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Papers of the Week


Papers: 25 May 2019 - 31 May 2019


Animal Studies, Pharmacology/Drug Development

PAIN TYPE:
Migraine/Headache


2019 Jul 24


J Neurosci


39


30

Editor's Pick

CSD-induced arterial dilatation and plasma protein extravasation are unaffected by fremanezumab: implications for CGRP’s role in migraine with aura.

Authors

Schain AJ, Melo A, Stratton J, Strassman AM, Burstein R
J Neurosci. 2019 Jul 24; 39(30):6001-6011.
PMID: 31127003.

Abstract

Cortical spreading depression (CSD) is a wave of neuronal depolarization thought to underly migraine aura. Calcitonin gene-related peptide (CGRP) is a potent vasodilator involved in migraine pathophysiology. Evidence for functional connectivity between CSD and CGRP has triggered scientific interest in the possibility that CGRP antagonism may disrupt vascular responses to CSD, and the ensuing plasma protein extravasation (PPE). Using imaging tools that allow us to generate continuous, live, high-resolution views of spatial and temporal changes that affect arteries and veins in the dura and pia, we determined the extent to which CGRP contributes to the induction of arterial dilatation or PPE by CSD in female rats, and how these events are affected by the anti-CGRP monoclonal antibody (anti-CGRP-mAb) fremanezumab. We found that the CSD-induced brief dilatation and prolonged constriction of pial arteries, prolonged dilatation of dural arteries and PPE are all unaffected by fremanezumab, whereas the brief constriction and prolonged dilatation of pial veins are. In comparison, whereas CGRP infusion gave rise to the expected dilatation of dural arteries, which was effectively blocked by fremanezumab, it did not induce dilatation in pial arteries, pial veins, or dural veins. It also failed to induce PPE. Regardless of whether the nociceptors become active before or after the induction of arterial dilatation or PPE by CSD, fremanezumab's inability to prevent them suggests that these events are not mediated by CGRP; a conclusion with important implications for our understanding of anti-CGRP-mAbs' mechanism of action in migraine prevention.The current study identifies fundamental differences between two commonly used models of migraine, CSD induction and systemic CGRP infusion. It raises the possibility that conclusions drawn from one model may not be true or relevant to the other. It sharpens the need to accept the view that to migraine pathophysiology and that it is unlikely that one theory will explain all types of migraine headache or the mechanisms of action of drugs that prevent it. Regarding the latter, it is concluded that not all vascular responses in the meninges are born alike and consequently, that drugs that prevent vascular dilatation through different molecular pathways may have different therapeutic outcomes in different types of migraine.