Migraine is considered a chronic neurovascular disorder characterized by recurrent severe headaches, associated with nausea, vomiting, photophobia and phonophobia, which may be preceded by an aura [
73]. Studies have shown that the pain arising during migraine is generated by small unmyelinated fibers, originating from the trigeminal nerve, which surround cerebral blood vessels [
74]. These fibers contain CGRP and SP [
75]. CGRP is released from trigeminal ganglia neurons in vitro following their stimulation [
76]. A number of key data support an important role for CGRP in the generation of migraine pain; 1) electrical stimulation of the trigeminovascular system results in the release of CGRP from nociceptive trigeminal afferents [
77]; 2) CGRP levels are elevated in blood samples taken from patients during migraine attacks [
78]; 3) intravenous CGRP infusion causes headaches and migraines in migraineurs [
79]; and 4) small molecule CGRP receptor antagonist are successful at alleviating pain during acute migraine attacks [
80,
81]. The effects of these small molecule CGRP receptor antagonists have been investigated in animal models of migraine pain, revealing a complex mechanism of action involving both peripheral and central sites. CGRP receptor antagonists reduce spontaneous and evoked neuronal activity from the spinal trigeminal nucleus (STN; thought to have an important role in centrally mediated migraine pain) [
82] and inhibit nitric oxide induced sensitization of the STN [
83]. In addition, CGRP receptor antagonists inhibit electrically evoked activity of nociceptors of the trigeminocervical complex [
84] and reduce CGRP mediated trigeminovascular neurogenic inflammation [
85]. It appears that within the setting of migraine pain, CGRP has a role in modulating nociceptive responses both at peripheral and central levels. The balance of the relative importance of CGRP at these sites is unknown [
7].