Shared first authorship.
CGRP and NO in the Trigeminal System: Mechanisms and Role in Headache Generation
Article first published online: 12 JUL 2012
© 2012 American Headache Society
Headache: The Journal of Head and Face Pain
Volume 52, Issue 9, pages 1411–1427, October 2012
How to Cite
Messlinger, K., Lennerz, J. K., Eberhardt, M. and Fischer, M. J.M. (2012), CGRP and NO in the Trigeminal System: Mechanisms and Role in Headache Generation. Headache: The Journal of Head and Face Pain, 52: 1411–1427. doi: 10.1111/j.1526-4610.2012.02212.x
- Issue published online: 3 OCT 2012
- Article first published online: 12 JUL 2012
- Accepted manuscript online: 15 JUN 2012 08:26AM EST
- Accepted for publication June 5, 2012.
- calcitonin gene-related peptide;
- nitric oxide;
- dura mater;
- trigeminal ganglion;
- trigeminal nucleus
Calcitonin gene-related peptide (CGRP) and metabolic products of nitric oxide (NO) are increased in jugular venous plasma during migraine attacks and other primary headaches. Patients suffering from primary headaches are particularly sensitive to CGRP and NO donors responding with delayed headaches to an infusion of either of these substances. Accordingly, both CGRP and NO are considered as key mediators in migraine, and clinical trials have shown that inhibitors of CGRP receptors and NO synthase are effective in treating migraine. There is an implicit understanding that CGRP and NO systems interact, and here, we review the body of preclinical work on these systems focusing on the trigeminovascular system in migraine.
NO derives from various cell types via 3 isoforms of NO synthase, whereas CGRP is produced from a subset of trigeminal afferents. In rodents, NO donors cause activity alterations on different levels of the trigeminal system including enhancement of CGRP release, which in turn results in arterial vasodilatation and possibly mast cell degranulation in the meninges. The activity of spinal trigeminal neurons, which is a sensitive integrative measure for trigeminal activity, is partly under the control of CGRP and NO. Both mediators facilitate nociceptive transmission, possibly via presynaptic mechanisms. These functions are supported by immunolocalization of CGRP receptor components on 3 trigeminovascular levels: cranial dura mater, trigeminal ganglion, and spinal trigeminal nucleus.
Current data support a relationship of CGRP and NO actions on all levels of the trigeminovascular system and emphasize central CGRP receptors as possible therapeutic targets.