Over the past two decades, evidence has gradually accumulated in support of the cortical spreading depression (CSD) theory of migraine, which proposes that CSD is the physiological event that underlies the visual aura that precedes the migrainous headache. According to this theory, CSD is also the endogenous process that triggers the migraine headache, presumably through the activation of meningeal nociceptors via the release of excitatory molecules from the parenchyma. Recently, it has been shown that CSD indeed can promote persistent activation of meningeal nociceptors. However, the observed time course of the nociceptor activation following CSD does not easily fit with the mechanisms typically proposed in the CSD theory or the known properties of CSD. First, the onset of this nociceptor activation cannot be accounted for solely by the propagation time of the CSD wave, because in the majority of cases there is a substantial delay between the end of the CSD and the onset of activation. Second, once initiated, the nociceptor activation persists for much longer than can be accounted for by the known actions of the excitatory agents that are released during the CSD wave. Our preliminary data had led us to hypothesize that the persistent and often delayed activation of meningeal nociceptors that occurs in the wake of CSD does not depend upon the brief release of excitatory mediators or a resultant brief nociceptor activation, but rather occurs due to the CSD-evoked vascular and metabolic changes, in particular the cerebral oligemia, hypoxia, and parenchymal lactate elaboration. This working hypothesis will be tested using a series of in vivo electrophysiological recordings of meningeal nociceptors'activity combined with multi-parametric measurements of changes in regional cerebral blood flow (rCBF), parenchymal tissue oxygen tension (tpO2) and lactate concentration as well pharmacological interventions.
Specific Aim 1 will determine whether the CSD-related persistent activation of meningeal nociceptors is mediated by the local brief elaboration of excitatory molecules during the CSD phase b) a coinciding brief nociceptor excitation and c) resultant meningeal neurogenic inflammation.
Specific Aim 2 will examine the relative contribution of the CSD-evoked cerebral oligemia and hypoxia to the persistent activation of meningeal nociceptors using treatments that inhibit these processes.
Specific Aim 3 will employ pharmacological blockers to examine whether CSD-evoked lactate elaboration and ensuing activation of the acid-sensing ion channel 3 (ASIC3) mediates the persistent activation of meningeal nociceptors following CSD. We hope that these studies will provide a better understanding of the endogenous mechanism that play a role in the genesis of migraine headache, which can propel the development of much needed evidence-based approaches to treat this type of pain.

Public Health Relevance

Cortical spreading depression (CSD) can trigger migraine pain by promoting persistent activation of the sensory neurons that innervate the intracranial meninges. The exact endogenous processes that play a role in mediating this nociceptive event remain elusive. The proposed project will investigate the hypothesis that vascular and metabolic events that occur as a result of CSD, including cerebral hypoperfusion, hypoxia and lactate elaboration play a key role in mediating the persistent activation of meningeal sensory neurons.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Porter, Linda L
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Beth Israel Deaconess Medical Center
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Levy, Dan; Abdian, Lorin; Dekel-Steinkeller, Michal et al. (2018) Experimental evidence for weaker endogenous inhibition of trigeminal pain than extra-trigeminal pain in healthy individuals. Cephalalgia 38:1307-1315
Zhao, Jun; Levy, Dan (2018) Dissociation between CSD-Evoked Metabolic Perturbations and Meningeal Afferent Activation and Sensitization: Implications for Mechanisms of Migraine Headache Onset. J Neurosci 38:5053-5066
Bree, Dara; Levy, Dan (2018) Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: Implications for mechanisms of post-traumatic headache. Cephalalgia 38:246-258
Levy, Dan; Labastida-Ramirez, Alejandro; MaassenVanDenBrink, Antoinette (2018) Current understanding of meningeal and cerebral vascular function underlying migraine headache. Cephalalgia :333102418771350
Zhao, Jun; Levy, Dan (2018) The CGRP receptor antagonist BIBN4096 inhibits prolonged meningeal afferent activation evoked by brief local K+ stimulation but not cortical spreading depression-induced afferent sensitization. Pain Rep 3:e632
Gariepy, Helaine; Zhao, Jun; Levy, Dan (2017) Differential contribution of COX-1 and COX-2 derived prostanoids to cortical spreading depression-Evoked cerebral oligemia. J Cereb Blood Flow Metab 37:1060-1068
Zhao, Jun; Bree, Dara; Harrington, Michael G et al. (2017) Cranial dural permeability of inflammatory nociceptive mediators: Potential implications for animal models of migraine. Cephalalgia 37:1017-1025
Levy, Dan; Edut, Shahaf; Baraz-Goldstein, Renana et al. (2016) Responses of dural mast cells in concussive and blast models of mild traumatic brain injury in mice: Potential implications for post-traumatic headache. Cephalalgia 36:915-23
Zhao, Jun; Levy, Dan (2016) Cortical Spreading Depression Promotes Persistent Mechanical Sensitization of Intracranial Meningeal Afferents: Implications for the Intracranial Mechanosensitivity of Migraine. eNeuro 3:
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