TREK Channel Activation Suppresses Migraine Pain Phenotype

Pablo Ávalos Prado,Anne-Amandine Chassot,Clément Verkest,Guillaume Sandoz,Arnaud Landra-Willm,Anne Baron

doi:10.2139/ssrn.3850367

Abstract

Activation and sensitization of trigeminal (TG) ganglia sensory neurons, leading to the release of pro-inflammatory peptides such as calcitonin gene-related peptide (CGRP), are likely a key component in migraine-related headache induction. Reducing TG neuron excitability represents therefore an attractive alternative strategy to relieve migraine pain. Here by using pharmacology and genetic invalidation ex vivo and in vivo, we demonstrate that activating TREK1- and TREK2- Two-Pore-Domain potassium ( K 2P ) channels inhibits TG neuronal firing sufficiently to fully reverse the migraine-like phenotype induced by NO-donors in rodents. Finally, targeting TREK is as efficient as treatment with CGRP antagonists, which represents one of the most effective migraine therapies. Altogether, our results demonstrate that inhibiting TG excitability by pharmacological activation of TREK channels should be considered as an alternative to the current migraine treatment.

Highlights

Migraine is considered one of the most disabling conditions worldwide, affecting around 15% of the global population (Burch et al, 2015)
We recently found that the human mutation of K2P-TRESK channel, ‘‘TRESK-MT’’, related to migraine, inhibits K2P-TREK1 and TREK2 channels and sufficiently increases sensory trigeminal ganglia (TG) neuronal excitability to generate a migraine-like phenotype (Royal et al, 2019)
TREK1 and TREK2 activation by ML67-33 reverses the migraine-like cutaneous allodynia in mice To investigate whether targeting TREK1 and TREK2 activity would treat migraine, we first verified whether the TREK agonist ML67-33 (Bagriantsev et al, 2013) activated TREK1 and TREK2 channels

Summary

Introduction

Migraine is considered one of the most disabling conditions worldwide, affecting around 15% of the global population (Burch et al, 2015). It manifests as a unilateral throbbing headache and is accompanied by multiple symptoms such as nausea, vomiting, photophobia, phonophobia, or cutaneous allodynia. Hyperexcitability of TG fibers innervating meninges induces the release of neuropeptides (e.g. substance P and the calcitonin gene-related peptide [CGRP]) that triggers vasodilatation of surrounding blood vessels and local neurogenic inflammation, leading to migraine (Frederiksen et al, 2019; Goadsby et al, 2017; Khan et al, 2019). Targeting the pro-inflammatory peptides secreted by TG neurons such as CGRP constitutes one of the most effective current strategy to treat migraine (Edvinsson et al, 2018). About 50% of the patients do not respond to this treatment and suffer from secondary effects (joint pain, dizziness, constipation, flu-like symptoms) and alternative patient care needs to be developed

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