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.