Endoplasmic Reticulum Stress in Spinal Cord Contributes to the Development of Morphine Tolerance.

Daiqiang Liu,Daiqiang Liu,Peng Su,Peng Su,Zheng Li,Hui Yang,Hui Yang,Qiaoqiao Xu,Qiaoqiao Xu,Wei Mei,Wei Mei,Yaqun Zhou,Yaqun Zhou,Yawen Peng,Ye Tu,Ye Tu,Zhen Wu,Zhen Wu,Feng Gao,Feng Gao,Xuebi Tian

doi:10.3389/fnmol.2018.00072

Abstract

Morphine tolerance remains an intractable problem, which hinders its prolonged use in clinical practice. Endoplasmic reticulum (ER) stress has been proved to play a fundamental role in the pathogenesis of Alzheimer’s disease, diabetes, atherosclerosis, cancer, etc. In this study, we provide the first direct evidence that ER stress may be a significant driver of morphine tolerance. Binding immunoglobulin protein (BiP), the ER stress marker, was significantly upregulated in neurons in spinal dorsal horn in rats being treated with morphine for 7 days. Additionally, chronic morphine treatment resulted in the activation of three arms of unfolded protein response (UPR): inositol-requiring enzyme 1/X-box binding protein 1 (IRE1/XBP1), protein kinase RNA-like ER kinase/eukaryotic initiation factor 2 subunit alpha (PERK/eIF2α), and activating transcription factor 6 (ATF6). More importantly, inhibiting either one of the three cascades could attenuate the development of morphine tolerance. Taken together, our results suggest that ER stress in spinal cord might contribute to the development of morphine tolerance. These findings implicate a potential clinical strategy for preventing morphine tolerance and may contribute to expanding the morphine usage in clinic.

Highlights

Morphine is a classical agonist of μ opioid receptor, which has been widely used for the treatment of acute and chronic pain due to its potent analgesic effect
On day 7, increased expressions of Binding immunoglobulin protein (BiP) mRNA (F2,11 = 20.01) and protein (F2,11 = 14.21) were detected in spinal cord of rats treated with morphine (Figures 1B–D, p < 0.01 compared to naïve and saline-treated rats), indicating that Endoplasmic reticulum (ER) stress might be induced by chronic morphine treatment
Our study demonstrated the potential role of ER stress in spinal cord in the development of morphine tolerance

Summary

INTRODUCTION

Morphine is a classical agonist of μ opioid receptor, which has been widely used for the treatment of acute and chronic pain due to its potent analgesic effect. ER stress has been reported to play a fundamental role in the pathogenesis of many diseases including neurodegenerative disorders (Doyle et al, 2011), metabolic syndrome (Piperi et al, 2012), cardiovascular diseases (Liu et al, 2016) and cancer (Wang et al, 2014) It might be involved in the induction and maintenance of neuropathic pain (Inceoglu et al, 2015; Zhang et al, 2015) and inflammatory pain (Yang E.S. et al, 2014). We sought to investigate the expressions of BiP and ER stress-related signaling pathways in spinal cord, and evaluate the effects of inhibiting spinal ER stress sensors during the development of morphine tolerance, to explore the potential role of ER stress in morphine tolerance

MATERIALS AND METHODS

RESULTS

DISCUSSION