The K + channel GIRK2 is both necessary and sufficient for peripheral opioid‐mediated analgesia

Dinah Nockemann,Paul A Heppenstall,Fernanda C Reis,Dominika Labuz,Christoph Stein,Philip Hublitz,Morgane Rouault,Kate Mcknelly

doi:10.1002/emmm.201201980

Abstract

The use of opioid agonists acting outside the central nervous system (CNS) is a promising therapeutic strategy for pain control that avoids deleterious central side effects such as apnea and addiction. In human clinical trials and rat models of inflammatory pain, peripherally restricted opioids have repeatedly shown powerful analgesic effects; in some mouse models however, their actions remain unclear. Here, we investigated opioid receptor coupling to K+ channels as a mechanism to explain such discrepancies. We found that GIRK channels, major effectors for opioid signalling in the CNS, are absent from mouse peripheral sensory neurons but present in human and rat. In vivo transgenic expression of GIRK channels in mouse nociceptors established peripheral opioid signalling and local analgesia. We further identified a regulatory element in the rat GIRK2 gene that accounts for differential expression in rodents. Thus, GIRK channels are indispensable for peripheral opioid analgesia, and their absence in mice has profound consequences for GPCR signalling in peripheral sensory neurons.GIRK channels are indispensable for peripheral opioid analgesia. The absence of GIRK channels from mouse dorsal root ganglion neurons questions the predictive validity of mice as a model organism for investigating peripheral GPCRmediated analgesia.

Highlights

Opioid agonists such as morphine are the gold standard for the treatment of severe pain
We demonstrate that GIRK channels, primary effectors for G protein‐coupled receptors (GPCRs) in the central nervous system (CNS), are absent from mouse peripheral sensory neurons but are expressed in rat and human
We further show that functional GIRK channels are sufficient for peripheral opioid‐mediated analgesia in vivo, and identify a short regulatory region distal to the promoter of the rat Kcnj6 gene that accounts for expression in rat sensory neurons

Summary

Introduction

Opioid agonists such as morphine are the gold standard for the treatment of severe pain. Their effects are mediated by m, d and k‐opioid receptors that function as G protein‐coupled receptors (GPCRs). Despite the widespread use of opioids to control pain, their clinical effectiveness is hampered by adverse side effects that result mainly from activation of receptors in the central nervous system (CNS). Such effects include apnea and addiction and have recently lead to an epidemic of overdoses, death and abuse (Paulozzi et al, 2012; Schumacher et al, 2009). Widely variable responses to opioids have been reported between rats and mice, and species differences have gained relevance for predictive validity since prototype compounds with demonstrated analgesic efficacy in rodents have often failed in humans (Mogil, 2009)

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