BK channels in microglia are required for morphine-induced hyperalgesia.

Yoshinori Hayashi,Saori Morinaga,Takahiro Nakata,Jing Zhang,Zhou Wu,Yasushi Satoh,Hiroshi Nakanishi,Kazuhide Inoue,Andrea L Meredith,Shinichi Kohsaka

doi:10.1038/ncomms11697

Abstract

Although morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance. Microglia-to-neuron signalling is critically involved in pain hypersensitivity. However, molecules that control microglial cellular state under chronic morphine treatment remain unknown. Here we show that the microglia-specific subtype of Ca2+-activated K+ (BK) channel is responsible for generation of MIH and anti-nociceptive tolerance. We find that, after chronic morphine administration, an increase in arachidonic acid levels through the μ-opioid receptors leads to the sole activation of microglial BK channels in the spinal cord. Silencing BK channel auxiliary β3 subunit significantly attenuates the generation of MIH and anti-nociceptive tolerance, and increases neurotransmission after chronic morphine administration. Therefore, microglia-specific BK channels contribute to the generation of MIH and anti-nociceptive tolerance.

Highlights

Morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance
Based on our previous finding that BK channels in the spinal microglia were a potential novel molecular target of S-ketamine[18], we considered that the effect of an ultra-low dose of S-ketamine on MIH and anti-nociceptive tolerance in the clinical setting might be due to suppression of the microglial BK channel activation
We previously reported that the activation of BK channels in spinal microglia causes the tactile allodynia[18]

Summary

Introduction

Morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance. Silencing BK channel auxiliary b3 subunit significantly attenuates the generation of MIH and anti-nociceptive tolerance, and increases neurotransmission after chronic morphine administration. Opioids are still gold standard medications for pain management in the clinical setting, even after the discovery of novel therapeutic strategies for chronic pain Despite their common use, there are still serious problems associated with the use of opioids, including opioid-induced hyperalgesia and anti-nociceptive tolerance, which frequently hamper medical adherence. BK channels in microglia play a crucial role in the ionic homeostasis that regulates the cellular activation state, resulting in an increase in the pain perception and attenuation of opioid anti-nociception

Methods

Results

Conclusion