CGRP signaling mediates prolonged meningeal afferent activation evoked by brief local K+ stimulation but not cortical spreading depression-induced afferent sensitization

Abstract

IntroductionCortical spreading depression (CSD) is believed to promote migraine headache by enhancing the activity and mechanosensitivity of trigeminal intracranial meningeal afferents. One putative mechanism underlying this afferent response involves an acute excitation of meningeal afferents by cortical efflux of K+ and the ensuing antidromic release of pro-inflammatory sensory neuropeptides, such as calcitonin gene-related peptide (CGRP).\n\nObjectivesWe sought to investigate whether (i) a brief meningeal K+ stimulus leads to CGRP-dependent enhancement of meningeal afferent responses, and (ii) CSD-induced meningeal afferent activation and sensitization involve CGRP receptor signaling.\n\nMethodsExtracellular single-unit recording were used to record the activity of meningeal afferents in anesthetized male rats. Stimulations included a brief meningeal application of K+ or induction of CSD in the frontal cortex using pinprick. CSD was documented by recording changes in cerebral blood flow using laser Doppler flowmetery. CGRP receptor activity was inhibited with BIBN4096 (333M, i.v.).\n\nResultsMeningeal K+ stimulation acutely activated 86% of the afferent tested and also promoted in ~65% of the afferents a 3-fold increase in ongoing activity which was delayed by 23.3{+/-}4.1 min and lasted for 22.2{+/-}5.6 min. K+ stimulation did not promote mechanical sensitization. Pretreatment with BIBN4096 suppressed the K+- induced delayed afferent activation, reduced CSD-evoked cortical hyperemia, but had no effect on the enhanced activation or mechanical sensitization of meningeal afferents following CSD.\n\nConclusionWhile CGRP-mediated activation of meningeal afferents evoked by cortical efflux of K+ could promote headache, acute activation of CGRP receptors may not play a key role in mediating CSD-evoked headache.\n\nPrevious presentation of the research, manuscript, or abstractParts of the manuscript have been presented previously only in an abstract form.