the gamma-aminobutyric acid (GABA) GABAA receptor have lead to studies of their effects on models of trigeminovascular nociception. Extracellular recordings were made from neurons in the trigeminocervical complex activated by supramaximal electrical stimulation of superior sagittal sinus (SSS) in the cat. Intravenous administration of the benzodiazepine receptor agonist midazolam, resulted in a dose-dependent inhibition of superior sagittal sinus evoked trigeminocervical nucleus activity. The inhibition at 50 microg/kg midazolam was 65+/-11% compared to the baseline response (n=11). Intravenous administration of the benzodiazepine receptor antagonist flumazenil, resulted in a dose-dependent recovery of superior sagittal sinus evoked trigeminocervical nucleus activity. At a dose of 50 microg/kg, there was a 64+/-5% recovery (n=6). The data demonstrate a potent, reproducible effect of facilitation of GABA transmission at the GABAA receptor that results in inhibition of trigeminovascular nociceptive transmission. These data are consistent with the useful clinical effects reported with compounds that can augment GABAergic transmission in the central nervous system (CNS).
Storer
Robin James
RJ
Headache Group, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
Akerman
Simon
S
Shields
Kevin G
KG
Goadsby
Peter J
PJ
D000818:Animals; D002415:Cats; D004347:Drug Interactions; D005442:Flumazenil / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008874:Midazolam / Q000494:pharmacology*; D008881:Migraine Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009619:Nociceptors / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D014278:Trigeminal Nuclei / Q000187:drug effects / Q000378:metabolism
D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D005442:Flumazenil; D008874:Midazolam