Abstract text (incl. figure legends and references)

Objective: The activation of the trigeminovascular system (TGVS), nociception, neurogenic neuroinflammation, as well as the release of the neuropeptide calcitonin gene-related peptide (CGRP) from C-fibers in the meninges and trigeminal ganglion (TG) have been proposed to be part of migraine pathophysiology. Resveratrol is a polyphenol with therapeutic effects on various conditions and diseases, however little research has been conducted of this compound in the context of migraines, which was therefore the purpose of this study.

Methods: The effect of resveratrol on CGRP release was investigated in the TG and dura mater of rats, where we applied the following stimuli: KCl induced depolarization, TRPV1 activation (capsaicin) and TRPM3 activation (CIM0216), which are all CGRP release stimulants. Finally, resveratrol was tested in an in vivo inflammatory model, where rats were administered with Complete Freund"s Adjuvant (CFA) to their dura, followed by periorbital allodynia testing using an electronical von Frey.

Results: Resveratrol did not stimulate CGRP release per se. Further, resveratrol reduced capsaicin induced CGRP release in the TG by 29.9±12.1% (p=0.02), and reduced CIM0216 and KCl induced CGRP release in the dura by 32.2±2.8% (p=0.02) and 29.8±6.3% (p=0.01), respectively. Despite inhibitory effects on CGRP, two days of intraperitoneal injection of 100 mg/kg resveratrol did not alleviate periorbital allodynia in the inflammation model.

Conclusion: The ex vivo data provides arguments and encouragement for further migraine studies to investigate resveratrol as a therapeutic agent, and we postulate that this could be caused by the ability of resveratrol to potentially interact with the function of TRPV1 channels and TRPM3 channels, and thereby reduce membrane excitation in the TGVS. Although we did not observe positive effect in the in vivo model, we believe that with the optimal dosing resveratrol could show positive effects.