Robin J Storer1, Peter J Goadsby. 1. Headache Group, Department of Neurology, UCSF Headache Center, 1701 Divisadero St., San Francisco, CA 94115, USA. pgoadsby@headache.ucsf.edu
Abstract
BACKGROUND: To facilitate understanding the locus and mechanism of action of antimigraine preventives, we examined the effect of topiramate on trigeminocervical activation in the cat. METHODS: Cats were anesthetized and physiologically monitored. Electrical stimulation of the superior sagittal sinus activated nociceptive trigeminovascular afferents. Extracellular recordings were made from neurons in the trigeminocervical complex. RESULTS: Microiontophoretically delivered topiramate, applied locally at the second order synapse of the trigeminovascular system in the trigeminocervical complex, produced significant inhibition of L-glutamate-evoked firing of neurons only at the highest microiontophoretic currents (27 ± 7% at -160 nA; P < 0.05, N = 14 cells), but did not inhibit firing of these neurons evoked by stimulation of the craniovascular afferents (2 ± 5%, P = 0.762, N = 13 cells). In contrast, systemically administered topiramate (30 mg/kg intravenously) partly inhibited this firing (32 ± 10% at 15 min; F 5,35 = 3.5, P < 0.05, N = 8 cats). After this systemic administration, profound inhibition (70 ± 10%, P < 0.001, N = 7) of L-glutamate-evoked firing of cells in the trigeminocervical complex at the second order synapse of the trigeminovascular system was observed. CONCLUSIONS: These data suggest that topiramate acts outside of the trigeminocervical complex in the cat. Determining the sites of action of preventive antimigraine treatments is crucial to developing laboratory models for the development of new therapeutics, and may vary between species.
BACKGROUND: To facilitate understanding the locus and mechanism of action of antimigraine preventives, we examined the effect of topiramate on trigeminocervical activation in the cat. METHODS:Cats were anesthetized and physiologically monitored. Electrical stimulation of the superior sagittal sinus activated nociceptive trigeminovascular afferents. Extracellular recordings were made from neurons in the trigeminocervical complex. RESULTS: Microiontophoretically delivered topiramate, applied locally at the second order synapse of the trigeminovascular system in the trigeminocervical complex, produced significant inhibition of L-glutamate-evoked firing of neurons only at the highest microiontophoretic currents (27 ± 7% at -160 nA; P < 0.05, N = 14 cells), but did not inhibit firing of these neurons evoked by stimulation of the craniovascular afferents (2 ± 5%, P = 0.762, N = 13 cells). In contrast, systemically administered topiramate (30 mg/kg intravenously) partly inhibited this firing (32 ± 10% at 15 min; F 5,35 = 3.5, P < 0.05, N = 8 cats). After this systemic administration, profound inhibition (70 ± 10%, P < 0.001, N = 7) of L-glutamate-evoked firing of cells in the trigeminocervical complex at the second order synapse of the trigeminovascular system was observed. CONCLUSIONS: These data suggest that topiramate acts outside of the trigeminocervical complex in the cat. Determining the sites of action of preventive antimigraine treatments is crucial to developing laboratory models for the development of new therapeutics, and may vary between species.
Authors: A Laine Green; Pengfei Gu; Milena De Felice; David Dodick; Michael H Ossipov; Frank Porreca Journal: Cephalalgia Date: 2013-12-11 Impact factor: 6.292