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.

A photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals

“…3e ). This UV light-induced thermal hypersensitivity was prevented by co-application of LAKI with ML67.33, a specific TREK channel agonist 23 , 24 , supporting TREK channel involvement ( P > 0.21) (Fig. 3g ).…”

What Is the Role of 2-Pore Domain Potassium Channels (K2P) in 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 In addition to TREK and TRESK channels, primary afferents express TWIK1, TWIK2, TASK1, TASK3, THIK1, and THIK2 (K2P12) channels. 45,46,51 These channels also participate in mechanisms of neuropathic or inflammatory pain.…”

“…97 Several compounds were shown to increase TRK1 and TRAAK channel activity, hyperpolarize DRG neurons, and reduce in phenotypes in rodents. 93,[98][99][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…”

Rizatriptan benzoate-loaded dissolving microneedle patch for management of acute migraine therapy

“…CGRP is a potent vasodilatory neuropeptide that acts on the middle meningeal artery to induce cranial vasodilation and stimulate Aδ-fibers expressing calcitonin receptor-like receptor/receptor activity-modifying protein (CLR/RAMP 1 , CGRP receptor). 5 CGRP receptor activation, which in turn initiates adenylate cyclase (AC) activation, causes the accumulation of intracellular cyclic adenosine monophosphate (cAMP), cAMP-dependent sensitization of Aδ-fibers and enhanced nociceptive transmission in the trigeminal caudate nucleus. 6,7 One of the current targets for migraine treatment is the 5-HT receptor.…”