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Rescue of HSP70 in Spinal Neurons Alleviates Opioids-Induced Hyperalgesia via the Suppression of Endoplasmic Reticulum Stress in Rodents

A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opioids. Endoplasmic reticulum (ER) stress has been shown to contribute to neuropathic or inflammatory pain, but its roles in opioids-induced hyperalgesia (OIH) are el...

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Autores principales: Lin, Tong-Tong, Qu, Jie, Wang, Chao-Yu, Yang, Xing, Hu, Fan, Hu, Liang, Wu, Xue-Feng, Jiang, Chun-Yi, Liu, Wen-Tao, Han, Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243285/
https://www.ncbi.nlm.nih.gov/pubmed/32500072
http://dx.doi.org/10.3389/fcell.2020.00269
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author Lin, Tong-Tong
Qu, Jie
Wang, Chao-Yu
Yang, Xing
Hu, Fan
Hu, Liang
Wu, Xue-Feng
Jiang, Chun-Yi
Liu, Wen-Tao
Han, Yuan
author_facet Lin, Tong-Tong
Qu, Jie
Wang, Chao-Yu
Yang, Xing
Hu, Fan
Hu, Liang
Wu, Xue-Feng
Jiang, Chun-Yi
Liu, Wen-Tao
Han, Yuan
author_sort Lin, Tong-Tong
collection PubMed
description A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opioids. Endoplasmic reticulum (ER) stress has been shown to contribute to neuropathic or inflammatory pain, but its roles in opioids-induced hyperalgesia (OIH) are elusive. Here, we provide the first direct evidence that ER stress is a significant driver of OIH. GRP78, the ER stress marker, is markedly upregulated in neurons in the spinal cord after chronic morphine treatment. At the same time, morphine induces the activation of three arms of unfolded protein response (UPR): inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1), protein kinase RNA-like ER kinase/eukaryotic initiation factor 2 subunit alpha (PERK/eIF2α), and activating transcription factor 6 (ATF6). Notably, we found that inhibition on either IRE1α/XBP1 or ATF6, but not on PERK/eIF2α could attenuate the development of OIH. Consequently, ER stress induced by morphine enhances PKA-mediated phosphorylation of NMDA receptor subunit 1(NR1) and leads to OIH. We further showed that heat shock protein 70 (HSP70), a molecular chaperone involved in protein folding in ER, is heavily released from spinal neurons after morphine treatment upon the control of K(ATP) channel. Glibenclamide, a classic K(ATP) channel blocker that inhibits the efflux of HSP70 from cytoplasm to extracellular environment, or HSP70 overexpression in neurons, could markedly suppress morphine-induced ER stress and hyperalgesia. Taken together, our findings uncover the induction process and the central role of ER stress in the development of OIH and support a novel strategy for anti-OIH treatment.
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spelling pubmed-72432852020-06-03 Rescue of HSP70 in Spinal Neurons Alleviates Opioids-Induced Hyperalgesia via the Suppression of Endoplasmic Reticulum Stress in Rodents Lin, Tong-Tong Qu, Jie Wang, Chao-Yu Yang, Xing Hu, Fan Hu, Liang Wu, Xue-Feng Jiang, Chun-Yi Liu, Wen-Tao Han, Yuan Front Cell Dev Biol Cell and Developmental Biology A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opioids. Endoplasmic reticulum (ER) stress has been shown to contribute to neuropathic or inflammatory pain, but its roles in opioids-induced hyperalgesia (OIH) are elusive. Here, we provide the first direct evidence that ER stress is a significant driver of OIH. GRP78, the ER stress marker, is markedly upregulated in neurons in the spinal cord after chronic morphine treatment. At the same time, morphine induces the activation of three arms of unfolded protein response (UPR): inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1), protein kinase RNA-like ER kinase/eukaryotic initiation factor 2 subunit alpha (PERK/eIF2α), and activating transcription factor 6 (ATF6). Notably, we found that inhibition on either IRE1α/XBP1 or ATF6, but not on PERK/eIF2α could attenuate the development of OIH. Consequently, ER stress induced by morphine enhances PKA-mediated phosphorylation of NMDA receptor subunit 1(NR1) and leads to OIH. We further showed that heat shock protein 70 (HSP70), a molecular chaperone involved in protein folding in ER, is heavily released from spinal neurons after morphine treatment upon the control of K(ATP) channel. Glibenclamide, a classic K(ATP) channel blocker that inhibits the efflux of HSP70 from cytoplasm to extracellular environment, or HSP70 overexpression in neurons, could markedly suppress morphine-induced ER stress and hyperalgesia. Taken together, our findings uncover the induction process and the central role of ER stress in the development of OIH and support a novel strategy for anti-OIH treatment. Frontiers Media S.A. 2020-05-12 /pmc/articles/PMC7243285/ /pubmed/32500072 http://dx.doi.org/10.3389/fcell.2020.00269 Text en Copyright © 2020 Lin, Qu, Wang, Yang, Hu, Hu, Wu, Jiang, Liu and Han. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Lin, Tong-Tong
Qu, Jie
Wang, Chao-Yu
Yang, Xing
Hu, Fan
Hu, Liang
Wu, Xue-Feng
Jiang, Chun-Yi
Liu, Wen-Tao
Han, Yuan
Rescue of HSP70 in Spinal Neurons Alleviates Opioids-Induced Hyperalgesia via the Suppression of Endoplasmic Reticulum Stress in Rodents
title Rescue of HSP70 in Spinal Neurons Alleviates Opioids-Induced Hyperalgesia via the Suppression of Endoplasmic Reticulum Stress in Rodents
title_full Rescue of HSP70 in Spinal Neurons Alleviates Opioids-Induced Hyperalgesia via the Suppression of Endoplasmic Reticulum Stress in Rodents
title_fullStr Rescue of HSP70 in Spinal Neurons Alleviates Opioids-Induced Hyperalgesia via the Suppression of Endoplasmic Reticulum Stress in Rodents
title_full_unstemmed Rescue of HSP70 in Spinal Neurons Alleviates Opioids-Induced Hyperalgesia via the Suppression of Endoplasmic Reticulum Stress in Rodents
title_short Rescue of HSP70 in Spinal Neurons Alleviates Opioids-Induced Hyperalgesia via the Suppression of Endoplasmic Reticulum Stress in Rodents
title_sort rescue of hsp70 in spinal neurons alleviates opioids-induced hyperalgesia via the suppression of endoplasmic reticulum stress in rodents
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243285/
https://www.ncbi.nlm.nih.gov/pubmed/32500072
http://dx.doi.org/10.3389/fcell.2020.00269
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