Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients

Abstract

Calcitonin gene-related peptide (CGRP)-containing nerves are closely associated with cranial blood vessels. CGRP is the most potent vasodilator known in isolated cerebral blood vessels. CGRP can induce migraine attacks, and two selective CGRP receptor antagonists are effective in the treatment of migraine attacks. It is therefore important to investigate its mechanism of action in patients with migraine. We here investigate the effects of intravenous human alpha-CGRP (hαCGRP) on intracranial hemodynamics. In a double-blind, cross-over study, the effect of intravenous infusion of hαCGRP (2 μg/min) or placebo for 20 min was studied in 12 patients with migraine without aura outside attacks. Xenon-133 inhalation SPECT-determined regional cerebral blood flow (rCBF) and transcranial Doppler (TCD)-determined blood velocity (Vmean) in the middle cerebral artery (MCA), as well as the heart rate and blood pressure, were the outcome parameters. No change of rCBF was observed at the end of infusion [1.2% ± 1.7 with hαCGRP, vs. −1.6% ± 3.1 with placebo (mean ± SD)] (P = 0.43). Vmean in MCA decreased to 13.5% ± 3.6 with hαCGRP versus 0.6% ± 1.8 with placebo (P < 0.005). Since rCBF was unchanged, this indicates a dilation of the MCA. hαCGRP induced a decrease in MAP (12%) (P < 0.005) and an increase in heart rate (58%) (P < 0.0001). CGRP dilates cerebral arteries, but the effect is so small that it is unlikely to be the only mechanism of CGRP-induced migraine.

Neurons of the Dopaminergic/Calcitonin Gene-Related Peptide A11 Cell Group Modulate Neuronal Firing in the Trigeminocervical Complex: An Electrophysiological and Immunohistochemical Study

“…This activation is associated with release of calcitonin gene-related peptide (CGRP) (Goadsby et al, 1988(Goadsby et al, , 1990Juhasz et al, 2003), which itself can trigger migraine (Lassen et al, 2008), is involved in activation of neurons in the trigeminocervical complex (Storer et al, 2004), and blockade of its effects is effective in acute migraine (Olesen et al, 2004;Ho et al, 2008). Trigeminal primary afferents innervating dural vessels are mainly nociceptive A␦-and C-fibers of the ophthalmic (first) division of the trigeminal nerve (Feindel et al, 1960).…”

Future drugs for migraine

“…Events subsequent to the trigger phase inducing neurological symptoms, such as aura, and events related to pain are thought to have a common neurovascular basis. According to this supposition, CGRP could represent an important neuromediator of both peripheral and central transmission of this pathway [10,11].…”

“…The CGRP receptor originates from the association between the calcitonin receptor-like receptor (CLR) with the receptor activity-modifying protein-1 (RAMP1). The former is a seven-transmembrane domain receptor, which is a component belonging to G protein-coupled receptors, while the latter is part of a three-member family (RAMP1, -2, and -3) [10,11].…”

Anti-CGRP monoclonal antibodies in migraine: current perspectives

“…Its levels are, in fact, elevated during migraine pain in patients, with normalization after administration of the anti-migraine agents, the triptans (5-HT 1B/1D agonists), and concurrent resolution of the headache component [66][67][68][69][70]. Intravenous infusion of CGRP can induce migraine-like attacks in migraine patients, i.e., a delayed headache about 2-4 h after injection with some headaches meeting criteria for migraine [71][72][73][74]. During the migraine-like attack, Asghar et al (2011) show a CGRP-induced dilatation of both the middle meningeal artery and the middle cerebral artery; sumatriptan administration effectively reverses the CGRP-induced migraine [71].…”