It is one of the most prevalent neurological disorders, affecting more than ten percent of
people worldwide,1-4 and one of the most common reasons people consult a
doctor.5 The impact of this debilitating disease is significant, yet it remains
under-recognized and undertreated.6-9 It is migraine and it is among the leading
causes of years lived with disability.3,10 Migraine is a complex neurological
disease characterized by recurrent headaches and associated symptoms. Headaches can be
incapacitating and vary in frequency.11,12 Women are two to three times more
likely than men to be affected5 and migraine may have a genetic component.5,11,13
As a migraine attack progresses, patients can experience a range of symptoms, especially
sensory disturbances and pain.11,12,14-23 Research continues to reveal a complex
pathophysiology underlying migraine that involves multiple processes in both the central
nervous system, or CNS, and in the periphery.6,24 These may include neuropeptide
release11, neurogenic inflammation,11,25 vasodilation, stimulation of
sensory neurons11 and the activation of specific regions within the brain and
brainstem.14 Researchers have yet to determine which of these processes play a
causal role, or if they occur as a result of or in parallel with migraine.11,14
In addition, it has been proposed that feedback from a hypersensitized brain may further
exacerbate pain signaling.11,25 Despite what we know of migraine pathophysiology,
the roles played by central and peripheral processes in migraine are not yet fully
understood. Nonetheless, one particular neuropeptide has been shown to play an important
role in migraine pathogenesis. Calcitonin gene-related peptide, or CGRP,1,11,25
is expressed within the trigeminal pathway,1,25 a neurovascular system with
components located both centrally and in the periphery.25,26 In contrast with
other neuropeptides, CGRP levels have been shown to increase during migraine27,28
and are reduced with headache relief.11,25,28,29 As well, experimental
intravenous infusion of CGRP induces migraine-like headache in
patients,11,14,30,31 suggesting that CGRP may play a causal role in
migraine.20,30,31 The CGRP receptor is a complex of calcitonin receptor-like
receptor, receptor activity modifying protein 1, and receptor component
protein.11,25 CGRP receptors are localized at several sites within the
trigeminovascular pathway, including the trigeminal ganglion and brainstem.26,32
The interaction of CGRP with CGRP receptors within the trigeminovascular pathway is believed
to contribute to migraine pathophysiology. In the periphery, the binding of CGRP to its
receptor on vascular smooth muscle can lead to the dilation of cerebral and meningeal blood
vessels.11 The activation of nociceptive trigeminal neurons relays the migraine
pain signal through the brainstem into the CNS, ultimately leading to the experience of
migraine pain.11 CGRP receptor signaling at sites within the CNS may have
numerous effects including central sensitization11 and exacerbation of pain
signals10, which contributes to11 common migraine symptoms.11,16
Central processes can also lead to migraine pain signaling and activation of other pathways
within the brain.11,24 The important role of CGRP in migraine pathogenesis is of
great interest to researchers in their quest to understand more about this common disabling
disease.25
References
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- Hirtz D, et al. Neurology. 2007;68:326-337.
- Global Burden of Disease Study 2017 Collaborators. Lancet. 2018;392:1789-1858.
- Stovner L, et al. Cephalalgia. 2007;27:193-210.
- Fumal A, et al. J Neuropsych Dis Treat. 2008;4:1043-1057.
- Goadsby P, et al. N Engl J Med. 2002;346:257-270.
- World Health Organization. Neurological disorders: Public health challenges.
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- Bigal M, et al. Neurology. 2008;71:559-566.
- Diamond S, et al. Headache. 2007;47:355-363.
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- Russo A. Annu Rev Pharmacol Toxicol. 2015;55:533-552.
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- Edvinsson L. Brit J Clin Pharmacol. 2008;155:967-969.
- Edvinsson L. Brit J Clin Pharmacol. 2015;80:193-199.
- Charles A. Headache. 2012;53:413-419.
- Charles A. Curr Opin Neurol. 2013;26:235-239.
- Binfalah M, et al. Pain Res Treat. 2018;2018:2516953.
- Dodick D. Headache. 2018;58:4-16.
- Burstein R, et al. J Neurosci. 2015;17:6619-6629.
- Blau J. Lancet.1992;339:1202-1207.
- Ashkenazi A, et al. Cephalalgia. 2009;29:1042-1048.
- Vuralli D, et al. J Headache Pain. 2018;19:109.
- Goadsby P, et al. Physiol Rev. 2017;97:553-622.
- Silberstein S, et al. Headache. 2015;55:1171-1182.
- Raddant A, et al. Expert Rev Mol Med. 2011;13:1-18.
- Eftekhari A, Edvinsson L. Ther Adv Neurol Disord. 2010;3:369-378.
- Goadsby P, et al. Ann Neurol. 1990;28:183-187.
- Edvinsson L, et al. Eur J Neurol. 1998;5:329-341.
- Goadsby P, et al. Ann Neurol. 1993;33:48-56.
- Lassen L, et al. Cephalalgia. 2002;22:54-61.
- Guo S, et al. Pain. 2016;157:2773-2781.
- Miller S, et al. Neuroscience. 2016;328:165-183.
