Short Term Morphine Exposure In Vitro Alters Proliferation and Differentiation of Neural Progenitor Cells and Promotes Apoptosis via Mu Receptors

Abstract

BackgroundChronic morphine treatment inhibits neural progenitor cell (NPC) progression and negatively effects hippocampal neurogenesis. However, the effect of acute opioid treatment on cell development and its influence on NPC differentiation and proliferation in vitro is unknown. We aim to investigate the effect of a single, short term exposure of morphine on the proliferation, differentiation and apoptosis of NPCs and the mechanism involved.MethodsCell cultures from 14-day mouse embryos were exposed to different concentrations of morphine and its antagonist naloxone for 24 hours and proliferation, differentiation and apoptosis were studied. Proliferating cells were labeled with bromodeoxyuridine (BrdU) and cell fate was studied with immunocytochemistry.ResultsCells treated with morphine demonstrated decreased BrdU expression with increased morphine concentrations. Analysis of double-labeled cells showed a decrease in cells co-stained for BrdU with nestin and an increase in cells co-stained with BrdU and neuron-specific class III β-tubuline (TUJ1) in a dose dependent manner. Furthermore, a significant increase in caspase-3 activity was observed in the nestin- positive cells. Addition of naloxone to morphine-treated NPCs reversed the anti-proliferative and pro-apoptotic effects of morphine.ConclusionsShort term morphine exposure induced inhibition of NPC proliferation and increased active caspase-3 expression in a dose dependent manner. Morphine induces neuronal and glial differentiation and decreases the expression of nestin- positive cells. These effects were reversed with the addition of the opioid antagonist naloxone. Our results demonstrate the effects of short term morphine administration on the proliferation and differentiation of NPCs and imply a mu-receptor mechanism in the regulation of NPC survival.

Use of Analgesics (Opioids and Nonsteroidal Anti-Inflammatory Drugs) and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort

“…Alternatively, it may be that opioids act through a different pathway which does not produce the neuropathologic findings we examined, or that current techniques are not well suited to detect the effects of opioids on the brain. Basic science studies suggest that opioid exposure may reduce the number of neuronal cells, decrease neuronal progenitor cell proliferation, and increase apoptosis,[6, 7] which could conceivably lead to cognitive impairment without an increase in neurofibrillary tangles or neuritic plaques. If opioid exposure decreases cognitive reserve, it may enhance the impact of existing neuropathologic changes, ultimately leading to dementia.…”

“…[5] On the other hand, morphine decreased neuronal cell density and increased apoptosis in a hippocampal cell culture model,[6] and in mouse fetal brain cells, short-term morphine exposure reduced cell proliferation and increased apoptosis. [6, 7] Morphine also promotes hyperphosphorylation of tau, a key component of neurofibrillary tangles. [8] Taken together, these findings suggest a need to investigate the potential association between prescription opioid use and neuropathologic changes.…”

The role of reactive oxygen species in morphine addiction of SH-SY5Y cells

“…It plays a crucial role in controlling the perception of intense pain and serving as a connecting link in the central analgesic regulatory system [35]. And it is recently reported that the MOR mechanism is involved in the increased apoptosis of neural progenitor cells and enhanced differentiation of neuronal and glial cells induced by acute administration of morphine [36]. And some studies propose that MOR proteins are in fact not downregulated but instead desensitized and uncoupled from downstream signaling pathways.…”

Neurobiological Effects of Morphine after Spinal Cord Injury

“…Moreover, the apoptotic effects of morphine are not limited to neurons. Morphine-induced cell death has also been reported for neuroprogenitor cells, 51 T cells, 52 microglia, 53 macrophages, 54 and astrocytes. 49,55 As noted above, some studies suggest that morphine induces cell death by increasing FasL expression and activating downstream targets of the Fas receptor, including Caspases-3 and 8.…”