Calcitonin gene-related peptide (CGRP) and migraine

Abstract

The neuropeptide calcitonin gene-related peptide (CGRP) has long been postulated to play an integral role in the pathophysiology of migraine. While clinical findings are consistent with such a role, the specific pathogenic mechanisms of CGRP in migraine have remained speculative until recently. Through advances in molecular neuroscience, the pathogenic mechanisms of CGRP in migraine have begun to be elucidated. This paper discusses the hypothesized role of CGRP in migraine and reviews recent findings on the molecular mechanisms of this neuropeptide in migraine pathophysiology. Studies in cultured trigeminal neurons demonstrate that CGRP is released from trigeminal ganglia cells, that CGRP transcription is increased under conditions mimicking neurogenic inflammation, that migraine pharmacotherapies can both reduce CGRP release and inhibit CGRP transcription, and that tumor necrosis factor-alpha (TNF-alpha), an endogenous inflammatory mediator implicated in migraine, can stimulate CGRP transcription. Together, the results suggest that, in migraine, activation of trigeminal nerves release CGRP and other peptides that cause the release of proinflammatory mediators. These mediators further increase CGRP synthesis and release over hours to days in correspondence with the 4- to 72-hour duration of a typical migraine episode. The increased CGRP synthesis and release might be mediated by activation of mitogen-activated protein kinase pathways, which, in turn, can be modulated by endogenous inflammatory substances such as TNF-alpha and affected by drugs such as sumatriptan.

Figures

Fig 1

Expression and release of CGRP from cultured trigeminal neurons. The relative amount of CGRP released in 1 hour from untreated control cells or cells treated with 60 mM potassium chloride, a cocktail of inflammatory agents, or 10 µM capsaicin. The mean basal rate of CGRP release was 148 ± 5 pg/hour/dish (n = 36). *P < .001 compared with control. (Reproduced with permission from Durham PL, Russo AF. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J Neurosci. 1999;19:3423–3429).

Fig 2

Repression of CGRP promoter activity (expressed as % of control CGRP reporter gene activity) in cultured trigeminal neurons. CGS 12066A, sumatriptan, eletriptan, and rizatriptan administered at 5 µM for 18 hours repressed reporter gene activity relative to control values. *P < .05 compared with control. (Reproduced with permission from Durham PL, Dong PX, Belasco KT, et al. Neuronal expression and regulation of CGRP promoter activity following viral gene transfer into cultured trigeminal ganglia neurons. Brain Res. 2004;997:103–110).

Fig 3

CGRP regulation in trigeminal ganglia neurons. Activation of trigeminal nerves causes initial release of CGRP and other neuropeptides that promote release of inflammatory mediators. The inflammatory mediators, including TNF-α, further increase CGRP synthesis and release via MAPKs. Sumatriptan can block MAPK activation by causing sustained elevation of intracellular calcium. CNS = central nervous system. (Reproduced with permission from Durham PL, Russo AF. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J Neurosci. 1999;19:3423–3429).