Infusion of a NO donor has been shown to cause a delayed headache in humans and delayed activation of central trigeminal neurons that process intracranial afferent input in rats (Ashina 2004, Koulchitsky 2004). NO may increase the production of calcitonin gene related peptide (CGRP), also a key mediator in primary headaches (Fanciullacci 1995). NO donors applied to cultured primary trigeminal ganglion cells have been shown to enhance gene expression of CGRP (Bellamy 2006).

Freshly dissected trigeminal ganglia of adult male Wistar rats were stimulated by application of inflammatory mediators for 5 min (pH 6,1; PGE2 10 mM, bradykinin 10 mM, histamine 10 mM, serotonin 10 mM). A reversible increase in CGRP release was measured by an enzyme linked immunoassay after stimulation. Identical experiments were performed after the infusion of the NO donor glyceroltrinitrate (GTN, 500 mg/kg), the NO synthase inhibitor N-omega-nitro-L-arginine-methyl-ester (L-NAME, 60 mg/kg) or saline over two hours under isoflurane anaesthesia. Inflammatory mediators increased CGRP release from the trigeminal ganglion after infusion of GTN by 80% compared to animals with saline infusion, whereas pretreatment with L-NAME led to a suppression by 40%.

NO-dependent facilitation of CGRP release from trigeminal ganglia may be a link between NO production and ongoing sensitisation in inflammatory and vascular headaches.