Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides, which in humans exists in two forms, alpha-CGRP and beta-CGRP, both of which exhibit similar biological functions. The 37-amino acid alpha-CGRP arises from alternate splicing of the calcitonin-CGRP gene, while beta-CGRP is encoded by a different gene that is homologous to the calcitonin-CGRP gene.2
CGRP exerts its biological effects via receptors on target cells, which are composed of the calcitonin-like receptor (CL receptor) and a single transmembrance domain protein called "receptor activity modifying protein" (RAMP). CGRP receptors are divided into two classes, CGRP1 and CGRP2, based on the RAMP associated with the CL receptor.2
CGRP is recognized as a potent vasodilator and can function in pain transmission. The widespread distribution of CGRP-containing nerve endings (where CGRP is released) and CGRP receptors throughout the body suggests that protein modulates a multitude of physiological functions in all major systems (eg, respiratory, endocrine, gastrointestinal, immune, and cardiovascular systems).2
The Role of CGRP in Headache
An accumulating body of evidence supports the integral role of alpha-CGRP and its CGRP1 receptor in the pathophysiology of certain primary headache disorders.2–4
Preclinical evidence suggests that during migraine-activated primary sensory neurons (meningeal nociceptors) release CGRP from their peripherally projecting nerve endings located within the meninges.4
CGRP binds to and activates CGRP1 receptors located within and around meningeal vessels to cause vasodilation, mast cell degranulation, and plasma extravasation.2–4
Activated meningeal nociceptors also release CGRP from their centrally projecting nerve endings within the trigeminal nucleus caudalis (TNC), thereby activating second-order neurons, which relay information to brain regions, mediating the perception of headache pain.4
Observations in humans also support the role of CGRP in the pathophysiology of headache. The activation of primary sensory neurons (ie, meningeal nociceptors) of the trigeminovascular system (TGVS) during migraine leads to the release of CGRP, which can be measured in humans from samples of saliva and plasma drawn from the external jugular vein.2–4
During spontaneous attacks of migraine (with and without aura), there are elevated concentration5 of CGRP in both saliva and plasma.3,5–7
In addition, intravenous administration of alpha-CGRP induces headache in individuals subsceptible to migraine.8
2. Arulmani U, MaassenVanDenBrink A,
Villalón CM, Saxena PR. Calcitonin gene-related peptide and its role
in migraine pathophysiology.
Eur J Pharmacol. 2004;500:315–330.
3. Edvinsson L. Neuronal signal substances as biomarkers
of migraine. Headache.
2006;46:1088–1094.
4. Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache.
2006;46(Suppl1):S3–S8.
5. Goadsby PJ, Edvinnson L, Ekman R. Vasoactive peptide release
in the extracerebral circulation of humans during migraine headache. Ann
Neurol. 1990;28:183–187.
6. Gallai V, Sarchielli P, Floridi A, et al. Vasoactive peptide
levels in the plasma of young migraine patients with and without aura assessed
both interictally and ictally.
Cephalalgia. 1995;15:384–390.
7. Sarchielli P, Alberti A, Vaianella L, et al. Chemokine
levels in the jugular venous blood of migraine without aura patients during
attacks. Headache.
2004;44:961–968.
8. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling
B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia.
2002;22:54–61.
