Gabapentin increases extracellular glutamatergic level in the locus coeruleus via astroglial glutamate transporter-dependent mechanisms
Gabapentin increases extracellular glutamatergic level in the locus coeruleus via astroglial glutamate transporter-dependent mechanisms
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DOI：
10.1016/j.neuropharm.2014.01.040
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发表时间：
2014-06-01
影响因子：
4.7
通讯作者：
Hayashida, Ken-ichiro
中科院分区：
文献类型：
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作者：
Suto, Takashi;Severino, Amie L.;Hayashida, Ken-ichiro
加巴喷丁已被证明是有效的动物和人类急性术后和慢性疼痛。然而，加巴喷丁减轻疼痛的机制尚未完全解决。本研究在正常和脊神经结扎（SNL）大鼠的蓝斑（LC）中进行体内微透析，以检查加巴喷丁对细胞外谷氨酸浓度的影响及其作用机制，重点是突触前GABA-B受体，星形胶质细胞谷氨酸转运蛋白-1（GLT-1），以及与电压门控Ca 2+通道α 2 δ亚基和内源性去甲肾上腺素的相互作用。SNL大鼠LC细胞外基础浓度和组织中谷氨酸含量均高于正常大鼠。腹腔注射加巴喷丁和LC灌注增加了LC细胞外谷氨酸浓度。加巴喷丁增加的谷氨酸净含量在SNL大鼠中比正常大鼠大，尽管从基线增加的百分比没有差异。加巴喷丁相关的α 2 δ配体普瑞巴林增加了LC中的细胞外谷氨酸浓度，而另一种α 2 δ配体3-外氨基双环[2.2.1]庚烷-2-外羧酸（ABHCA）则没有。选择性阻断二氢红藻氨酸或敲低GLT-1的小干扰RNA废除加巴喷丁诱导的谷氨酸增加的LC，而GABA-B受体的CGP-35348和多巴胺β-羟化酶抗体结合皂草素消耗去甲肾上腺素的封锁没有。这些结果表明，加巴喷丁通过GLT-1依赖性机制诱导LC中星形胶质细胞释放谷氨酸，以刺激下行抑制。本研究还表明，加巴喷丁在星形胶质细胞中的这种靶点不需要与神经元中的α 2 δ亚基相互作用。(C)2014爱思唯尔有限公司版权所有。
Gabapentin has shown to be effective in animals and humans with acute postoperative and chronic pain. Yet the mechanisms by which gabapentin reduces pain have not been fully addressed. The current study performed in vivo microdialysis in the locus coeruleus (LC) in normal and spinal nerve ligated (SNL) rats to examine the effect of gabapentin on extracellular glutamate concentration and its mechanisms of action with focus on presynaptic GABA-B receptors, astroglial glutamate transporter-1 (GLT-1), and interactions with alpha 2 delta subunits of voltage-gated Ca2+ channels and endogenous noradrenaline. Basal extracellular concentration and tissue content of glutamate in the LC were greater in SNL rats than normal ones. Intravenously administered and LC-perfused gabapentin increased extracellular glutamate concentration in the LC. The net amount of glutamate increased by gabapentin is larger in SNL rats compared with normal ones, although the percentage increases from the baseline did not differ. The gabapentin-related alpha 2 delta ligand pregabalin increased extracellular glutamate concentration in the LC, whereas another alpha 2 delta ligand, 3-exo-aminobicyclo [2.2.1] heptane-2-exo-carboxylic acid (ABHCA), did not. Selective blockade by the dihydrokainic acid or knock-down of GLT-1 by the small interfering RNA abolished the gabapentin-induced glutamate increase in the LC, whereas blockade of GABA-B receptors by the CGP-35348 and depletion of noradrenalin by the dopamine-beta-hydroxylase antibody conjugated to saporin did not. These results suggest that gabapentin induces glutamate release from astrocytes in the LC via GLT-1-dependent mechanisms to stimulate descending inhibition. The present study also demonstrates that this target of gabapentin in astrocytes does not require interaction with alpha 2 delta subunits in neurons. (C) 2014 Elsevier Ltd. All rights reserved.