title: Critical role of calcitonin gene-related peptide receptors in cortical spreading depression.
abstract: Cortical spreading depression (CSD) is a key pathogenetic step in migraine with aura. Dysfunctions of voltage-dependent and receptor-operated channels have been implicated in the generation of CSD and in the pathophysiology of migraine. Although a known correlation exists between migraine and release of the calcitonin gene-related peptide (CGRP), the possibility that CGRP is involved in CSD has not been examined in detail. We analyzed the pharmacological mechanisms underlying CSD and investigated the possibility that endogenous CGRP contributes to this phenomenon. CSD was analyzed in rat neocortical slices by imaging of the intrinsic optical signal. CSD was measured as the percentage of the maximal surface of a cortical slice covered by the propagation of intrinsic optical signal changes during an induction episode. Reproducible CSD episodes were induced through repetitive elevations of extracellular potassium concentration. AMPA glutamate receptor antagonism did not inhibit CSD, whereas NMDA receptor antagonism did inhibit CSD. Blockade of voltage-dependent sodium channels by TTX also reduced CSD. CSD was also decreased by the antiepileptic drug topiramate, but not by carbamazepine. Interestingly, endogenous CGRP was released in the cortical tissue in a calcium-dependent manner during CSD, and three different CGRP receptor antagonists had a dose-dependent inhibitory effect on CSD, suggesting a critical role of CGRP in this phenomenon. Our findings show that both glutamate NMDA receptors and voltage-dependent sodium channels play roles in CSD. They also demonstrate that CGRP antagonism reduces CSD, supporting the possible use of drugs targeting central CGRP receptors as antimigraine agents.
authors.affiliation: Clinica Neurologica, Università di Perugia, 06156 Perugia,  Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.forename: Antonio
authors.initials: A
authors.lastname: de Iure
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Di Filippo
authors.forename: Cinzia
authors.initials: C
authors.lastname: Costa
authors.forename: Stefano
authors.initials: S
authors.lastname: Caproni
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
authors.forename: Paola
authors.initials: P
authors.lastname: Bonsi
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
authors.forename: Letizia M
authors.initials: LM
authors.lastname: Cupini
authors.forename: Serena
authors.initials: S
authors.lastname: Materazzi
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
authors.forename: Paola
authors.initials: P
authors.lastname: Sarchielli
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002220:Carbamazepine / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013181:Cortical Spreading Depression / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077236:Topiramate; D061566:Voltage-Gated Sodium Channels
chemical_list: D000927:Anticonvulsants; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D018091:Receptors, AMPA; D018015:Receptors, Calcitonin Gene-Related Peptide; D016194:Receptors, N-Methyl-D-Aspartate; D061566:Voltage-Gated Sodium Channels; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D015740:Calcitonin Gene-Related Peptide