Tramadol is a centrally acting analgesic drug, used for the management of moderate to severe pain in a variety of diseases. The long-term use of tramadol can induce endocrinopathy. This study aimed to evaluate the effect of tramadol dependence on the adrenal cortex and the effect of its withdrawal. Thirty adult male rats were divided into three experimental groups: the control group, the tramadol-dependent group that received increasing therapeutic doses of tramadol orally for 1 month, and the recovery group that received tramadol in a dose and duration similar to the previous group followed by a withdrawal period for another month. Specimens from the adrenal cortex were processed for histological, immunohistochemical, enzyme assay, and quantitative real-time PCR (RT-qPCR) studies. Tramadol induced a significant increase in malondialdehyde level and a significant decrease in the levels of glutathione peroxidase and superoxide dismutase. A significant decrease in the levels of adrenocorticotrophic hormones, aldosterone, cortisol, corticosterone, and dehydroepiandrosterone sulfate was also detected. Severe histopathological changes in the adrenal cortex were demonstrated in the form of disturbed architecture, swollen cells, and shrunken cells with pyknotic nuclei. Inflammatory cellular infiltration and variable-sized homogenized areas were also detected. A significant increase in P53 and Bax immunoreaction was detected and confirmed by RT-qPCR. The ultrastructural examination showed irregular, shrunken adrenocorticocytes with dense nuclei. Dilated smooth endoplasmic reticulum, mitochondria with disrupted cristae, and numerous coalesced lipid droplets were also demonstrated. All these changes started to return to normal after the withdrawal of tramadol. Thus, it was confirmed that the long-term use of tramadol can induce severe adrenal changes with subsequent insufficiency.

中文翻译：

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曲马多促进成年雄性大鼠肾上腺皮质的氧化应激、纤维化、细胞凋亡、超微结构和生化改变，戒断后可能具有可逆性

曲马多是一种中枢作用的镇痛药，用于治疗多种疾病的中度至重度疼痛。长期使用曲马多可诱发内分泌疾病。本研究旨在评估曲马多依赖对肾上腺皮质的影响及其戒断的影响。将 30 只成年雄性大鼠分为三个实验组：对照组、口服曲马多治疗剂量增加 1 个月的曲马多依赖组和接受曲马多剂量和持续时间与前一组相似的恢复组。退出期再延长一个月。处理来自肾上腺皮质的样本用于组织学、免疫组织化学、酶测定和定量实时 PCR (RT-qPCR) 研究。曲马多诱导丙二醛水平显着增加，谷胱甘肽过氧化物酶和超氧化物歧化酶水平显着降低。还检测到促肾上腺皮质激素、醛固酮、皮质醇、皮质酮和硫酸脱氢表雄酮水平显着降低。肾上腺皮质的严重组织病理学变化表现为结构紊乱、细胞肿胀和细胞核收缩萎缩。还检测到炎症细胞浸润和大小不一的均质化区域。显着增加 还检测到硫酸脱氢表雄酮。肾上腺皮质的严重组织病理学变化表现为结构紊乱、细胞肿胀和细胞核收缩萎缩。还检测到炎症细胞浸润和大小不一的均质化区域。显着增加 还检测到硫酸脱氢表雄酮。肾上腺皮质的严重组织病理学变化表现为结构紊乱、细胞肿胀和细胞核收缩萎缩。还检测到炎症细胞浸润和大小不一的均质化区域。显着增加P53和巴克斯通过 RT-qPCR 检测和确认免疫反应。超微结构检查显示不规则、萎缩的肾上腺皮质细胞，核致密。还显示了扩张的平滑内质网、具有破坏的嵴的线粒体和许多聚结的脂滴。所有这些变化在曲马多撤出后开始恢复正常。因此，证实长期使用曲马多可引起严重的肾上腺变化并随后出现功能不全。