Triptans and CGRP blockade – impact on the cranial vasculature
Benemei et al. The Journal of Headache and Pain
Triptans and CGRP blockade - impact on the cranial vasculature
Silvia Benemei 0 1 2
Francesca Cortese 0 2 4
Alejandro Labastida-Ramírez 0 2 3
Francesca Marchese 0 2 7
Lanfranco Pellesi 0 2 6
0 Equal contributors
1 Health Sciences Department, University of Florence, and Headache Centre, Careggi University Hospital , Viale Pieraccini 6, 50134 Florence , Italy
2 Michele Romoli
3 Dept Internal Medicine, Division of Vascular Pharmacology, Erasmus Medical Center , Rotterdam , The Netherlands
4 Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome , Polo Pontino, Latina , Italy
5 Neurology Clinic , University
6 Medical Toxicology Headache and Drug Abuse Center, University of Modena and Reggio Emilia , Modena , Italy
7 Child Neuropsichiatry Unit, University of Palermo , Palermo , Italy
The trigeminovascular system plays a key role in the pathophysiology of migraine. The activation of the trigeminovascular system causes release of various neurotransmitters and neuropeptides, including serotonin and calcitonin gene-related peptide (CGRP), which modulate pain transmission and vascular tone. Thirty years after discovery of agonists for serotonin 5-HT1B and 5-HT1D receptors (triptans) and less than fifteen after the proof of concept of the gepant class of CGRP receptor antagonists, we are still a long way from understanding their precise site and mode of action in migraine. The effect on cranial vasculature is relevant, because all specific anti-migraine drugs and migraine pharmacological triggers may act in perivascular space. This review reports the effects of triptans and CGRP blocking molecules on cranial vasculature in humans, focusing on their specific relevance to migraine treatment.
Triptans; Calcitonin gene related peptide - CGRP; Anti-CGRP (receptor) monoclonal antibodies - mAbs; Middle meningeal artery; Middle cerebral arteries; Migraine models; Magnetic resonance angiography (MRA)
Keypoints
Triptans constrict extracerebral, but no intracerebral
arteries, in healthy volunteers and migraine patients. The
vasoconstrictor action of sumatriptan on extracerebral
arteries could be relevant to relief migraine pain.
However, sumatriptan also inhibits perivascular neurogenic
inflammation and sensitization in animal models.
Gepants prevent CGRP-induced dilation of extracerebral
arteries (e.g. middle meningeal and temporal arteries) in
experimental human models.
Data on effect of anti-CGRP (receptor) monoclonal
antibodies on cranial vasculature is still lacking. Importantly,
preclinical models show their ability to inhibit CGRP-induced
neurogenic vasodilation of the middle meningeal artery.
Background
Over the last century, controversies have raised around
the vascular, neural or neurovascular origin of migraine
[
1
]. From Galen original conjecture [
2
], with a meningeal
involvement in the throbbing pain, several centuries
passed before Willis, in 1672, hinted for the first time at
a “vascular hypothesis” of migraine [
3
]. Throughout the
1930s and early 1940s headache science has emerged
from studies by Graham, Ray and Wolff, who reported
head pain after in vivo stimulation of dural and cerebral
arteries, hypothesizing perivascular space as the possible
site of migraine pain [
4–7
]. Pial, dural and extracranial
vessels are part of a trigeminovascular system, a
functional pathway that, on one side, releases vasoactive
neuropeptides from perivascular nerve fibers and, on the
other, reacts to them with nociception and vasodilation
[8]. Pursuing the vascular hypothesis, several
pharmacological triggers (such as glyceryl trinitrate (GTN),
calcitonin gene-related peptide (CGRP) and pituitary
adenylate cyclase-activating peptide (PACAP-38) were
found to induce attacks phenotypically indistinguishable
from spontaneous migraine in migraine patients [
9–11
].
The fact that all migraine-provoking molecules are
vasoactive and sumatriptan constricts arteries [
12, 13
],
further granted a key role of cranial vasculature in
migraine pathophysiology [14].
Cranial arteries dilation has been shown, with different
techniques, in both provocation and spontaneous
migraine studies. Since the early 1990s, ultrasonography
has been used to measure blood flow velocity in
intracranial arteries [
15
] and extracranial artery diameter [
16
]
during migraine attacks. Blood flow velocity correlates
to vessel autoregulation and reactivity. Moreover, if
cerebral blood flow does not change during an attack, blood
flow velocity may be a surrogate marker of artery
diameter (i.e. decreased blood flow velocity means increased
middle cerebral artery lumen) [
17
]. In the last decade,
investigation techniques have moved from
ultrasonography to magnetic resonance angiography (MRA),
allowing researchers to directly measure artery circumference
[
18–22
]. MRA studies reported modest artery dilation
during attacks, which was inhibited by triptans [ (...truncated)