Chronic oxycodone induces axonal degeneration in rat brain.
Chronic oxycodone induces axonal degeneration in rat brain.
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DOI：
10.1186/s12868-018-0417-0
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发表时间：
2018-03-23
期刊：
影响因子：
2.4
通讯作者：
Korneeva NL
中科院分区：
文献类型：
--
作者：
Fan R;Schrott LM;Arnold T;Snelling S;Rao M;Graham D;Cornelius A;Korneeva NL
在过去的15年中，用于非恶性疼痛状况的慢性阿片类药物治疗显着增加。最近，阿片类镇痛药与脑结构改变（如白质脑病、轴突脱髓鞘和白色病变）之间的相关性已在长期使用处方阿片类药物的患者中得到证实。阿片类药物对中枢神经系统神经毒性作用的确切机制尚未完全了解。我们使用动物模型研究了慢性阿片类药物的作用，在该动物模型中，雌性大鼠每24小时经口灌胃15 mg/kg羟考酮，持续30天。此外，我们在乳腺癌MCF 7细胞中测试了羟考酮、吗啡和DAMGO，已知其表达μ-阿片受体。我们观察到羟考酮给药动物的白色物质发生了几种变化：轴突轨迹变形、轴突束尺寸减小、髓鞘碱性蛋白丢失和淀粉样前体蛋白β（β-APP）蓄积，表明慢性羟考酮造成了轴突损伤。此外，我们证明了促凋亡机制的激活和轴突轨道中的抗凋亡信号的抑制，这与羟考酮暴露后这些结构中的综合应激反应（ISR）的生物标志物的激活相关。使用MCF 7细胞，我们观察到阿片类药物处理后ISR和促凋亡信号的诱导。我们发现ISR抑制剂ISRIB抑制了MCF 7细胞中阿片类药物诱导的Bax和CHOP表达。总之，我们的数据表明，慢性阿片类药物给药可能会导致神经元变性激活的综合应激反应，导致诱导的神经元凋亡信号，也通过促进CNS脱髓鞘。
Chronic 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. We 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. Altogether, 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.
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影响因子：
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