Down-regulation of astroglial glutamate transporter-1 in the locus coeruleus impairs pain-evoked endogenous analgesia in rats.
Down-regulation of astroglial glutamate transporter-1 in the locus coeruleus impairs pain-evoked endogenous analgesia in rats.
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DOI：
10.1016/j.neulet.2015.09.036
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发表时间：
2015-11-03
影响因子：
2.5
通讯作者：
Hayashida K
中科院分区：
文献类型：
--
作者：
Kimura M;Suto T;Eisenach JC;Hayashida K
从蓝斑（LC）下行至脊髓的去甲肾上腺素能抑制是一种重要的内源性疼痛缓解机制，其可被局部谷氨酸信号激活。在这里，我们测试是否在LC细胞外谷氨酸水平失调引起下调星形胶质细胞谷氨酸转运蛋白-1（GLT-1）损害内源性镇痛。在用GLT-1选择性或非靶向小干扰RNA（siRNA）的重复LC注射处理的大鼠中，皮下注射辣椒素用于检查伤害性刺激诱导的镇痛（NSIA），诱发LC谷氨酸和脊髓去甲肾上腺素释放，以及诱发LC神经元活性。与非靶向siRNA相比，LC注射的GLT-1 siRNA降低了LC中GLT-1的表达（P=0.02），增加了LC神经元的基础活性（P<0.01），并增加了LC谷氨酸（P<0.01）和脊髓去甲肾上腺素（P<0.01）的基础细胞外浓度，但不影响后爪的机械缩回阈值（P=0.83）。LC注射GLT-1 siRNA损害辣椒素诱发的LC谷氨酸和脊髓去甲肾上腺素释放、辣椒素诱发的LC神经元激活和NSIA。这些结果表明，星形胶质细胞GLT-1是必不可少的正常LC功能和细胞外谷氨酸通过下调GLT-1损害诱发的LC活动和NSIA，基本上采取LC“离线”。
Descending noradrenergic inhibition to the spinal cord from the locus coeruleus (LC) is an important endogenous pain-relief mechanism which can be activated by local glutamate signaling. Here we tested whether dysregulation of extracellular glutamate level in the LC induced by down-regulating astroglial glutamate transporter-1(GLT-1) impairs endogenous analgesia. In rats treated with repeated LC injections of GLT-1 selective or non-targeting small interfering RNA (siRNA), a subdermal injection of capsaicin was used to examine noxious stimulation–induced analgesia (NSIA), evoked LC glutamate and spinal noradrenaline release, and evoked LC neuronal activity. LC-injected GLT-1 siRNA reduced expression of GLT-1 in the LC (P=0.02), increased basal activity of LC neurons (P<0.01), and increased basal extracellular concentrations of LC glutamate (P<0.01) and spinal noradrenaline (P<0.01), but did not affect mechanical withdrawal thresholds in the hindpaw (P=0.83), compared to non-targeting siRNA. LC-injected GLT-1 siRNA impaired capsaicin-evoked release of LC glutamate and spinal noradrenaline, capsaicin-evoked LC neuronal activation, and NSIA. These results suggest that astroglial GLT-1 is essential to normal LC function and that increased extracellular glutamate by down-regulating GLT-1 impairs evoked LC activity and NSIA, essentially taking the LC “off-line”.