Triptans and CGRP blockade – impact on the cranial vasculature

The Journal of Headache and Pain, Oct 2017

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.

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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)


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Silvia Benemei, Francesca Cortese, Alejandro Labastida-Ramírez, Francesca Marchese, Lanfranco Pellesi, Michele Romoli, Anne Luise Vollesen, Christian Lampl, Messoud Ashina, On behalf of the School of Advanced Studies of the European Headache Federation (EHF-SAS). Triptans and CGRP blockade – impact on the cranial vasculature, The Journal of Headache and Pain, 2017, pp. 103, Volume 18, Issue 1, DOI: 10.1186/s10194-017-0811-5