GLT-1 overexpression attenuates bladder nociception and local/cross-organ sensitization of bladder nociception.
GLT-1 overexpression attenuates bladder nociception and local/cross-organ sensitization of bladder nociception.
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DOI：
10.1152/ajprenal.00009.2011
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发表时间：
2011-06
期刊：
影响因子：
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通讯作者：
M. Yang;K. Roman;D-F Chen;Z-G Wang;Yuan Lin;Robert L. Stephens
中科院分区：
文献类型：
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作者：
M. Yang;K. Roman;D-F Chen;Z-G Wang;Yuan Lin;Robert L. Stephens
谷氨酸能通路介导疼痛的传递。减少多巴胺能神经传递的策略可能对减轻伤害性感受具有有益作用。最近的工作表明，过度表达星形胶质细胞谷氨酸转运蛋白（GLT-1）的转基因或药理学方法产生了减少内脏伤害性反应结肠扩张。本研究的目的是确定GLT-1过表达对膀胱扩张内脏反应的影响。与溶剂处理的小鼠相比，1周头孢曲松（CTX）处理产生的谷氨酸摄取活性增加减弱了60-64%的内脏对分级膀胱扩张的反应。选择性GLT-1拮抗剂二氢红藻氨酸预处理1小时，逆转了1周CTX引起的膀胱扩张的钝性内脏反应，表明GLT-1过表达介导了CTX的镇痛作用。此外，致敏的内脏反应膀胱膨胀产生的局部膀胱刺激（丙烯醛）也减弱了1周的CTX治疗。接下来研究膀胱内脏对膨胀的反应的跨器官致敏模型，以确定GLT-1的表达增加是否可以减轻结肠对膀胱的致敏。与接受结肠内载体的动物相比，在引发内脏对分级膀胱扩张的反应之前1小时给予结肠内三硝基苯磺酸（TNBS）产生内脏反应增加75-138%。与此形成鲜明对比的是，与1周溶剂+结肠内溶剂组相比，1周CTX +结肠内TNBS治疗的动物未显示出增强的内脏反应。该研究表明，GLT-1过表达减弱了内脏对膀胱扩张的反应以及局部刺激物诱导的和跨器官致敏的内脏对膀胱扩张的反应。
Glutamatergic pathways mediate transmission of pain. Strategies to reduce glutamatergic neurotransmission may have beneficial effects to mitigate nociception. Recent work revealed that overexpression of the astrocytic glutamate transporter (GLT-1) by transgenic or pharmacologic approaches produced a diminished visceral nociceptive response to colonic distension. The purpose of this study was to determine the effect of GLT-1 overexpression on the visceromotor response to bladder distension. Increased glutamate uptake activity produced by 1-wk ceftriaxone (CTX) treatment attenuated 60-64% the visceromotor response to graded bladder distension compared with vehicle-treated mice. One-hour pretreatment with selective GLT-1 antagonist dihydrokainate reversed the blunted visceromotor response to bladder distension produced by 1-wk CTX, suggesting that GLT-1 overexpression mediated the analgesic effect of CTX. Moreover, sensitization of the visceromotor response to bladder distension produced by local bladder irritation (acrolein) was also attenuated by 1-wk CTX treatment. A model of cross-organ sensitization of bladder visceromotor response to distension was next studied to determine whether increased expression of GLT-1 can mitigate colon to bladder sensitization. Intracolonic trinitrobenzene sulfonic acid (TNBS) administered 1 h before eliciting the visceromotor response to graded bladder distension produced a 75-138% increase in visceromotor response compared with animals receiving intracolonic vehicle. In marked contrast, animals treated with 1-wk CTX + intracolonic TNBS showed no enhanced visceromotor response compared with the 1-wk vehicle + intracolonic vehicle group. The study suggests that GLT-1 overexpression attenuates the visceromotor response to bladder distension and both local irritant-induced and cross-organ-sensitized visceromotor response to bladder distension.