Regulation of mammalian MOR-1 gene expression after chronic treatment with morphine

Abstract

Morphine is an effective analgesic that acts by binding to the μ-opioid receptor (MOR) coded in the human by the OPRM1 gene. In the present study, we investigated the regulation of μ-opioid receptor (MOR-1) mRNA levels in all-trans-retinoic acid-differentiated SH-SY5Y human neuroblastoma cells under in vitro conditions with 10 μM morphine treatment for 24 h. In addition, we measured the MOR-1 levels in recombinant Chinese hamster ovary (CHO) cells, transfected with human μ-opioid receptor gene (hMOR) with 10 μM morphine treatment for 24 h. The isolated mRNA from these cells was subjected to real-time quantitative RT-PCR analysis to determine the regulation of μ-opioid receptor gene expression. It was observed that morphine treatment did not alter MOR-1 levels in undifferentiated SH-SY5Y cells compared to undifferentiated control cells. However, the MOR-1 levels in all-trans-retinoic acid-differentiated cells were significantly higher compared to the undifferentiated cells. Morphine treatment in differentiated SH-SY5Y cells caused significant downregulation of MOR-1 expression compared to the control cells. In the morphine-treated CHO cells, the hMOR-1 mRNA levels remained the same as the untreated control. Finally, pretreatment of SH-SY5Y cells with 10 μM naloxone, the antagonist of μ-opioid receptor, for 1 h significantly blocked the downregulation of MOR-1 mRNA levels with morphine treatment. These findings suggest that regulation of MOR-1 gene expression is cell-type specific after chronic morphine treatment and provide some evidence in the understanding of morphine tolerance.

Exploring neuroadaptive cellular pathways in chronic morphine exposure: An in‐vitro analysis of cabergoline and Mdivi‐1 co‐treatment effects on the autophagy–apoptosis axis

“…The acute morphine exposure led to a significant increase in MOR expression in the SK‐N‐MC cell line, potentially enhancing sensitivity and binding or compensating for receptor internalization. However, chronic treatment resulted in a notable decline in MOR expression, aligning with prior research on human NB cells (SH‐SY5Y) 36 . This downregulation can be attributed to the activation of various MOR downstream pathways, such as Mitogen‐activated protein kinases (MAPK)/Extracellular signal‐regulated kinases (ERK), p38, and c‐Jun N‐terminal kinases (JNK), possibly through intermediaries like protein kinase A (PKA), protein kinase C (PKC), and Phosphoinositide 3‐kinases (PI3K) 37 .…”

“…However, chronic treatment resulted in a notable decline in MOR expression, aligning with prior research on human NB cells (SH-SY5Y). 36 This downregulation can be attributed to the activation of various MOR downstream pathways, such as Mitogen-activated protein kinases (MAPK)/ Extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinases (JNK), possibly through intermediaries like protein kinase A (PKA), protein kinase C (PKC), and Phosphoinositide 3-kinases (PI3K). 37 MAPK/ ERK, in particular, are deeply involved in drug-induced neuroadaptive changes, and specifically the progression of chronic morphine neuroadaptation.…”

Gene Expression Profile of Calcium/Calmodulin-Dependent Protein Kinase IIα in Rat Spinal Cord and Midbrain During Induction of Morphine Analgesic Tolerance

“…This form of long-term plasticity in the brain requires relative stable changes in gene expression, which may alter neurotransmission and the structure of target neurons (McClung & Nestler, 2008 ; Robinson & Kolb, 2004 ). Recent studies have shown that the altered gene expression due to morphine exposure is responsible for behavioral changes in drug addicts (Prenus, Luscar, Zhu, Badisa & Goodman, 2012 ; Zhu, Badisa, Palm & Goodman, 2012 ). It has been shown that expression of many receptors and second messengers are affected by chronic morphine treatment.…”

Effect of repeated intraperitoneal injections of different concentrations of oxycodone on immune function in mice

“…This indicates that morphine selectively decreased MOR mRNA levels on peripheral CD4 + T cells, a result that deviates from those of previous studies ( Brejchova et al, 2020 ). However, one in vitro study ( Prenus et al, 2012 ) also confirmed that chronic morphine treatment leads to the downregulation of MOR gene expression, and the regulation of MOR gene expression is cell-type specific. Additionally, morphine did not affect the expression of KOR and DOR on either CD4 + T cells or CD8 + T cells.…”