The seminal proposal by Graham and Wolff [
54] who associated the headache phase of the migraine attack with the throbbing dilatation of the superficial temporal artery, and pain termination by ergotamine with a dramatic reduction in arterial pulsatility, has been subsequently challenged by the failure to measure any significant vasodilatation during migraine attacks either by using a laser Doppler flowmetry technique [
55] or more recently in a magnetic resonance angiography (MRA) study [
56]. However, more recent findings, obtained with a novel high-resolution direct MRA imaging technique [
21] during headache and migraine attacks provoked by a 20 min CGRP infusion, suggest the reconsideration of the rejection of vasodilatation as a major contributing mechanism of migraine pain, and the resulting dismissal of Wolff’s hypothesis. In migraine patients, infusion of CGRP-evoked delayed, unilateral migraine pain associated with dilatation of the middle meningeal artery (MMA, with a more pronounced dilatation) and of the middle cerebral artery (MCA, with a less pronounced dilatation) on the pain side, but not on the pain-free side. In patients with bilateral migraine pain, bilateral dilatation of both the MMA and MCA was recorded [
21]. Thus, the migraine pain was associated with arterial vasodilatation both with respect to the time course and the side of the event.
The series of enlightening clinical provocation tests in healthy volunteers and migraine patients by the Copenhagen group has greatly contributed to our current understanding of the role of CGRP and vasodilatation in migraine. CGRP infusion caused headaches and migraine-like attacks in migraineurs [
57], although this effect, as those of other vasodilators, occurs when presumably the concentration of the vasodilator substance in blood is low or negligible. Further studies showed that in healthy volunteers, the CGRP receptor antagonist, olcegepant, significantly reduced the immediate and delayed headache evoked by CGRP administration [
58]. If the ability of CGRP receptor activation or inhibition to provoke or abort, respectively, headache and migraine attacks has been well established, the site of action of CGRP to evoke head pain is unclear. It is possible that the absence of or the very limited [
59] dilation of MCA evoked by CGRP infusion is due to the inability/poor ability of exogenously administered CGRP to cross the blood–brain barrier (BBB), and therefore to act in the intracerebral vascular compartment [
60]. This conclusion is further supported by the observation that olcegepant (a CGRP antagonist of peptoid nature, which does not easily cross the BBB) [
61,
62] had no effect on the slight increase in MCA vasodilatation, but inhibited the much larger dilation of extracerebral arteries, such as the superficial temporal and the radial arteries [
58]. A mechanism similar to that found in patients with migraine without aura (MO) should occur in patients with migraine with aura (MA), as CGRP infusion triggered migraine-like attacks (some with aura) in patients suffering exclusively from MA [
63]. However, CGRP infusion failed to induce migraine attack in patients affected by the familial hemiplegic migraine (FHM) with known mutations in the calcium channel, voltage-dependent, P/Q type, alpha 1A subunit, the ATPase, Na
+/K
+ transporting, alpha 2 (+) polypeptide genes or without known mutations [
63]. Although the obviously small number of patients with FHM limits the robustness of the conclusion, these data suggest differences in the mechanism of head pain between patients with FHM and patients with MO/MA.
An emerging role for CGRP and neurogenic vasodilatation in chronic migraine is suggested by findings obtained by the injection of botulinum neurotoxin type A (BoNTA) into the rat craniofacial muscles, a procedure that decreased mechanical sensitization mediated by glutamate and CGRP-induced neurogenic vasodilatation [
64]. Similar observation was previously obtained in the human skin where pretreatment with BoNTA reduced the pain and the neurogenic vasodilatation evoked by topical capsaicin application [
65]. Thus, preclinical and clinical evidence suggests that BoNTA, recently introduced for the treatment of chronic migraine and medication overuse headache [
66‐
68], may exert its beneficial effect by decreasing mechanical sensitivity of cranial muscle nociceptors through inhibition of glutamate release and by attenuating the release of CGRP from muscle nociceptors.