Increased glial glutamate transporter EAAT2 expression reduces visceral nociceptive response in mice
Increased glial glutamate transporter EAAT2 expression reduces visceral nociceptive response in mice
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DOI：
10.1152/ajpgi.90556.2008
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发表时间：
2009-01-01
影响因子：
4.5
通讯作者：
Stephens, Robert L., Jr.
中科院分区：
文献类型：
--
作者：
Lin, Yuan;Tian, Guilian;Stephens, Robert L., Jr.
林Y，田G，罗曼K，汉迪C，特拉弗斯JB，林CG，RL。神经胶质谷氨酸转运体EAAT 2表达增加降低小鼠内脏伤害性反应。美国生理学胃肠和肝脏生理学杂志296：G129-G134，2009年。首次发表于2008年11月20日; doi：10.1152/ajpgi.90556.2008。内脏超敏反应是功能性肠病的主要主诉。谷氨酸受体激活介导的中枢敏化与内脏痛的病理生理学有关。神经胶质谷氨酸转运体EAAT 2是谷氨酸清除的主要介质，以终止谷氨酸介导的反应。过表达人EAAT 2的转基因小鼠（EAAT 2小鼠）表现出两倍的谷氨酸摄取增强，对腹腔内乙酸的扭体反应比非转基因同窝小鼠低39%。此外，EAAT 2转基因小鼠在对压力分级增加的反应评估中显示对结肠直肠扩张（CRD）的内脏反应（VMR）降低53-64%。证实了谷氨酸摄取增加的参与，用头孢曲松（一种EAAT 2表达激活剂）治疗1周的野生型小鼠显示VMR至CRD降低49-70%。此外，全身预处理与选择性EAAT 2转运体阻断剂二氢红藻氨酸逆转头孢曲松钝化伤害性反应CRD。然而，增强VMR CRD产生的结肠内乙醇并没有显着衰减1周头孢曲松预处理。这些数据表明，增强的谷氨酸摄取提供了对结肠扩张诱导的伤害性感受的保护作用，并代表了一种令人兴奋的新的机制方法，从而为内脏疼痛疾病提供了更好的治疗选择。
Lin Y, Tian G, Roman K, Handy C, Travers JB, Lin CG, RL. Increased glial glutamate transporter EAAT2 expression reduces visceral nociceptive response in mice. Am J Physiol Gastrointest Liver Physiol 296: G129-G134, 2009. First published November 20, 2008; doi:10.1152/ajpgi.90556.2008.-Visceral hypersensitivity is the leading complaint of functional bowel disorders. Central sensitization mediated by glutamate receptor activation is implicated in pathophysiology of visceral pain. The glial glutamate transporter EAAT2 is the principal mediator of glutamate clearance to terminate glutamate-mediated responses. Transgenic mice overexpressing human EAAT2 (EAAT2 mice), which exhibited a twofold enhanced glutamate uptake, showed 39% less writhing response to intraperitoneal acetic acid than nontransgenic littermates. Moreover, EAAT2 transgenic mice showed a 53-64% reduction in visceromotor response (VMR) to colorectal distension (CRD) in assessments of the response to graded increase in pressures. Corroborating the involvement of enhanced glutamate uptake, wild-type mice treated for 1 wk with ceftriaxone, an EAAT2 expression activator, showed a 49-70% reduction in VMR to CRD. Moreover, systemic pretreatment with the selective EAAT2 transporter blocker dihydrokainate reversed the ceftriaxone-blunted nociceptive response to CRD. However, the enhanced VMR to CRD produced by intracolonic ethanol was not significantly attenuated by 1-wk ceftriaxone pretreatment. The data suggest that enhanced glutamate uptake provides protective effects against colonic distension-induced nociception and represents an exciting new mechanistic approach leading to better therapeutic options to visceral pain disorders.