TREK1 channel activation as a new analgesic strategy devoid of opioid adverse effects.

Jérôme Busserolles,Serge Richard,Julien Schopp,Céline Judon,Mathieu Meleine,Maïly Devilliers,Nicolas Marie,Sylvie Ducki,Florence Noble,Laetitia Pouchol,Florian Lesage,Laura Poupon,Ismail Ben Soussia,Eric Chapuy,Loïc Clémenceau,Alain Eschalier,Stéphane Lolignier

doi:10.1111/bph.15243

Abstract

Opioids are effective painkillers. However, their risk-benefit ratio is dampened by numerous adverse effects and opioid misuse has led to a public health crisis. Safer alternatives are required, but isolating the antinociceptive effect of opioids from their adverse effects is a pharmacological challenge because activation of the μ opioid receptor triggers both the antinociceptive and adverse effects of opioids. The TREK1 potassium channel is activated downstream of μ receptor and involved in the antinociceptive activity of morphine but not in its adverse effects. Bypassing the μ opioid receptor to directly activate TREK1 could therefore be a safer analgesic strategy. We developed a selective TREK1 activator, RNE28, with antinociceptive activity in naive rodents and in models of inflammatory and neuropathic pain. This activity was lost in TREK1 knockout mice or wild-type mice treated with the TREK1 blocker spadin, showing that TREK1 is required for the antinociceptive activity of RNE28. RNE28 did not induce respiratory depression, constipation, rewarding effects, or sedation at the analgesic doses tested. This proof-of-concept study shows that TREK1 activators could constitute a novel class of painkillers, inspired by the mechanism of action of opioids but devoid of their adverse effects.

Highlights

Opioids are reference analgesics, for nociceptive pain, their risk–benefit ratio is not optimal because of frequentAbbreviations: %MPE, percentage of the maximum possible effect; KO, knockout; NCBI, National Center for Biotechnology Information; WT, wild-type.and potentially serious adverse effects
This study provides a proof-of-concept of the antinociceptive activity and safety of selective TREK1 pharmacological activation in mice using the newly developed compound RNE28
No data regarding the antinociceptive effect of BL-1249, ML335, ML402, ML67-33 and GI-530159 have yet been generated, but we show that activation of TREK1 alone by RNE28 is able to produce an antinociceptive effect in naive animals

Summary

| INTRODUCTION

Opioids are reference analgesics, for nociceptive pain, their risk–benefit ratio is not optimal because of frequent. In October 2018, the US Food and Drug Administration decided not to grant it approval owning to doubts whether the benefits associated with the drug outweighed the risks (Mores, Cummins, Cassell, & van Rijn, 2019) Against this background, we initiated a different strategy involving direct activation of an analgesic effector protein downstream of the μ receptor. The strategy is based on the finding that TREK1 potassium channels, activated downstream of the μ receptor, play an important part in the antinociceptive effect of morphine and fentanyl without being involved in opioid adverse effects (Devilliers et al, 2013). RNE28 treatment does not induce constipation, respiratory depression, sedation or rewarding effects at the analgesic doses tested, which validates the concept of TREK1 activation as an alternative to opioids. TREK1 activators could constitute a new class of analgesic drugs with improved risk–benefit ratio

| METHODS

| Evaluation of pain thresholds

| RESULTS

| DISCUSSION