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.
Highlights
Recent evidence suggests that exposure of children to anesthesia during the prenatal and neonatal periods and early childhood may have significant influences on behavior and cognition [1,2]
Morphine decreases proliferation of neural progenitor cell (NPC) and induces the apoptotic enzyme caspase-3 in a dose dependent manner
Of the cells treated with 0.13 mM morphine, 30.263.2% were BrdU- positive and 22.663.3% and 7.861.8% BrdU- positive cells were observed with 1.3 mM and 13 mM morphine, respectively (p,0.001) (Figure 1A, 1B)
Summary
Recent evidence suggests that exposure of children to anesthesia during the prenatal and neonatal periods and early childhood may have significant influences on behavior and cognition [1,2]. Significant research has focused on these two mediator pathways, surprisingly, the effects of opioids, the most common analgesic used in anesthetic practice, have not been thoroughly investigated in the developing brain. Anesthetic research has only recently delved into the possible neurotoxic effects of opioids and research has predominantly focused on chronic exposure in animal models and not on the developmental impact of short term exposure to such drugs during early brain formation [8,9]. 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
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