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Zhao, Jun

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Zhao

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Jun

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Zhao, Jun

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2016 - 20172

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Author's Publications: search.filters.isAuthorOfPublication.4ba025fe-c080-4a38-adac-99eefc82f3f7

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    The CGRP receptor antagonist BIBN4096 inhibits prolonged meningeal afferent activation evoked by brief local K+ stimulation but not cortical spreading depression-induced afferent sensitization
    (Wolters Kluwer, 2017) Zhao, Jun; Levy, Dan
    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.
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    Cortical Spreading Depression Promotes Persistent Mechanical Sensitization of Intracranial Meningeal Afferents: Implications for the Intracranial Mechanosensitivity of Migraine
    (Society for Neuroscience, 2016) Zhao, Jun; Levy, Dan
    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.