Abstract
BackgroundChronic opioid therapy for non-malignant pain conditions has significantly increased over the last 15 years. Recently, the correlation between opioid analgesics and alternations in brain structure, such as leukoencephalopathy, axon demyelination, and white matter lesions, has been demonstrated in patients with a history of long-term use of prescription opioids. The exact mechanisms underlying the neurotoxic effect of opioids on the central nervous system are still not fully understood. We investigated the effect of chronic opioids using an animal model in which female rats were orally gavaged with 15 mg/kg of oxycodone every 24 h for 30 days. In addition we tested oxycodone, morphine and DAMGO in breast adenocarcinoma MCF7 cells, which are known to express the μ-opioid receptor.ResultsWe observed several changes in the white matter of animals treated with oxycodone: deformation of axonal tracks, reduction in size of axonal fascicles, loss of myelin basic protein and accumulation of amyloid precursor protein beta (β-APP), suggesting axonal damages by chronic oxycodone. Moreover, we demonstrated activation of pro-apoptotic machinery amid suppression of anti-apoptotic signaling in axonal tracks that correlated with activation of biomarkers of the integrated stress response (ISR) in these structures after oxycodone exposure. Using MCF7 cells, we observed induction of the ISR and pro-apoptotic signaling after opioid treatment. We showed that the ISR inhibitor, ISRIB, suppresses opioid-induced Bax and CHOP expression in MCF7 cells.ConclusionsAltogether, our data suggest that chronic opioid administration may cause neuronal degeneration by activation of the integrated stress response leading to induction of apoptotic signaling in neurons and also by promoting demyelination in CNS.
Highlights
Chronic opioid therapy for non-malignant pain conditions has significantly increased over the last 15 years
Using breast adenocarcinoma MCF7 cells, which are known to express the opioid receptors, we observed induction of the integrated stress response (ISR) and pro-apoptotic signaling after opioid treatment, which were suppressed by the ISR inhibitor, integrated stress response inhibitor (ISRIB)
Prolonged oxycodone administration affects axonal brain structures To investigate whether 30-days of 15 mg/kg oxycodone administration causes structural abnormalities in rat brain we analyzed staining for the myelin basic protein (MBP) and neurofilaments (NF) in various brain areas
Summary
Chronic opioid therapy for non-malignant pain conditions has significantly increased over the last 15 years. We investigated the effect of chronic opioids using an animal model in which female rats were orally gavaged with 15 mg/kg of oxycodone every 24 h for 30 days. Interpretation of a study involving human subjects may be complicated by the possibility that patients have a genetic predisposition or lived in a certain environment that contributed to neurodegeneration and that prolonged administration of opioids is not a primary cause of leukoencephalopathy but an exuberant of individual patient factors To investigate the effect of chronic opioid administration on brain structures, we treated rats with either water or oxycodone (15 mg/ kg) for 30 days and analysed changes in axons and induction of the pro-apoptotic markers in animal brains. We observed increased levels of proapoptotic Bax and activated caspase 3 in oxycodone rat brain areas containing white matter
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