TREK Channel Activation Suppresses Migraine Pain Phenotype

Abstract

Activation and sensitization of trigeminal ganglia (TG) 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.

What Is the Role of 2-Pore Domain Potassium Channels (K2P) in Pain?

“…97 Several compounds were shown to increase TRK1 and TRAAK channel activity, hyperpolarize DRG neurons, and reduce in phenotypes in rodents. 93,98-100 However, several factors limit the full understanding of K2P channels in pain disorders and their therapeutic potential. For example, although changes in K2P channel expression in experimental pain models may have a pathogenic role, they may also reflect in some case a compensatory mechanism to reduce pain.…”

“…16,20 This is supported by the finding that activation of TREK1 and TREK2 inhibited trigeminal ganglion neuron firing sufficiently to reverse the migraine-like phenotype induced by nitric oxide donors in rodents. 93…”