Aquaporin 4 deficiency modulates morphine pharmacological actions
Aquaporin 4 deficiency modulates morphine pharmacological actions
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DOI：
10.1016/j.neulet.2008.10.065
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发表时间：
2008-12-26
影响因子：
2.5
通讯作者：
Li, Jin
中科院分区：
文献类型：
--
作者：
Wu, Ning;Lu, Xin-Qiang;Li, Jin
急性施用阿片类药物会产生镇痛作用，而长期施用则会引起耐受性和依赖性。水通道蛋白4（AQP4）在整个中枢神经系统的星形胶质细胞中表达最强，在大脑的一些病理生理过程中发挥重要作用。然而，AQP4 是否调节阿片类镇痛、耐受性和依赖性仍不清楚。在本研究中，研究了 AQP4 缺乏对吗啡镇痛、耐受性和身体依赖性的影响。 (1)在热板试验中，吗啡镇痛的ED50值在AQP4敲除雄性和雌性小鼠中分别为3.77和3.96mg/kg。低于野生型小鼠（雄性和雌性分别为 5.23 和 5.20 mg/kg）。 (2)重复吗啡治疗导致野生型小鼠对吗啡产生镇痛耐受，而AQP4敲除小鼠按相同方案治疗吗啡耐受减弱。 (3)重复给予吗啡后，纳洛酮沉淀可诱导野生型小鼠显着的禁欲跳跃，而在AQP4敲除小鼠中未观察到纳洛酮诱导的禁欲跳跃。这表明AQP4缺乏抑制吗啡身体依赖性的发展。 (4)重复吗啡给药小丑调节野生型小鼠脑谷氨酸转运蛋白I (GLT-1)的表达。然而，在 AQP4 敲除小鼠中，GLT-1 表达的小丑调节作用减弱。总而言之，这些结果表明 AQP4 缺乏会增强吗啡镇痛作用，减弱吗啡耐受性和身体依赖性。大脑 GLT1 表达下调的抑制可能介导 AQP4 缺陷对吗啡耐受和依赖的减弱。 (C) 2008 Elsevier Ireland Ltd. 保留所有权利。
Acute administration of opioids produces analgesia, while chronic administration induces tolerance and dependence. Aquaporin 4 (AQP4) is most strongly expressed in astrocytes throughout central nervous system, and plays an important role in some pathophysiological processes in brain. However, whether AQP4 modulates opioid analgesia, tolerance and dependence or not remains unknown. In the present study, the effects of AQP4 deficiency on morphine analgesia, tolerance and physical dependence were investigated. (1) In hot-plate tests, ED50 values of morphine analgesia were 3.77 and 3.96 mg/kg in male and female AQP4 knockout mice. which were lower than that in wild-type mice (5.23 and 5.20 mg/kg in males and females). (2) Repeated treatment with morphine resulted in analgesic tolerance to morphine in wild-type mice, whereas the morphine tolerance was attenuated in AQP4 knockout mice treated as the same schedule. (3) After repeated morphine administration, naloxone precipitation induced significant abstinent jumping in wild-type mice, whereas naloxone-induced abstinent jumping was not observed in AQP4 knockout mice. This suggested that AQP4 deficiency inhibited the development of morphine physical dependence. (4) Repeated morphine administration clown-regulated cerebral glutamate transporter I (GLT-1) expression in wild-type mice. However, the clown-regulation of GLT-1 expression diminished in AQP4 knockout mice. Taken together, these results demonstrated that AQP4 deficiency potentiated morphine analgesia, attenuated morphine tolerance and physical dependence. The suppression of down-regulation of cerebral GLT1 expression might mediate the attenuation of AQP4 deficiency to morphine tolerance and dependence. (C) 2008 Elsevier Ireland Ltd. All rights reserved.