Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene‐related peptide induced dilation of dural meningeal vessels

Abstract

1 The detailed pathophysiology of migraine is beginning to be understood and is likely to involve activation of trigeminovascular a erents.2 Clinically e ective anti-migraine compounds are believed to have actions that include peripheral inhibition of calcitonin gene-related peptide (CGRP) release from trigeminal neurones, or preventing dural vessel dilation, or both. CGRP antagonists can block both neurogenic and CGRP-induced dural vessel dilation. 3 Nitric oxide (NO) can induce headache in migraine patients and often triggers a delayed migraine. The initial headache is thought to be caused via a direct action of the NO ± cGMP pathway that causes vasodilation by vascular smooth muscle relaxation, while the delayed headache is likely to be a result of triggering trigeminovascular activation. Nitric oxide synthase (NOS) inhibitors are e ective in the treatment of acute migraine. 4 The present studies used intravital microscopy to examine the e ects of speci®c NOS inhibitors on neurogenic dural vasodilation (NDV) and CGRP-induced dilation. 5 The non-speci®c and neuronal NOS (nNOS) inhibitors were able to partially inhibit NDV, while the non-speci®c and endothelial NOS (eNOS) inhibitors were able to partially inhibit the CGRP induced dilation. 6 There was no e ect of the inducible NOS (iNOS) inhibitor. 7 The data suggest that the delayed headache response triggered by NO donors in humans may be due, in part, to increased nNOS activity in the trigeminal system that causes CGRP release and dural vessel dilation. 8 Further, eNOS activity in the endothelium causes NO production and smooth muscle relaxation by direct activation of the NO ± cGMP pathway, and may be involved in the initial headache response.

Calcitonin Gene–Related Peptide Receptor Antagonist BIBN 4096 BS for the Acute Treatment of Migraine

“…11 Similarly, triptans can block meningeal vascular dilation, 28 a response that involves CGRP 7 and nitric oxide. 29 Studies that have used microiontophoresis have shown that BIBN 4096 BS blocks activity in the trigeminocervical complex of the cat that is induced by CGRP, l -glutamate, or stimulation of the superior sagittal sinus. 30 This effect is shared with ergot derivatives and triptans.…”

Anandamide Is Able to Inhibit Trigeminal Neurons Using an in Vivo Model of Trigeminovascular-Mediated Nociception

“…CGRP injections trigger both migraine (Lassen et al, 2002) and dural vessel dilation (Williamson et al, 1997a) and CGRP antagonists have acute antimigraine properties (Olesen et al, 2003). NO is another known trigger of migraine (Dalsgaard-Nielsen, 1955;Thomsen et al, 1994) and dural vessel dilation (Akerman et al, 2002c). Both NO-induced dural vessel dilation (Akerman et al, 2002a) and headache (Iversen and Olesen, 1996) are affected by the antimigraine compound sumatriptan.…”

The Role of Dopamine in a Model of Trigeminovascular Nociception

“…Significance was assessed at the P Ͻ 0.05 level or below. The reproducibility of the neurogenic vasodilator response has been tested previously using four consecutive salinecontrolled stimuli (Akerman et al, 2002) in the same experimental setup.…”