Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio 43210, USA.
Am J Physiol Renal Physiol. 2011 Jun;300(6):F1353-9. doi: 10.1152/ajprenal.00009.2011. Epub 2011 Mar 23.
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.
谷氨酸能通路介导疼痛的传递。减少谷氨酸能神经传递的策略可能对减轻伤害感受有有益的影响。最近的工作表明，通过转基因或药理学方法过度表达星形胶质细胞谷氨酸转运体（GLT-1）可使结肠扩张引起的内脏伤害感受反应减弱。本研究的目的是确定 GLT-1 过表达对膀胱扩张引起的内脏运动反应的影响。与载体处理的小鼠相比，1 周头孢曲松（CTX）治疗增加的谷氨酸摄取活性使分级膀胱扩张引起的内脏运动反应减弱 60-64%。1 小时前用选择性 GLT-1 拮抗剂二氢海因酸盐预处理可逆转 1 周 CTX 引起的膀胱扩张引起的内脏运动反应减弱，表明 GLT-1 过表达介导了 CTX 的镇痛作用。此外，局部膀胱刺激（丙烯醛）引起的膀胱运动反应敏感性增加也被 1 周 CTX 治疗减弱。接下来研究了膀胱运动反应对扩张的跨器官敏感化的模型，以确定 GLT-1 的表达增加是否可以减轻结肠对膀胱的敏感化。在诱发对分级膀胱扩张的内脏运动反应前 1 小时给予直肠内三硝基苯磺酸（TNBS），与接受直肠内载体的动物相比，内脏运动反应增加 75-138%。相比之下，与接受 1 周载体+直肠内载体的组相比，用 1 周 CTX+直肠内 TNBS 治疗的动物没有表现出增强的内脏运动反应。研究表明，GLT-1 过表达可减弱膀胱扩张引起的内脏运动反应，以及局部刺激诱导和跨器官敏化的膀胱扩张引起的内脏运动反应。
