Calcitonin gene-related peptide in migraine: intersection of peripheral inflammation and central modulation

Abstract

Over the past two decades, a convergence of basic and clinical evidence has established the neuropeptide calcitonin-gene-related peptide (CGRP) as a key player in migraine. Although CGRP is a recognised neuromodulator of nociception, its mechanism of action in migraine remains elusive. In this review, we present evidence that led us to propose that CGRP is well poised to enhance neurotransmission in migraine by both peripheral and central mechanisms. In the periphery, it is thought that local release of CGRP from the nerve endings of meningeal nociceptors following their initial activation by cortical spreading depression is critical for the induction of vasodilation, plasma protein extravasation, neurogenic inflammation and the consequential sensitisation of meningeal nociceptors. Mechanistically, we propose that CGRP release can give rise to a positive-feedback loop involved in localised increased synthesis and release of CGRP from neurons and a CGRP-like peptide called procalcitonin from trigeminal ganglion glia. Within the brain, the wide distribution of CGRP and CGRP receptors provides numerous possible targets for CGRP to act as a neuromodulator.

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).…”

Expression of substance P, calcitonin gene-related peptide, β-endorphin and methionine-enkephalin in human dental pulp tissue after orthodontic intrusion: A pilot study

“…4 It presents a dose-dependent effect and causes vasodilatation by direct action over endothelial cells and indirect mastcell stimulation for histamine release, a dual effect shared with calcitonin gene-related peptide (CGRP). 5,6 CGRP is recognized as the most potent vasodilatory peptide 7 and is found in nearly 50% of the neurons of the trigeminal system. 6 Frequently collocated and released with SP, 8 it is capable of extending this neuropeptide activity by inhibiting enzyme degrada-tion.…”

“…5,6 CGRP is recognized as the most potent vasodilatory peptide 7 and is found in nearly 50% of the neurons of the trigeminal system. 6 Frequently collocated and released with SP, 8 it is capable of extending this neuropeptide activity by inhibiting enzyme degrada-tion. 9 Both are well-known key factors related to painful clinical scenarios.…”

Targeting CGRP: A New Era for Migraine Treatment

“…CGRP may work at the intersection between the peripheral and central components of migraine [36]. In the periphery, CGRP is abundantly present in dorsal horn cells co-stored with substance P in primary sensory ganglia, and with acetylcholine in motor neurons [37,38].…”