CGRP and NO in the Trigeminal System: Mechanisms and Role in Headache Generation

1. Karl Messlinger¹, 
2. Jochen K. Lennerz^2,3,†,
3. Mirjam Eberhardt¹, 
4. Michael J. M. Fischer^1,4

DOI: 10.1111/j.1526-4610.2012.02212.x

Abstract

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 pre-clinical work on these systems focusing on the trigeminovascular system in migraine.

NO derives from various cell types via three 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 three 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.

© 2012 American Headache Society

Neurological mechanisms of migraine: potential of the gap-junction modulator tonabersat in prevention of migraine.

Durham PL, Garrett FG.
Center for Biomedical and Life Sciences, Missouri State University, Springfield, MO 65897, USA. pauldurham@missouristate.edu

Migraine is a neurovascular disorder characterized by recurrent episodic headaches, and is caused by abnormal processing of sensory information due to peripheral and/or central sensitization. The exact pathophysiological mechanism underlying migraine is not fully understood; however, cortical spreading depression (CSD) is thought to provide the basis for migraine aura and may serve as a trigger of migraine pain. CSD depends on neuronal-glial cell communication, which is mediated by intercellular transfer of messengers through connexin-containing gap junctions, as well as messengers released into the extracellular space by non-junctional connexin-containing hemichannels. These processes are believed to be important in peripheral sensitization within the trigeminal ganglion and to lead to central sensitization. The novel benzopyran compound tonabersat binds selectively to a unique site in the brain. In preclinical studies, tonabersat markedly reduced CSD and CSD-associated events and inhibited gap-junction communication between neurons and satellite glial cells in the trigeminal ganglion. Together, these findings suggest that tonabersat should have clinical application in preventing migraine attacks.

Cephalalgia. 2009 Nov;29 Suppl 2:1-6