• Serena Materazzi, Silvia Benemei, Camilla Fusi, Roberta Gualdani, Gaetano De Siena, Nisha Vastani, David A Andersson, Gabriela Trevisan, Maria Rosa Moncelli, Xiaomei Wei, Gregory Dussor, Federica Pollastro, Riccardo Patacchini, Giovanni Appendino, Pierangelo Geppetti, and Romina Nassini.
• Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy.
• Pain. 2013 Dec 1;154(12):2750-8.

AbstractAlthough feverfew has been used for centuries to treat pain and headaches and is recommended for migraine treatment, the mechanism for its protective action remains unknown. Migraine is triggered by calcitonin gene-related peptide (CGRP) release from trigeminal neurons. Peptidergic sensory neurons express a series of transient receptor potential (TRP) channels, including the ankyrin 1 (TRPA1) channel. Recent findings have identified agents either inhaled from the environment or produced endogenously that are known to trigger migraine or cluster headache attacks, such as TRPA1 simulants. A major constituent of feverfew, parthenolide, may interact with TRPA1 nucleophilic sites, suggesting that feverfew's antimigraine effect derives from its ability to target TRPA1. We found that parthenolide stimulates recombinant (transfected cells) or natively expressed (rat/mouse trigeminal neurons) TRPA1, where it, however, behaves as a partial agonist. Furthermore, in rodents, after initial stimulation, parthenolide desensitizes the TRPA1 channel and renders peptidergic TRPA1-expressing nerve terminals unresponsive to any stimulus. This effect of parthenolide abrogates nociceptive responses evoked by stimulation of peripheral trigeminal endings. TRPA1 targeting and neuronal desensitization by parthenolide inhibits CGRP release from trigeminal neurons and CGRP-mediated meningeal vasodilatation, evoked by either TRPA1 agonists or other unspecific stimuli. TRPA1 partial agonism, together with desensitization and nociceptor defunctionalization, ultimately resulting in inhibition of CGRP release within the trigeminovascular system, may contribute to the antimigraine effect of parthenolide.Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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