Headache Medicine 2020, 11(1):25-26 ISSN 2178-7468, e-ISSN 2763-6178

ASAA

DOI: 10.48208/HeadacheMed.2020.7

Headache Medicine

Thesis

Peripheral projections of the trigeminovascular system as

antimigraine target

Projeções periféricas do sistema trigeminovascular como alvo anti-enxaqueca

Alejandro Labastida-Ramírez Antoinette Maassen Van Den Brink

Erasmus MC, Division of Vascular Medicine and Pharmacology, Rotterdam, Zuid Holland, Holland.

Calcitonin gene-related peptide (CGRP) is a key neuropeptide, highly expressed in the

central and peripheral trigeminovascular system, involved in craniofacial nociceptive modu-

lation.

In migraine patients, CGRP infusion generates migraine-like headaches

, and during

spontaneous attacks this peptide is released in the extracerebral circulation

. The treatment

of choice currently available for terminating migraine attacks are the triptans, 5-HT1B/1D

receptor agonists, of which some also display afnity for the 5-HT1F receptor.

These drugs

have the ability to decrease elevated CGRP levels by inhibiting further release from trige-

minal perivascular afferents and consequently decrease nociceptive transmission from the

periphery to the central nervous system.

However, due to their coronary vasoconstrictor

potential, they are contraindicated in patients with cardiovascular diseases. This concern

has resulted in the development of novel drugs devoid of vascular side-effects, such as mo-

noclonal antibodies targeting CGRP or its receptor. Moreover, these drugs have shown that

migraine attacks can be prevented exclusively via peripheral blockade of CGRP. This thesis

focused on the pharmacological modulation of the peripheral CGRPergic projections of the

trigeminovascular system.

We investigated in rodents the modulation of trigeminal CGRP release by lasmiditan, a

highly selective 5-HT1F receptor agonist (ditan), and comparatively studied sumatriptan.

CGRP release was diminished similarly by both drugs in all the trigeminovascular system

components (dura mater, trigeminal ganglion and trigeminal nucleus caudalis) ex vivo. In

vivo, lasmiditan or higher doses of sumatriptan signicantly attenuated endogenous CGRP

release, but not exogenous CGRP effects. These ndings suggest that selective 5HT1F receptor

activation (by lasmiditan) is sufcient to presynaptically inhibit CGRP release in peripheral

and central trigeminal nerve terminals, and, consequently, attenuate nociceptive transmission

in the trigeminovascular system.

Since activation of 5HT1F receptors is not associated with

coronary vasoconstriction, lasmiditan may represent a cardiovascular safety advantage over

the vasoactive triptans.

In addition to the trigeminovascular CGRP release inhibition by lasmiditan, further (anti-

migraine) mechanisms of action described with previous 5HT1F receptor agonists include

modulation of glutamate release from sensory bers.

The co-localization of 5HT1F receptors

and glutamate in the vestibular nuclei of rats, suggests that the 5HT1F receptor might also

modulate glutamate release in CNS structures.

Moreover, since glutamate receptor anta-

gonism prevents the initiation of cortical spreading depressions (CSDs), a key pathogenic

event in migraine with aura, 5-HT1F receptor agonism could attenuate CSDs via a central

inhibition of glutamate. Therefore, after taking into account these additional mechanisms,

future experiments are needed to determine whether lasmiditan can: (I) inhibit glutamatergic

neurons in the central nervous system, or (II) attenuate CSDs initiation and its associated

hyperaemia; and if all or none of these mechanisms are associated with ts clinical antimi-

graine efcacy.

Alejandro Labastida-Ramírez

a.labastidaramirez@erasmusmc.nl

Received: March 6, 2020.

Accepted: March 11, 2020.

Edited by

Mario Fernando Prieto Peres

ASAA

Labastida-Ramírez A, Van Den Brink AM

Peripheral projections of the trigeminovascular

Competing Interests:

The authors declare that they have no

competing interests.

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