Short-term sensitization of colon mechano receptors is associated with long-term hypersensitivity to colon distention in the mouse
Short-term sensitization of colon mechano receptors is associated with long-term hypersensitivity to colon distention in the mouse
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DOI：
10.1053/j.gastro.2007.04.042
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发表时间：
2007-07-01
期刊：
影响因子：
29.4
通讯作者：
Gebhart, G. F.
中科院分区：
文献类型：
--
作者：
Carter, R.;Jones, W., III;Gebhart, G. F.
背景与目的：利用复制肠易激综合征(肠易激综合征)主要特征的小鼠模型，研究瞬时受体电位香草酸1(TRPV1)和加感离子通道3(ASIC3)两种蛋白在行为超敏反应中的作用，并探讨机械感受器在超敏反应小鼠结肠机械感受器中的作用。方法：采用内脏伤害性行为测定方法，观察酵母多糖或生理盐水结肠内注射前后大鼠对大肠扩张的内脏运动反应(VMR)。在平行实验中，通过量化髓过氧化物酶活性、肠腔内pH值和组织学来评估结肠病理。使用体外结肠-盆腔神经制剂，在幼稚和酵母多糖处理的过敏小鼠上进行了电生理实验。结果：酵母多糖，而不是生理盐水，使对照组小鼠的VMRS显著和持续增加；酵母多糖对TRPV1和ASIC3基因敲除小鼠的VMRS无显著增加。结肠髓过氧化物酶活性和pH值不受CRD或结肠内处理的影响。从酵母多糖处理的小鼠或幼小鼠记录的盆神经机械感受器对结肠拉伸的敏感性相似。当剧烈应用时，酵母多糖敏化肌肉/粘膜。幼稚和过敏性小鼠的机械感受器。结论：酵母多糖在体外可引起机械感受器的敏化，在无炎症的情况下可引起慢性(7周)行为超敏反应。行为超敏反应部分依赖于TRPV1和ASIC3，因为这两个基因中的任何一个的缺失都减弱了酵母多糖的作用，这表明这些蛋白可能是功能性(即非炎症性)内脏超敏反应发展的重要外周介质。
Background & Aims: Using a mouse model that reproduces major features of irritable bowel syndrome (long-lasting colon hypersensitivity without inflammation), we examined the contributions of 2 proteins, transient receptor potential vanilloid 1 (TRPV1) and add-sensing ion channel 3 (ASIC3), on development of behavioral hypersensitivity and assessed the function of colon mechanoreceptors of hypersensitive mice. Methods: Visceral nociceptive behavior was measured as the visceromotor response (VMR) to colorectal distention (CRD) before and after intracolonic treatment with zymosan or saline. Colon pathology was assessed in parallel experiments by quantifying myeloperoxidase activity, intralumenal pH, and tissue histology. Electrophysiologic experiments were performed on naive and zymosan-treated hypersensitive mice using an in vitro colon-pelvic nerve preparation. Results: Zymosan, but not saline, produced significant and persistent increases in the VMRs of control mice; zymosan produced nonsignificant increases in the VMRs in TRPV1 and ASIC3 knockout mice. Colon myeloperoxidase activity and pH were unaffected by either CRD or intracolonic treatments. Pelvic nerve mechanoreceptors recorded from zymosan-treated or naive mice had similar sensitivity to stretch of the colon. When applied acutely, zymosan sensitized muscular/mucosal. mechanoreceptors in both naive and hypersensitive mice. Conclusions: Zymosan produced sensitization of colon mechanoreceptors acutely in vitro and chronic (>= 7 weeks) behavioral hypersensitivity in the absence of inflammation. The behavioral hypersensitivity was partially dependent on both TRPV1 and ASIC3 because deletions of either of these genes blunted zymosan's effect, suggesting that these proteins may be important peripheral mediators for development of functional (ie, noninflammatory) visceral hypersensitivity.