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The involvement of midbrain astrocyte in the development of morphine tolerance

机译：中脑星形胶质细胞参与吗啡耐受性的发展

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Aims Systemic administration of opiate analgesics such as morphine remains the most effective treatment for alleviating severe pain across a range of conditions including acute pain. However, chronic or repeated administration of opiate analgesics results in the development of analgesic tolerance. Glial cells such as microglia and astrocytes are known to release various inflammatory cytokines and neurotrophic factors leading to regulation of neuronal function. Recently, glial cells were reported to play important roles in the development of analgesic tolerance to morphine. Here, we focused on the involvement of midbrain glial cells, particularly astrocytes, in the development of analgesic tolerance to morphine. Main methods Mice were treated with morphine (10 mg/kg, s.c.) or vehicle once a day for 5 days. Pentoxifylline (an inhibitor of glial activation; 20 mg/kg, i.p. or 50 and 100 μg/mouse, i.c.v.) was administered 30 min before morphine treatment. Flavopiridol (a cyclin-dependent kinase inhibitor; 5 nmol/mouse, i.c.v.) was administered 10 min before and 10 h after morphine treatment. The analgesic effect of morphine was measured using the tail flick method. Key findings The development of analgesic tolerance to morphine was gradually observed during daily treatment of morphine for 5 days in mice. On days 1 and 3 after repeated morphine treatment, astrocyte marker glial fibrillary acidic protein expression levels were significantly increased, as determined by western blot analyses. These phenomena were significantly inhibited following pre-treatment with pentoxifylline or flavopiridol. Significance We demonstrated that midbrain astrocytes play an important role in the development of analgesic tolerance to morphine.
机译：目的全身性服用阿片类镇痛药（例如吗啡）仍然是减轻包括急性疼痛在内的各种病症的严重疼痛的最有效方法。然而，鸦片类镇痛药的长期或反复给药导致镇痛耐受性的发展。已知诸如小胶质细胞和星形胶质细胞的神经胶质细胞释放各种炎性细胞因子和神经营养因子，从而调节神经元功能。最近，据报道神经胶质细胞在吗啡镇痛耐受性的发展中起重要作用。在这里，我们集中于中脑神经胶质细胞，特别是星形胶质细胞对吗啡镇痛耐受性的发展。主要方法每天一次用吗啡（10 mg / kg，皮下注射）或溶媒治疗小鼠，持续5天。在吗啡治疗前30分钟给予了己酮可可碱（一种胶质细胞活化抑制剂;腹膜内注射剂量为20 mg / kg，或腹膜内注射剂量为50和100μg/小鼠，静脉注射）。在吗啡治疗前10分钟和治疗后10小时施用Flavopiridol（一种依赖细胞周期蛋白的激酶抑制剂; 5 nmol /小鼠，静脉内）。使用甩尾法测定吗啡的镇痛作用。关键发现在小鼠吗啡每日治疗5天期间，逐渐观察到对吗啡的镇痛耐受性的发展。如通过蛋白质印迹分析所确定的，在重复吗啡处理后的第1和第3天，星形胶质细胞标记神经胶质原纤维酸性蛋白的表达水平显着增加。用己酮可可碱或黄酮哌啶醇预处理后，这些现象得到了显着抑制。意义我们证明中脑星形胶质细胞在吗啡镇痛耐受性发展中起重要作用。

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