Activation of Meningeal Nociceptors by Cortical Spreading Depression: Implications for Migraine with Aura

Abstract

Attacks of migraine with aura represent a phenomenon in which abnormal neuronal activity in the cortex produces sensory disturbances (aura) some 20 -40 min before the onset of headache. The purpose of this study was to determine whether cortical spreading depression (CSD)-an event believed to underlie visual aura-can give rise to activation of nociceptors that innervate the meninges-an event believed to set off migraine headache. CSD was induced in anesthetized male rats by stimulation of the visual cortex with electrical pulses, pin prick, or KCl; single-unit activity of meningeal nociceptors was monitored in vivo in the rat before and after CSD. Regardless of the method of cortical stimulation, induction of CSD was recorded in 64 trials. In 31 of those trials, CSD induced a twofold increase in meningeal nociceptor firing rate that persisted for 37.0 Ϯ 4.6 min in trials in which activity returned to baseline, or Ͼ68 min in trials in which activity remained heightened at the time recording was interrupted. In two-thirds of the trials, onset of long-lasting neuronal activation began ϳ14 min after the wave of CSD. The findings demonstrates for the first time that induction of CSD by focal stimulation of the rat visual cortex can lead to long-lasting activation of nociceptors that innervate the meninges. We suggest that migraine with aura is initiated by waves of CSD that lead up to delayed activation of the trigeminovascular pathway.

Role of different voltage-gated Ca2+channels in cortical spreading depression: Specific requirement of P/Q-type Ca2+channels

“…9,10 Neuroimaging studies in humans indicate that CSD underlies the migraine aura; animal studies indicate that CSD may also trigger the migraine headache mechanisms. [11][12][13] To study the cortical mechanisms that produce facilitation of CSD in FHM1 mutant mice, we investigated cortical neurotransmission in neuronal microcultures and in brain slices from FHM1 KI ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

Targeting CGRP: A New Era for Migraine Treatment

“…Cortical spreading depression is the electrophysiological manifestation of aura in the cerebral cortex thought to activate the trigeminovascular system and ultimately provoke headache. Controversy exists as to whether this process happens through CGRP release from peripheral trigeminal terminals [34,108,109]. Studies in rats showed endogenous release of CGRP during extracellular hyperkalemia-induced cortical spreading depression and inhibition of this phenomena by CGRP-RAs [110].…”

Role of cortical spreading depression in the pathophysiology of migraine

“…Such neurogenic inflammation is thought to trigger a headache via stimulation of trigeminal afferents. Consistent with this hypothesis, cortical SD induced intracranial neurogenic inflammation around the meningeal blood vessels [13][14][15] , and subsequent activation of both peripheral [16] and central [17] trigeminal nociceptive pathways has been described. Here, we review the experimental evidence mainly from neurophysiological studies that has advanced the understanding of whether and how the neurovascular phenomenon of cortical SD causes intracranial neurogenic inflammation, and subsequently participates in triggering a migraine headache.…”