Chronic oxycodone induces integrated stress response in rat brain.
Chronic oxycodone induces integrated stress response in rat brain.
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DOI：
10.1186/s12868-015-0197-8
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发表时间：
2015-09-16
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;Snelling S;Ndi J;Arnold T;Korneeva NL
羟考酮是一种阿片类药物，用于治疗多种类型的疼痛，特别是当其他阿片类药物无效时。不幸的是，与其他阿片类药物相似，羟考酮重复给药有可能导致镇痛耐受、戒断和成瘾。研究表明，慢性阿片类药物暴露，包括羟考酮，改变基因表达谱，这些变化有助于阿片类药物诱导的镇痛作用，耐受性和依赖性。然而，关于阿片类药物改变中枢神经系统的翻译机制知之甚少。考虑到阿片类药物诱导临床显著水平的缺氧，增加细胞内Ca 2+水平，并诱导一氧化氮的产生和细胞外谷氨酸的传递，我们假设阿片类药物还触发了一种称为综合应激反应（ISR）的防御机制。ISR激活的关键事件，无论触发因素如何，都是翻译起始因子2 α（eIF 2 α）的磷酸化，它调节对适应应激很重要的特定mRNA的表达和翻译激活。为了检验这一假设，我们使用了一种动物模型，其中雌性大鼠每24小时口服强饲15 mg/kg羟考酮，持续30天。我们证明羟考酮给药后，大鼠不同脑区hsp 70和BiP表达水平以及eIF 2 α磷酸化水平升高。多聚体分析表明羟考酮诱导的ATF 4和PDGFRα mRNA的翻译刺激，先前已证明其依赖于eIF 2 α激酶激活。此外，使用已知表达μ-阿片受体的乳腺癌MCF 7细胞，我们观察到用羟考酮处理24小时后ISR途径的诱导。结合体内和体外数据表明，长期阿片类药物治疗诱导中枢神经系统的综合应激反应;它调节翻译机制，有利于特定的mRNA，这可能有助于药物诱导的神经元可塑性的变化。
Oxycodone is an opioid that is prescribed to treat multiple types of pain, especially when other opioids are ineffective. Unfortunately, similar to other opioids, repetitive oxycodone administration has the potential to lead to development of analgesic tolerance, withdrawal, and addiction. Studies demonstrate that chronic opioid exposure, including oxycodone, alters gene expression profiles and that these changes contribute to opioid-induced analgesic effect, tolerance and dependence. However, very little is known about opioids altering the translational machinery of the central nervous system. Considering that opioids induce clinically significant levels of hypoxia, increase intracellular Ca2+ levels, and induce the production of nitric oxide and extracellular glutamate transmission, we hypothesize that opioids also trigger a defensive mechanism called the integrated stress response (ISR). The key event in the ISR activation, regardless of the trigger, is phosphorylation of translation initiation factor 2 alpha (eIF2α), which modulates expression and translational activation of specific mRNAs important for adaptation to stress. To test this hypothesis, we used an animal model in which female rats were orally gavaged with 15 mg/kg of oxycodone every 24 h for 30 days. We demonstrated increased levels of hsp70 and BiP expression as well as phosphorylation of eIF2α in various rat brain areas after oxycodone administration. Polysomal analysis indicated oxycodone-induced translational stimulation of ATF4 and PDGFRα mRNAs, which have previously been shown to depend on the eIF2α kinase activation. Moreover, using breast adenocarcinoma MCF7 cells, which are known to express the μ-opioid receptor, we observed induction of the ISR pathway after one 24-h treatment with oxycodone. The combined in vivo and in vitro data suggest that prolonged opioid treatment induces the integrated stress response in the central nervous system; it modulates translational machinery in favor of specific mRNA and this may contribute to the drug-induced changes in neuronal plasticity.