AIM AND BACKGROUND Tramadol is a synthetic analogue of codeine, mostly prescribed for the alleviation of mild to moderate pains. It bears several side effects including emotional instability and anxiety. In this study, we focused on the alteration in expression of autophagic and apoptotic genes in PC-12 cells for our in vitro and structural and functional changes of striatum for our in vivo under chronic exposure of tramadol. METHODS For in vitro side of the study, PC12 cells were exposed to tramadol (50 µM) and expression of apoptosis and autophagy genes were determined. In parallel, rats were daily treated with tramadol at doses of 50 mg/kg for three weeks for the in vivo side. Motor coordination, EMG, histopathology and gene expression were done. RESULTS Our in vitro findings revealed that tramadol increased expression of apoptosis and autophagy genes in PC12 cells. Moreover, our in vivo results disclosed that tramadol not only provoked atrophy of rats' striatum, but also triggered microgliosis along with neuronal death in the striatum. Tramadol also reduced motor coordination and muscular activity. CONCLUSION Altogether, our data indicated that tramadol induced neurotoxicity in the PC12 cells via apoptosis and autophagy and in striatum chiefly through activation of neuroinflammatory and apoptotic responses.

中文翻译：

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曲马多暴露上调 PC12 细胞和大鼠纹状体的细胞凋亡、炎症和自噬：一种体外-体内方法

目的和背景曲马多是一种合成的可待因类似物，主要用于缓解轻度至中度疼痛。它具有多种副作用，包括情绪不稳定和焦虑。在这项研究中，我们重点关注 PC-12 细胞中自噬和凋亡基因表达的改变，以在曲马多长期暴露下进行体外纹状体的结构和功能变化以及体内纹状体的结构和功能变化。方法 在体外研究方面，将 PC12 细胞暴露于曲马多 (50 µM) 并测定细胞凋亡和自噬基因的表达。同时，大鼠每天用 50 mg/kg 剂量的曲马多治疗体内三周。完成运动协调、肌电图、组织病理学和基因表达。结果 我们的体外研究结果表明曲马多增加了 PC12 细胞中凋亡和自噬基因的表达。此外，我们的体内研究结果表明，曲马多不仅会引起大鼠纹状体的萎缩，还会引发小胶质细胞增生以及纹状体中的神经元死亡。曲马多还降低了运动协调性和肌肉活动。结论 总而言之，我们的数据表明曲马多通过细胞凋亡和自噬诱导 PC12 细胞的神经毒性，主要通过激活神经炎症和细胞凋亡反应在纹状体中诱导神经毒性。