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

Capsaicin jelly against migraine pain

International Journal of Clinical Practice Volume 64 Issue 4, Pages 457 - 459
Published Online: 5 Feb 2010
C. Cianchetti
Neuropsichiatria Inf., University, Azienda Ospedaliero-Universitaria, Cagliari, Italy
Correspondence to Carlo Cianchetti, MD, Neuropsichiatria Inf., University, Azienda Ospedaliero-Universitaria, via Ospedale 119, 09124 Cagliari, Italy
Tel.: + 39 070 609 3425
Fax: + 39 070 609 3415
Email: cianchet@unica.it
Copyright © 2010 Blackwell Publishing Ltd

ABSTRACT
Objective: Recent studies support the role of extracranial perivascular afferents in a substantial percentage of migraineurs. Perivascular afferent fibres of the superficial temporal artery contain peptides, like calcitonin gene-related peptide (CGRP) and substance P (SP). CGRP and SP are considered relevant in the genesis of migraine pain. Capsaicin is an agonist of the transient receptor potential vanilloid type 1. It causes membrane depolarisation of sensory neurons, which release CGRP, SP and other pain peptides; excitation is followed by a refractory state, causing inactivation. Topical capsaicin has been found to be efficacious in several types of neuropathic pain. We attempted to verify whether topical periarterial capsaicin could ameliorate pain in absence of and during a migraine attack.

Methods: On 23 migraineurs showing pain at pressure on scalp arteries, we administered topical capsaicin 0.1% or vaseline jelly on painful arteries in absence of migraine attack. In those having pain reduction > 50%, we made the same comparison during a migraine attack.

Results: Topical capsaicin caused > 50% reduction of arterial pain in absence of attack in 17/23 patients, as opposed to two with vaseline. During attacks of mild- to moderate-intensity, > 50% improvement was obtained in 11/17 with capsaicin and in one with vaseline.

Conclusions: Although referring to a small number of patients, our data show that topical capsaicin may relieve arterial pain in absence of and during a migraine attack in a substantial number of patients experiencing scalp arterial tenderness. More active capsacinoids might be tried in the future and could provide a new method for treating migraine attacks.