Person:

Levy, Dan

Background: Cerebrospinal fluid (CSF) sodium concentration increases during migraine attacks, and both CSF and vitreous humor sodium increase in the rat migraine model. The Na,K-ATPase is a probable source of these sodium fluxes. Since Na,K-ATPase isoforms have different locations and physiological roles, our objective was to establish which alpha isoforms are present at sites where sodium homeostasis is disrupted. Methods: Specific Na,K-ATPase alpha isoforms were identified in rat tissues by immunohistochemistry at the blood-CSF barrier at the choroid plexus, at the blood-CSF-trigeminal barrier at the meninges, at the blood-retina barrier, and at the blood-aqueous barrier at the ciliary body. Calcitonin gene-related peptide (CGRP), occludin, or von Willibrand factor (vWF) were co-localized with Na,K-ATPase to identify trigeminal nociceptor fibers, tight junctions, and capillary endothelial cells respectively. Results: The Na,K-ATPase alpha-2 isoform is located on capillaries and intensely at nociceptive trigeminal nerve fibers at the meningeal blood-CSF-trigeminal barrier. Alpha-1 and −3 are lightly expressed on the trigeminal nerve fibers but not at capillaries. Alpha-2 is expressed at the blood-retina barriers and, with alpha-1, at the ciliary body blood aqueous barrier. Intense apical membrane alpha-1 was associated with moderate cytoplasmic alpha-2 expression at the choroid plexus blood-CSF barrier. Conclusion: Na,K-ATPase alpha isoforms are present at the meningeal, choroid plexus, and retinal barriers. Alpha-2 predominates at the capillary endothelial cells in the meninges and retinal ganglion cell layer.

Abstract Migraine is one of the most common and disabling diseases in the world. A major feature of migraine headache is its aggravation by maneuvers that momentarily increase intracranial pressure. A key hypothesis implicates mechanical sensitization of trigeminal afferents that innervate the intracranial meninges in mediating this feature of migraine. However, whether such pain-related neural response actually develops under endogenous conditions that are linked specifically to migraine remains to be established. Single-unit recordings in the trigeminal ganglion of anesthetized male rats were combined with quantitative mechanical stimulation of the cranial dura mater to determine whether cortical spreading depression (CSD), an endogenous migraine-triggering event, affects the mechanosensitivity of meningeal afferents. CSD gave rise to an almost threefold increase in the magnitude of the responses to mechanical stimuli in 17 of 23 of the afferents tested. CSD-evoked meningeal afferent mechanosensitization occurred with a delay of 23.1 ± 2.2 min and lasted 64.1 ± 6.8 min in recording sessions that lasted for 90 min and for 177.5 ± 22.1 min in recording sessions that were extended for 240 min. Some of the sensitized afferents also developed a shorter-lasting increase in their ongoing discharge rate that was not correlated with the increase in their mechanosensitivity, suggesting that CSD-evoked meningeal afferent sensitization and increase in ongoing activity are independent phenomena. These novel findings support the notion that mechanical sensitization of meningeal afferents serves as a key nociceptive process that underlies the worsening of migraine headache during conditions that momentarily increase intracranial pressure.

Abstract Introduction: Cortical 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 proinflammatory sensory neuropeptides, such as calcitonin gene-related peptide (CGRP). Objectives: We sought to investigate whether (1) a brief meningeal K+ stimulus leads to CGRP-dependent enhancement of meningeal afferent responses and (2) CSD-induced meningeal afferent activation and sensitization involve CGRP receptor signaling. Methods: Extracellular 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. Cortical spreading depression was documented by recording changes in cerebral blood flow using laser Doppler flowmetery. Calcitonin gene-related peptide receptor activity was inhibited with BIBN4096 (333 μM, i.v.). Results: Meningeal K+ stimulation acutely activated 86% of the afferents tested and also promoted in ∼65% of the afferents a 3-fold increase in ongoing activity, which was delayed by 23.3 ± 4.1 minutes and lasted for 22.2 ± 5.6 minutes. 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. Conclusion: While 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.