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

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 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.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…The initiation of migraine attacks has been attributed to a number of trigger mechanisms (reviewed in Kelman, 2007), including both environmental (e.g., air pollution, odors, alcohol consumption, as well as changes in temperature or weather) and physiologic factors (e.g., hormonal milieu or stress). Migraine headache is believed (at least in part) to reflect the activation of the trigeminovascular system, resulting in neurogenic inflammation of the meninges and the release of CGRP, a potent vasodilator (Geppetti et al, 2005;Raddant and Russo, 2011;Messlinger et al, 2012). This concept has gained strong experimental support by the efficacy of CGRP antagonists in clinical trials (Olesen and Ashina, 2011;Salvatore and Kane, 2011).…”

Elevated plasma total nitrite levels may be related to migraine attacks

“…So we could not make any comments on the patients' variables in relation to demographic or clinical data that might explain the involvement of NO pathways in the natural course of migraine. NO may be involved in some other primary headache types (18)(19)(20), but probably not in the same manner as in migraine attacks (20). On the other hand, it is not clear yet whether NO involvement in primary headaches is the cause or the consequence.…”

Nitroglycerin challenge induces lateralized headache in nasociliarynerve-ligated rats: implications for chronic migraine

“…Our model was valid and relevant to human migraine as cutaneous allodynia and altered thresholds of heat were demonstrated in the periorbital area. In the literature, NTG-induced allodynia and hyperalgesia in rodents is reversed by sumatriptan (25)(26)(27)(28)(29).…”