Inhibition of peripheral FAAH alleviates hyperalgesia induced by acute dural inflammation in experimental migraine

Abstract text (incl. figure legends and references)

Peripheral and central sensitization is an important pathophysiological process in migraine and its chronification, but the underlying mechanisms are largely unclear. Trigeminal hyperalgesia and/or facial allodynia have been tested in animal models to simulate clinical symptomatology and to investigate the mechanisms underlying migraine pain. Inhibition of the fatty-acid amide hydrolase (FAAH) activity, the enzyme that deactivates the endocannabinoid anandamide, may exert anti-nociceptive effects via the activation of peripheral cannabinoid (CB1) receptors. Aim - Here, we evaluated the effects of FAAH inhibition in a migraine model of peripheral sensitization obtained by evaluating trigeminal hypersensitivity at the orofacial formalin test in animals with dural inflammation. Methods – Dural inflammation was induced in male Sprague-Dawley rats with the infusion of an inflammatory soup (IS) onto the dura. Ten min after IS infusion, rats were treated, with the peripheral FAAH inhibitor URB937 (1mg/kg, i.p.) or vehicle. A first set of rats underwent the orofacial formalin test 2h after IS application, while a second experimental set was used to evaluate the expression of CGRP and pro-inflammatory cytokines in specific brain areas in toto. Results - IS infusion induced trigeminal hyperalgesia at the orofacial formalin test, associated with an increase in gene expression of CGRP and pro-inflammatory molecules in medulla-pons and trigeminal ganglia. URB937 administration inhibited IS-induced trigeminal hyperalgesia and the prevented the increase in gene expression of CGRP and pro-inflammatory molecules in the nervous tissues. Conclusions - The findings suggest that potentiation of the endocannabinoid tone, obtained via peripheral FAAH inhibition, may modulate trigeminal hyperalgesia induced by dural IS through the reduction of pro-inflammatory cytokines and CGRP synthesis at central and peripheral sites of the nervous system.