激活星型胶质细胞雌激素α受体缓解糖尿病周围神经病理性痛的机制研究

The nerve damage occurring as a consequence of glucose toxicity in diabetes leads to neuropathic pain, among other problems. This pain dramatically reduces the quality of life in afflicted patients. Although pain is regarded traditionally as neuronally mediated, recent progress shows an important role of spinal astrocytes in persistent pain sensitization. The glial glutamate transporter (GT) is abundantly expressed in astrocytes. Decreases in glutamate uptake activity and expression of spinal glutamate transporters are reported in animal models of pathological pain. However, initial GT upregulation hampered the development of neuropathic pain behaviors. We selectively deleted estrogen receptor-α (ERα) from either neurons or astrocytes using well-characterized Cre-loxP systems for conditional gene knockout in mice, and studied the effects of these conditional gene deletions on ERα ligand-mediated antiallodynic effects in a well-characterized model of ovariectomized streptozotocin-induced diabetic neuropathic pain. The behavior results demonstrate activation of ER-a in astrocytes, but not neurons, greatly relievies pain.In combination with molecular biological techniques and patch clamp recording techniques, our data show that expression and function of glutamate transporter improved by activation of ER-α in astrocytes. We hypothesized activation of estrogen receptor-alpha in astrocytes greatly reduces allodynia through up-regulation of glutamate transporter expression and function in mice caused by ovariectomized streptozotocin-induced diabetic neuropathic pain. The behavior results demonstrate activation of ER-a in astrocytes, but not neurons, greatly relievies pain.In combination with molecular biological techniques and patch clamp recording techniques, our data show that expression and function of glutamate transporter improved by activation of ER-α in astrocytes. We hypothesized activation of estrogen receptor-alpha in astrocytes greatly reduces allodynia through up-regulation of glutamate transporter expression and function in mice caused by ovariectomized streptozocin-induced diabetes. Therefore, these results argue that further efforts in understanding glutamate transporter regulated by estrogen receptor-alpha in astrocytes will yield novel opportunities in treating diabetic peripheral neuropathic pain.

糖尿病人身上常会出现糖尿病周围神经病变疼痛。这种疼痛大大降低了患者的生活质量。传统的观点认为，疼痛是由神经元介导的。目前研究表明脊髓星型细胞在病理性疼痛产生和维持过程扮演重要角色。谷氨酸运输体(GT)主要表达在星形胶质细胞上。在病理疼痛模型上，GT功能表达下降。然而，诱导GT功能表达上调可以缓解疼痛。我们分别利用Cre／loxP系统实现体内敲除神经元／星形胶质细胞雌激素α受体转基因小鼠构建性腺切除糖尿病周围神经病理性痛模型。动物行为学显示激活星形胶质细胞（而不是神经元）雌激素α受体显著缓解疼痛；膜片钳电生理记录及分子生物学实验显示激活星形胶质细胞雌激素α受体增强GT功能及表达。我们推测通过激活星形胶质细胞雌激素α受体增强GT功能及表达缓解糖尿病周围神经病变疼痛。因此对雌激素α受体、GT与糖尿病周围神经病变疼痛关系的研究, 必将为糖尿病周围神经病变疼痛机制的阐明及疼痛治疗提供新的思路。

传统的观点认为，疼痛是由神经元介导的。目前研究表明脊髓星型胶质细胞在病理性疼痛产生和维持过程扮演重要角色。谷氨酸运输体(GT)主要表达在星形胶质细胞上。在病理疼痛模型上，GT功能表达下降。然而，诱导GT功能表达上调可以缓解疼痛。我们分别利用Cre／loxP系统实现体内敲除神经元／星形胶质细胞AMPK转基因小鼠神经病理性痛模型。动物行为学显示激活星形胶质细胞（而不是神经元）AMPK显著缓解疼痛；膜片钳电生理记录及分子生物学实验显示激活星形胶质细胞AMPK增强GT功能及表达。我们推测通过激活星形胶质细胞AMPK增强GT功能及表达缓解神经病变疼痛。因此对AMPK、GT与神经病变疼痛关系的研究, 必将为神经病变疼痛机制的阐明及疼痛治疗提供新的思路。