Naloxone induces endoplasmic reticulum stress in PC12 cells

Abstract

Naloxone is an opioid inverse agonist used in the treatment of opiate overdose, with well known pharmacology. In the present study, we determined the effects of naloxone on the unfolded protein response (UPR) in PC12 cells. Data from a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that naloxone may accelerate PC12 cell apoptosis in a dose-dependent manner. We also demonstrated that naloxone upregulated gene expression of endoplasmic reticulum (ER) chaperones, including binding immunoglobulin protein (Bip), calnexin, ER protein 29 (ERp29) and protein disulfide isomerase (PDI), and ER stress sensors, including activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1) and protein kinase-like ER kinase (PERK). In addition, naloxone also induced typical ER stress phenomena, including ART6 proteolytic cleavage, eIF2α phosphorylation and XBP1 mRNA splicing. Furthermore, naloxone upregulated gene expression of ER chaperones and ER stress sensors in in vivo experiments. To the best of our knowledge, these results are the first to indicate that naloxone induces ER stress in vitro and in vivo.

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

“…Naloxone, an opioid receptor antagonist, could upregulate gene expression of ER chaperones in PC12 cells, including BiP, calnexin, ER protein 29 and protein disulfide isomerase, and ER stress sensors, including ATF6, IRE1, and PERK. In addition, naloxone could also induce typical ER stress phenomena, including ART6 proteolytic cleavage, eIF2α phosphorylation and XBP1 mRNA splicing ( Seo et al, 2014 ). Jian et al (2014) found that the retrieval of morphine memory was associated with the dephosphorylation of eIF2α expression in basolateral amygdala.…”

Erp29 Attenuates Cigarette Smoke Extract–Induced Endoplasmic Reticulum Stress and Mitigates Tight Junction Damage in Retinal Pigment Epithelial Cells

“…[1][2][3][4][5] Endoplasmic reticulum protein 29 is inducible under cellular stress, such as thapsigargin-or tunicamycin-induced ER stress in rat hepatoma cells 2 or naloxone-induced ER stress in PC12 cells. 6 Structural studies have revealed that ERp29 contains a N-terminal thioredoxin domain that resembles protein disulfide isomerase (PDI), 7 and may play a role in protein folding. Furthermore, ERp29 has been shown to interact with and enhance the function of other ER chaperones, such as GRP94, GRP78, ERp72, and calnexin.…”

Anakinra, an interleukin-1 receptor antagonist, increases the morphine analgesic effect and decreases morphine tolerance development by modulating oxidative stress and endoplasmic reticulum stress in rats

“…In addition, ER stress activation was found in the peripheral nervous system of diabetic nephropathy rats [24]. Moreover, a few recent studies have reported that ER stress has a role in morphine analgesia and tolerance mechanisms [27,28]. It has also been found that PERK/eIF2a ER stress pathway activation increased after tolerance in the spinal cord [28].…”