突触可塑性在内脏高敏感中的作用及机制的研究
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摘要
第一部分突触可塑性在急性束缚应激所致内脏高敏感中的作用
目的:研究突触可塑性在急性束缚应激所致内脏高敏感中的作用。
方法:20只SD大鼠随机分为对照组和急性束缚应激模型组。观察不同结直肠扩张压力下腹壁肌电图;采用透射电镜技术了解结肠突触超微结构的改变;采用RT-PCR和Western-blot检测回盲部、近端结肠和远端结肠突触素、PSD-95 mRNA和蛋白质水平的表达。
结果:(1)单位时间内曲线下面积(Area under curve,AUC)与直结肠扩张压力水平有显著正相关性(正常对照组相关系数=0.740,P=0.000;急性束缚应激组相关系数=0.777,P=0.000);在各结直肠扩张(colorectal distension, CRD)压力下,模型组AUC高于正常对照组。其中在40mmHg、60mmHg压力下,急性应激组AUC显著高于对照组(P值分别为0.003,0.049);(2)突触超微结构显示:与对照组比较,急性束缚应激组大鼠突触前终末聚集的突触囊泡显著增多(P=0.008),PSD长度延长(P=0.043),突触间隙缩小(P=0.017);(3)急性应激组大鼠近端结肠和远端结肠突触素在mRNA水平(P值分别为0.035,0.047)和蛋白质水平(P值分别为0.033,0.0450)的表达均较对照组显著增加。(4)PSD-95 mRNA在急性束缚应激组近段结肠和远端结肠较对照组显著增高(P=0.042,0.034),而急性束缚应激组PSD-95蛋白则在回盲部、近段结肠和远端结肠均较正常对照组显著升高(P=0.029,0.048,0.045)。
结论:急性束缚应激所致内脏高敏感性的形成与突触可塑性有关。
第二部分突触可塑性在一过性肠道感染大鼠模型内脏高敏感形成中的意义
目的:研究SD大鼠在感染旋毛虫后,从肠道转移至骨骼肌而形成的一过性肠道感染后内脏敏感性变化和突触可塑性在内脏高敏感中的作用。
方法:30只SD大鼠随机分为正常对照组、急性感染组和慢性感染组。3组分别在适应性喂养1周后给予旋毛虫感染。分别在2周和8周后,观察不同结直肠扩张压力下腹壁肌电活动反应内脏敏感性;HE染色后观察回盲部和结肠炎症变化;采用透射电镜观察结肠突触超微结构的改变;采用Western-blot检测回盲部、近端结肠和远端结肠突触素、PSD-95、Calbindin-D28K、GDNF蛋白质水平的表达。
结果:(1)正常对照组、急性感染组和慢性感染组中,CRD压力与AUC之间均有显著相关性,其中相关系数与P值分别为0.747, 0.000; 0.532, 0.016; 0.644, 0.002。在40mmHg和60mmHg扩张压力下,3组间AUC比较均有统计学意义(P=0.001,0.000);其中,慢性感染组AUC较正常对照组显著增加(P=0.012,0.005),急性感染组AUC较正常对照组显著降低(P=0.018,0.012)。在20mmHg, 80mmHg扩张压力下,3组间AUC比较无显著性差异(P=0.240,0.051)。(2)组织学评分结果显示,三组中回盲部和结肠炎症积分均有统计学差异(P分别为0.000, 0.000)。与正常对照组相比,慢性感染组炎症积分并无显著升高(P=0.57, 0.78)。急性感染组炎症积分显著高于正常对照组(P=0.018, 0.027)。(3)突触超微结构显示急性感染组可见突触前膜线粒体嵴消失,线粒体肿胀,或空泡化,与正常对照组相比囊泡数量显著减少,PSD长度显著低于正常对照组(P=0.045, 0.034)。慢性感染组中,囊泡性质无明显变化,但数量较正常对照组大鼠明显增加(P=0.021),突触后膜电子致密物长度延长(P=0.029)。三组之间突触间隙无明显差异。(4)在慢性感染组中,PSD-95、Synaptophysin Ab-4、Calbindin-D28和GDNF的表达较正常对照组显著增加(P<0.05)。而在急性感染期,则有PSD-95、Synaptophysin Ab-4、Calbindin-D28和GDNF表达显著下调(P<0.05),提示急性感染期神经递质释放的减少,突触后的传递效率下降以及炎症对ENS的结构和功能的破坏。
结论:一过性肠道感染SD大鼠模型内脏高敏感性的形成与ENS中突触可塑性有关。
第三部分NMDA-R1在一过性肠道感染大鼠模型内脏高敏感形成中的意义
目的:研究NMDA-R1在旋毛虫感染导致的一过性肠道感染SD大鼠后形成的内脏高敏感性中的作用。
方法: 40只大鼠随机分为正常对照组、内脏高敏感组、生理盐水组、MK-801治疗组。其中内脏高敏感组、生理盐水组和MK-801组分别给与旋毛虫感染。8周后,观察不同结直肠扩张压力下腹壁肌电活动反应内脏敏感性;采用RT-PCR和Western-blot检测远端结肠NMDA-R1 mRNA和蛋白质水平的表达。
结果: (1)正常对照组、内脏高敏感组、生理盐水组和MK-801治疗组AUC与扩张压力之间均有显著相关性(P<0.05)。各组相关系数与P值分别为正常对照组r=0.823,P=0.000;内脏高敏感组r=0.618,P=0.004;生理盐水治疗组r=0.913,P=0.000; MK-801治疗组r=0.889,P=0.000。在各扩张压力下,MK-801组与内脏高敏感组AUC之间均有显著性差异(P=0.015,0.000,0.000,0.013)。在各扩张压力下,MK-801治疗组AUC均小于正常对照组之间相比,但只在80mmHg下有统计学差异(P=0.029)。内脏高敏感组与生理盐水治疗组之间在各扩张压力下的AUC均无显著性差异(P>0.05)。(2)正常对照组、内脏高敏感组、生理盐水组和MK-801治疗组NMDA-R1mRNA的光密度定量(Integrated optical density,IOD)相对值分别为1.27±0.12,1.64±0.35,1.67±0.31,1.30±0.13。其中MK-801组较内脏高敏感组和生理盐水组显著降低(P值分别为0.047,0.032);而内脏高敏感组和生理盐水组较正常对照组显著升高(P值分别为0.034,0.023);内脏高敏感组和生理盐水组之间NMDA-R1的表达无显著性差异(P=0.844)。MK-801组与正常对照组之间差异无统计学意义(P=0.873)。(3)正常对照组、内脏高敏感组、生理盐水组和MK-801治疗组NMDA-R1蛋白IOD相对值分别为0.998±0.14,2.2312±0.45,2.104±0.22, 1.238±0.21。MK-801组较内脏高敏感组和生理盐水组显著降低(P值分别为0.025,0.046);而内脏高敏感组和生理盐水组较正常对照组显著升高(P值分别为0.007, 0.014);内脏高敏感组和生理盐水组之间NMDA-R1的表达差异无显著性(P=0.755)。MK-801组与正常对照组之间无显著性差异(P=0.558)。
结论:内脏高敏感的形成与突触后NMDA-R1的高表达密切相关。抑制ENS中NMDA-R1可调节内脏高敏感性。
PartⅠThe Role of Synaptic Plasticity on the Rats with Visceral Hypersensitivity induced by Acute Restraint Stress
Objective To investigate the role of synaptic plasticity on the formation of visceral hypersensitivity on rats induced by acute restraint stress.
Methods Twenty male Sprague-Dawley rats were randomly divided into control group and visceral hypersensitivity group. Visceral hypersensitivity was made by acute partial restraint stress (APRS) for 1h. All rats were received colorectal distension (CRD), and electromyography (EMG) was recorded at the same time. The areas under curve (AUCs) of EMG in 20s were calculated to evaluate the visceral sensitivity. The synaptic ultrstructure was observed with transmission electron microscope (TEM). RT-PCR and Western-blot were employed to detect the mRNA and protein expression of Synaptophysin and PSD-95.
Results (1) The AUCs of EMG in the two groups showed significantly positive correlation with CRD pressure. The Correlation coefficients and P value of APRS and control group were 0.740, 0.000; 0.777, 0.000 respectively. Under the pressure of 40mmHg、60mmHg, The AUCs in APRS group were significantly increased than that of control group(P=0.003,0.049). (2) The synaptic ultrastructure showed that more synaptic vesicles were accumulated in the presynaptical terminal in visceral hypersensitivity group. And post synaptic density was also increased. (3) In the proximal and distant colon, the expression of Synaptophysin mRNA and protein was significantly higher in visceral hypersensitivity group than that of control group (P=0.035,0.047;0.033,0.0450). (4) The expression of PSD-95 mRNA and protein were also significantly increased in APRS group than that of control group in the proximal and distant colon (P=0.042,0.034;0.029,0.048). In the ilececum, IOD of PSD-95 protein of APRS group was also higher than that of control (P=0.045).
Conclusion The synaptic plasticity has an important role in the formation of high visceral hypersensitivity on rats induced by acute restraint stress.
PartⅡThe Role of Synaptic Plasticity on the Rats with Visceral Hypersensitivity Induced by Transient Intestinal Infection
Objective Synaptic plasticity plays an important role in affecting the intensity of visceral reflex. It may also be involved in the development of visceral hypersensitivity. The aim of this study was to investigate the role of synaptic plasticity on visceral hypersensitivity of rats infected by Trichinella Spiralis.
Methods Thirty male Sprague-Dawley rats were randomly divided into control, acute and chronic infection group,and were investigated at 1 week after adaptive feeding, 2 week and 8 week post-infection(PI) by orally administering 1ml of PBS with 8000 Trichinella Spiralis larvae. Visceral sensitivity was evaluated by electromyography (EMG) recording during the colorectal distension. Intestinal inflammation was observed by HE staining. The synaptic ultrastructure, such as postsynaptic density (PSD) length, synaptic cleft and the number of synaptic vesicles, were examined by transmission electron microscopy (TEM). The expression of protein associated with synaptic plasticity, including postsynaptic density-95 (PSD-95), Synaptophysin, calbindin-D28K and glial cell line-derived neurotrophic factor (GDNF) were analyzed by Western-blot.
Results (1)Visceral hypersensitivity was noted in the chronic infection group, although the inflammation was nearly eliminated (P<0.05). Severe inflammation and down-regulation of visceral sensitivity were observed in acute infection group (P<0.05). (2) There were much more synaptic vesicles and longer PSD in chronic infection group than those in control group (P<0.05 respectively); However, in comparison with control rats, disappearance of mitochondria cristae in the synapses, decrease of synaptic vesicles and the length of PSD were observed in acute infection group. There was no significant difference in width of synaptic cleft among the three groups. (3) Compared with control, the expression of proteins associated synaptic plasticity was significantly up-regulated during chronic infection phase (P<0.05), and down-regulated during acute infection phase.
Conclusion Synaptic plasticity was observed in SD rats infected by Trichinella Spiralis and was associated with the visceral sensitivity, which suggested it may play an important role in the formation of visceral hypersensitivity.
PartⅢThe Role of NMDA-R1 on the Rats with Visceral Hypersensitivity Induced by Transient Intestinal Infection
Objective To investigate the role of NMDA-R1 of the postsynaptic terminal on the formation of visceral hypersensitivity on rats induced by transient intestinal infection.
Methods Forty male Sprague-Dawley rats were randomly divided into normal control, visceral hypersensitivity, saline and MK-801 group. The rats in visceral hypersensitivity, saline and MK-801 group were infected by administering 1.0ml of PBS containing 8000 T. spiralis larvae by gavage. Electromyography (EMG) was recorded for the four groups at 1 week after adaptive feeding for normal control and 8 week postinfection for visceral hypersensitivity, saline and MK-801 group. The areas under curve (AUC) of EMG in 20s were calculated to evaluate the visceral sensitivity. RT-PCR and Western-blot were respectively employed to detect mRNA and protein expression of NMDA-R1.
Results (1) There is significant difference in AUCs of normal control, visceral hypersensitivity, saline and MK-801 group(P < 0.05). The coefficient of multiple correlation and P value of the four groups were 0.823, 0.000; 0.618,0.004; 0.913, 0.000; 0.889, 0.000 respectively. Under every CRD pressure, the AUC of MK-801 group was significantly inferior to that of visceral hypersensitivity group(P=0.015,0.000,0.000, 0.013 respectively). The AUC of MK-801 group was also less than that of normal control. Only at 80mmHg, there is significant difference between normal control and MK-801 group (P=0.029). No significant difference was found between visceral hypersensitivity and saline group (P>0.05).
(2) In normal control, visceral hypersensitivity, saline and MK-801group, the IODs of NMDA-R1mRNA were 1.27±0.12,1.64±0.35,1.67±0.31,1.30±0.13 respectively. In visceral hypersensitivity and saline group, the expression of NMDA-R1 mRNA was significantly increased than normal control(P=0.034,0.023 respectively). The IOD of NMDA-R1 was significantly down-regulated in MK-801 group than visceral hypersensitivity and saline group(P=0.047,0.032). No significant difference was found between visceral hypersensitivity and saline group (P=0.873)
(3) In normal control, visceral hypersensitivity, saline and MK-801 group, the IODs of NMDA-R1 protein were 0.998±0.14,2.2312±0.45,2.104±0.22,1.238±0.21 respectively. The expression of NMDA-R1 of MK-801 group was significantly decreased than visceral hypersensitivity and saline group(P=0.025,0.046). The expression of NMDA-R1 was significantly increased in visceral hypersensitivity and saline group than that of normal control(P=0.007 , 0.014). No significant difference was found between visceral hypersensitivity and saline group (P=0.558).
Conclusion The increased expression of NMDA-R1 plays an important role in the formation of visceral hypersensitivity. To inhibit the expression of NMDA-R1 can relieve the visceral hypersensitivity in rats induced by transient intestinal infection.
目的:研究突触可塑性在急性束缚应激所致内脏高敏感中的作用。
方法:20只SD大鼠随机分为对照组和急性束缚应激模型组。观察不同结直肠扩张压力下腹壁肌电图;采用透射电镜技术了解结肠突触超微结构的改变;采用RT-PCR和Western-blot检测回盲部、近端结肠和远端结肠突触素、PSD-95 mRNA和蛋白质水平的表达。
结果:(1)单位时间内曲线下面积(Area under curve,AUC)与直结肠扩张压力水平有显著正相关性(正常对照组相关系数=0.740,P=0.000;急性束缚应激组相关系数=0.777,P=0.000);在各结直肠扩张(colorectal distension, CRD)压力下,模型组AUC高于正常对照组。其中在40mmHg、60mmHg压力下,急性应激组AUC显著高于对照组(P值分别为0.003,0.049);(2)突触超微结构显示:与对照组比较,急性束缚应激组大鼠突触前终末聚集的突触囊泡显著增多(P=0.008),PSD长度延长(P=0.043),突触间隙缩小(P=0.017);(3)急性应激组大鼠近端结肠和远端结肠突触素在mRNA水平(P值分别为0.035,0.047)和蛋白质水平(P值分别为0.033,0.0450)的表达均较对照组显著增加。(4)PSD-95 mRNA在急性束缚应激组近段结肠和远端结肠较对照组显著增高(P=0.042,0.034),而急性束缚应激组PSD-95蛋白则在回盲部、近段结肠和远端结肠均较正常对照组显著升高(P=0.029,0.048,0.045)。
结论:急性束缚应激所致内脏高敏感性的形成与突触可塑性有关。
第二部分突触可塑性在一过性肠道感染大鼠模型内脏高敏感形成中的意义
目的:研究SD大鼠在感染旋毛虫后,从肠道转移至骨骼肌而形成的一过性肠道感染后内脏敏感性变化和突触可塑性在内脏高敏感中的作用。
方法:30只SD大鼠随机分为正常对照组、急性感染组和慢性感染组。3组分别在适应性喂养1周后给予旋毛虫感染。分别在2周和8周后,观察不同结直肠扩张压力下腹壁肌电活动反应内脏敏感性;HE染色后观察回盲部和结肠炎症变化;采用透射电镜观察结肠突触超微结构的改变;采用Western-blot检测回盲部、近端结肠和远端结肠突触素、PSD-95、Calbindin-D28K、GDNF蛋白质水平的表达。
结果:(1)正常对照组、急性感染组和慢性感染组中,CRD压力与AUC之间均有显著相关性,其中相关系数与P值分别为0.747, 0.000; 0.532, 0.016; 0.644, 0.002。在40mmHg和60mmHg扩张压力下,3组间AUC比较均有统计学意义(P=0.001,0.000);其中,慢性感染组AUC较正常对照组显著增加(P=0.012,0.005),急性感染组AUC较正常对照组显著降低(P=0.018,0.012)。在20mmHg, 80mmHg扩张压力下,3组间AUC比较无显著性差异(P=0.240,0.051)。(2)组织学评分结果显示,三组中回盲部和结肠炎症积分均有统计学差异(P分别为0.000, 0.000)。与正常对照组相比,慢性感染组炎症积分并无显著升高(P=0.57, 0.78)。急性感染组炎症积分显著高于正常对照组(P=0.018, 0.027)。(3)突触超微结构显示急性感染组可见突触前膜线粒体嵴消失,线粒体肿胀,或空泡化,与正常对照组相比囊泡数量显著减少,PSD长度显著低于正常对照组(P=0.045, 0.034)。慢性感染组中,囊泡性质无明显变化,但数量较正常对照组大鼠明显增加(P=0.021),突触后膜电子致密物长度延长(P=0.029)。三组之间突触间隙无明显差异。(4)在慢性感染组中,PSD-95、Synaptophysin Ab-4、Calbindin-D28和GDNF的表达较正常对照组显著增加(P<0.05)。而在急性感染期,则有PSD-95、Synaptophysin Ab-4、Calbindin-D28和GDNF表达显著下调(P<0.05),提示急性感染期神经递质释放的减少,突触后的传递效率下降以及炎症对ENS的结构和功能的破坏。
结论:一过性肠道感染SD大鼠模型内脏高敏感性的形成与ENS中突触可塑性有关。
第三部分NMDA-R1在一过性肠道感染大鼠模型内脏高敏感形成中的意义
目的:研究NMDA-R1在旋毛虫感染导致的一过性肠道感染SD大鼠后形成的内脏高敏感性中的作用。
方法: 40只大鼠随机分为正常对照组、内脏高敏感组、生理盐水组、MK-801治疗组。其中内脏高敏感组、生理盐水组和MK-801组分别给与旋毛虫感染。8周后,观察不同结直肠扩张压力下腹壁肌电活动反应内脏敏感性;采用RT-PCR和Western-blot检测远端结肠NMDA-R1 mRNA和蛋白质水平的表达。
结果: (1)正常对照组、内脏高敏感组、生理盐水组和MK-801治疗组AUC与扩张压力之间均有显著相关性(P<0.05)。各组相关系数与P值分别为正常对照组r=0.823,P=0.000;内脏高敏感组r=0.618,P=0.004;生理盐水治疗组r=0.913,P=0.000; MK-801治疗组r=0.889,P=0.000。在各扩张压力下,MK-801组与内脏高敏感组AUC之间均有显著性差异(P=0.015,0.000,0.000,0.013)。在各扩张压力下,MK-801治疗组AUC均小于正常对照组之间相比,但只在80mmHg下有统计学差异(P=0.029)。内脏高敏感组与生理盐水治疗组之间在各扩张压力下的AUC均无显著性差异(P>0.05)。(2)正常对照组、内脏高敏感组、生理盐水组和MK-801治疗组NMDA-R1mRNA的光密度定量(Integrated optical density,IOD)相对值分别为1.27±0.12,1.64±0.35,1.67±0.31,1.30±0.13。其中MK-801组较内脏高敏感组和生理盐水组显著降低(P值分别为0.047,0.032);而内脏高敏感组和生理盐水组较正常对照组显著升高(P值分别为0.034,0.023);内脏高敏感组和生理盐水组之间NMDA-R1的表达无显著性差异(P=0.844)。MK-801组与正常对照组之间差异无统计学意义(P=0.873)。(3)正常对照组、内脏高敏感组、生理盐水组和MK-801治疗组NMDA-R1蛋白IOD相对值分别为0.998±0.14,2.2312±0.45,2.104±0.22, 1.238±0.21。MK-801组较内脏高敏感组和生理盐水组显著降低(P值分别为0.025,0.046);而内脏高敏感组和生理盐水组较正常对照组显著升高(P值分别为0.007, 0.014);内脏高敏感组和生理盐水组之间NMDA-R1的表达差异无显著性(P=0.755)。MK-801组与正常对照组之间无显著性差异(P=0.558)。
结论:内脏高敏感的形成与突触后NMDA-R1的高表达密切相关。抑制ENS中NMDA-R1可调节内脏高敏感性。
PartⅠThe Role of Synaptic Plasticity on the Rats with Visceral Hypersensitivity induced by Acute Restraint Stress
Objective To investigate the role of synaptic plasticity on the formation of visceral hypersensitivity on rats induced by acute restraint stress.
Methods Twenty male Sprague-Dawley rats were randomly divided into control group and visceral hypersensitivity group. Visceral hypersensitivity was made by acute partial restraint stress (APRS) for 1h. All rats were received colorectal distension (CRD), and electromyography (EMG) was recorded at the same time. The areas under curve (AUCs) of EMG in 20s were calculated to evaluate the visceral sensitivity. The synaptic ultrstructure was observed with transmission electron microscope (TEM). RT-PCR and Western-blot were employed to detect the mRNA and protein expression of Synaptophysin and PSD-95.
Results (1) The AUCs of EMG in the two groups showed significantly positive correlation with CRD pressure. The Correlation coefficients and P value of APRS and control group were 0.740, 0.000; 0.777, 0.000 respectively. Under the pressure of 40mmHg、60mmHg, The AUCs in APRS group were significantly increased than that of control group(P=0.003,0.049). (2) The synaptic ultrastructure showed that more synaptic vesicles were accumulated in the presynaptical terminal in visceral hypersensitivity group. And post synaptic density was also increased. (3) In the proximal and distant colon, the expression of Synaptophysin mRNA and protein was significantly higher in visceral hypersensitivity group than that of control group (P=0.035,0.047;0.033,0.0450). (4) The expression of PSD-95 mRNA and protein were also significantly increased in APRS group than that of control group in the proximal and distant colon (P=0.042,0.034;0.029,0.048). In the ilececum, IOD of PSD-95 protein of APRS group was also higher than that of control (P=0.045).
Conclusion The synaptic plasticity has an important role in the formation of high visceral hypersensitivity on rats induced by acute restraint stress.
PartⅡThe Role of Synaptic Plasticity on the Rats with Visceral Hypersensitivity Induced by Transient Intestinal Infection
Objective Synaptic plasticity plays an important role in affecting the intensity of visceral reflex. It may also be involved in the development of visceral hypersensitivity. The aim of this study was to investigate the role of synaptic plasticity on visceral hypersensitivity of rats infected by Trichinella Spiralis.
Methods Thirty male Sprague-Dawley rats were randomly divided into control, acute and chronic infection group,and were investigated at 1 week after adaptive feeding, 2 week and 8 week post-infection(PI) by orally administering 1ml of PBS with 8000 Trichinella Spiralis larvae. Visceral sensitivity was evaluated by electromyography (EMG) recording during the colorectal distension. Intestinal inflammation was observed by HE staining. The synaptic ultrastructure, such as postsynaptic density (PSD) length, synaptic cleft and the number of synaptic vesicles, were examined by transmission electron microscopy (TEM). The expression of protein associated with synaptic plasticity, including postsynaptic density-95 (PSD-95), Synaptophysin, calbindin-D28K and glial cell line-derived neurotrophic factor (GDNF) were analyzed by Western-blot.
Results (1)Visceral hypersensitivity was noted in the chronic infection group, although the inflammation was nearly eliminated (P<0.05). Severe inflammation and down-regulation of visceral sensitivity were observed in acute infection group (P<0.05). (2) There were much more synaptic vesicles and longer PSD in chronic infection group than those in control group (P<0.05 respectively); However, in comparison with control rats, disappearance of mitochondria cristae in the synapses, decrease of synaptic vesicles and the length of PSD were observed in acute infection group. There was no significant difference in width of synaptic cleft among the three groups. (3) Compared with control, the expression of proteins associated synaptic plasticity was significantly up-regulated during chronic infection phase (P<0.05), and down-regulated during acute infection phase.
Conclusion Synaptic plasticity was observed in SD rats infected by Trichinella Spiralis and was associated with the visceral sensitivity, which suggested it may play an important role in the formation of visceral hypersensitivity.
PartⅢThe Role of NMDA-R1 on the Rats with Visceral Hypersensitivity Induced by Transient Intestinal Infection
Objective To investigate the role of NMDA-R1 of the postsynaptic terminal on the formation of visceral hypersensitivity on rats induced by transient intestinal infection.
Methods Forty male Sprague-Dawley rats were randomly divided into normal control, visceral hypersensitivity, saline and MK-801 group. The rats in visceral hypersensitivity, saline and MK-801 group were infected by administering 1.0ml of PBS containing 8000 T. spiralis larvae by gavage. Electromyography (EMG) was recorded for the four groups at 1 week after adaptive feeding for normal control and 8 week postinfection for visceral hypersensitivity, saline and MK-801 group. The areas under curve (AUC) of EMG in 20s were calculated to evaluate the visceral sensitivity. RT-PCR and Western-blot were respectively employed to detect mRNA and protein expression of NMDA-R1.
Results (1) There is significant difference in AUCs of normal control, visceral hypersensitivity, saline and MK-801 group(P < 0.05). The coefficient of multiple correlation and P value of the four groups were 0.823, 0.000; 0.618,0.004; 0.913, 0.000; 0.889, 0.000 respectively. Under every CRD pressure, the AUC of MK-801 group was significantly inferior to that of visceral hypersensitivity group(P=0.015,0.000,0.000, 0.013 respectively). The AUC of MK-801 group was also less than that of normal control. Only at 80mmHg, there is significant difference between normal control and MK-801 group (P=0.029). No significant difference was found between visceral hypersensitivity and saline group (P>0.05).
(2) In normal control, visceral hypersensitivity, saline and MK-801group, the IODs of NMDA-R1mRNA were 1.27±0.12,1.64±0.35,1.67±0.31,1.30±0.13 respectively. In visceral hypersensitivity and saline group, the expression of NMDA-R1 mRNA was significantly increased than normal control(P=0.034,0.023 respectively). The IOD of NMDA-R1 was significantly down-regulated in MK-801 group than visceral hypersensitivity and saline group(P=0.047,0.032). No significant difference was found between visceral hypersensitivity and saline group (P=0.873)
(3) In normal control, visceral hypersensitivity, saline and MK-801 group, the IODs of NMDA-R1 protein were 0.998±0.14,2.2312±0.45,2.104±0.22,1.238±0.21 respectively. The expression of NMDA-R1 of MK-801 group was significantly decreased than visceral hypersensitivity and saline group(P=0.025,0.046). The expression of NMDA-R1 was significantly increased in visceral hypersensitivity and saline group than that of normal control(P=0.007 , 0.014). No significant difference was found between visceral hypersensitivity and saline group (P=0.558).
Conclusion The increased expression of NMDA-R1 plays an important role in the formation of visceral hypersensitivity. To inhibit the expression of NMDA-R1 can relieve the visceral hypersensitivity in rats induced by transient intestinal infection.
引文
1. Saito YA,Schoenfeld P,Locke GR.The epidemiology of irritable bowel syndrome in North America:a systematic review.Am J Gastroenterology 2002;97:1910-1915.
2.潘国宗,鲁素彩,柯美云,韩少梅,郭慧平,方秀才.北京地区肠易激综合征的流行病学研究:一个整群、分层、随机的调查.中华流行病学杂志2000;21(1):26-29.
3.周建宁,侯晓华,刘南植,朱尤庆,罗和生,许桦林.武汉地区消化内科就诊患者肠易激综合征的发病情况.胃肠病学2006; 11(6):356-8.
4. Drossman DA.The Functional Gastrointestinal Disorders and the Rome III Process. Gastroenterology 2006; 130:1377–1390.
5.房奇,冯海燕,杨晓云,王炳英,彭娜.井下煤矿工人肠易激综合征患病现状分析.工业卫生与职业病2006; 32(6):351-4
6.陈仕武,侯玉娟.青年士兵肠易激综合征影响因素分析华.北国防医药2007; l9 (3):39-40.
7.沈蕾,孔浩,侯晓华.不同专业硕士研究生肠易激综合征的流行病学调查.胃肠病学2007; l2 (1):14-18.
8. Monnikes H,Tebbe JJ,Hildebrandt M,Arck P,Osmanoglou E,Rose Klapp B,Wiedenmann B,Heymann-Monnikes I. The Role of stress in functional gastrointestinal disorders. Evidence for stress induced alterations in gastrointestinal motility and sensitivity.Dig Dis 2001; 19(3):201-11.
9.孙燕,柳锋霖,宋耿青,汪步海,钱伟,侯晓华.急性和慢性束缚应激对大鼠内脏敏感性和神经内分泌的影响.中华消化杂志2006; 26(1):38-41.
10. Wood JD,Grundy D.Little brain—big brain V. Neurogastroenterol Motil 1998;10 (5) :377-385.
11. Wood JD.Recent advances in understanding molecular mechanisms of primary afferent activation.Gut 2004; 53(Suppl 2):ii9-ii 12.
12.兰玲,陈玉龙.焦虑大鼠内脏敏感性增高以及行直结肠扩张后血清皮质酮的变化及意义.胃肠病学和肝病学杂志2005; l4 (1):125-128.
13. Blomhof S, Jacobsen MB, Vatn M, Malt UF.Intestinal reactivity to words with emotional content and brain information processing in irritable bowel syndrome.Dig Dis Sci 2000;45(6):1160—1165.
14.廖敏,刘能保,张敏海,李宏莲,刘少纯,刘向前,张伟.慢性捆绑应激致大鼠学习记忆受损及海马神经元突触素和突触后致密物-95表达的变化.华中科技大学学报(医学版) 2003; 32(4):367-370.
15. Williams CL, Villar RG, Peterson JM,Burks TF. Stress-induced changes in intestinal transit in the rat: a model for irritable bowel syndrome. Gastroenterology 1988; 94(3):6l-62.
16. Farr M, Mathews J, Zhu DF, Ambron RT. Inflammation Causes a Long-Term Hyperexcitability in the Nociceptive Sensory Neurons of Aplysia. Learning & Memory 1999; 6(3): 331-340.
17. Pan B, Yang DW, Han TZ. Changes of synaptic structure after long-lasting LTP induced by high and low frequency tetanus in slices of the rat visual cortex... Acta Physiologica Sinica 2005; 57(1):77—82.
18. Krauter EM, David R Linden DR, Sharkey KA, Mawe GM. Synaptic plasticity in myenteric neurons of the guinea pig distal colon: Presynaptic mechanisms of inflammation-induced synaptic facilitation. The journal of physiology.
19. Marrone DF, Leboutillier JC, Petit TL. Changes in synaptic ultrastructure during reactive synaptogenesis in the rat dentate gyrus. Brain research 2004; 1005(1-2):124-136.
20.刘劲松,杨菊,侯晓华.寒冷浸水应激对大鼠胃排空及肠肌间神经递质的影响.中华消化杂志2004; 24(8):492-493.
21. Alder J, Kanki H,Valtotta F, et al. Overexpression of Synaptophysin Enhances Neurotransmitter Secretion at Xenopus Neuromuscular Synapses The Journal of Neuroscience, 15(l): 511-519.
22. Thome J, Pesold B, Baader M, et al. Stress differentially regulates synaptophysin and synaptotagmin expression in hippocampus. Biological Psychiatry; 50(10):809-812.
23. El Husseini AE, Schnell E, Chetkovich DM, et al. PSD-95 involvement in maturation of excitatory synapses. Science 2000; 290:1364–1368.
24. Lin Y, Skeberdis VA, Francesconi A, et al. Postsynaptic density protein-95 regulates NMDA channel gating and surface expression. J Neurosci 2004; 24: 10138–10148.
25. Lavezzari G, McCallum J, Dewey CM, et al. Subunit-specific regulation of NMDA receptor endocytosis. J Neurosci 2004; 24: 6383–6391.
26. Bé?que JC, Lin DT, Kang MG, et al.Synapse-specific regulation of AMPA receptor function by PSD-95.Proc Natl Acad Sci USA. 2006,103(51):19535-40.
1.潘国宗,鲁素彩,柯美云,韩少梅,郭慧平,方秀才.北京地区肠易激综合征的流行病学研究:一个整群、分层、随机的调查.中华流行病学杂志2000;21:26-29.
2.王利华,方秀才,潘国宗.肠感染与肠易激综合征.中华内科杂志2002;41:90-93.
3. Wang LH, Fang XC, Pan GZ.Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesisi.Gut 2004; 53: 1096-1101.
4. Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: postal survey of patients. BMJ 1997; 314:77 9—782.
5. Drossman DA. What Does the Future Hold for Irritable Bowel Syndrome and the Functional Gastrointestinal Disorders? J Clin Gastroenterol 2005;(5 Suppl):S251-6.
6. Azpiroz F. Hypersensitivity in functional gastrointestinal disorders. Gut 2002;51(Suppl 1):i25-8.
7. Sharkey KA, Kroese ABA. Consequences of Intestinal In?ammation on the Enteric Nervous System: Neuronal Activation Induced by In?ammatory Mediators. The Anatomical Record 2001; 262:79–90.
8. Park JH, Rhee PL, Kim HS, et al. Mucosal mast cell counts correlate with visceral hypersensitivity in patients with diarrhea predominant irritable bowel syndrome. Journal of Gastroenterology and Hepatology 2006; 21: 71–78.
9. Swidinski A, Klilkin M, Ortner M, et al. Alteration of bacterial concentration in colonic biopsies from patients with irritable bowel syndrome (IBS). Gastroenterology 1999;116:A1.
10. David LM, Douglas GR, Eric AM, Carl DN. The Abdominal Brain and EntericNervous System. The Journal of Alternative and Complementary Medicine 1999; 5(6): 575-586.
11. Gabella G. On the plasticity of form and structure of enteric ganglia. J Auton Nerv Syst 1990; 30:S59–S66.
12. Collins SM. The immunomodulation of enteric neuromuscular function: implications for motility and in?ammatory disorders. Gastroenterology 1996;111:1683–1699.
13. Stead RH. Nerve remodelling during intestinal in?ammation. Ann NY Acad Sci 1992; 664: 443–455.
14. Giaroni C, De Ponti F, Cosentino M, Lecchini S, Frigo G. Plasticity in the enteric nervous system. Gastroenterology 1999;117:1438–1458.
15. Miller MJS, Sadowska-Krowicka H, Jeng AY, et al. Substance P levels in experimental ileitis in guinea pigs: effects of misoprostol. Am J Physiol Gastrointest Liver Physiol 1993; 265:G321–G330.
16. Palmer JM,Wong-RileyM, Sharkey KA . Functional alterations in jejunal myenteric neurons during in?ammation in nematode-infected guinea pigs. Am J Physiol Gastrointest Liver Physiol 1998; 275: G922–G935.
17. Miampamba M, Sharkey KA. c-Fos expression in the myenteric plexus, spinal cord and brainstem following injection of formalin in the rat colonic wall. J Auton Nerv Syst 1999; 77:140–151.
18. Sharkey KA, Parr EJ, Keenan CM. Immediate-early gene expression in the inferior mesenteric ganglion and colonic myenteric plexus of the guinea pig. J Neurosci 1999; 19:2755–2764.
19. Barbara G, Vallance BA, Collins SM. Persistent intestinal neuromuscular dysfunction after acute nematode infection in mice. Gastroenterology 1997; 113(4):1224–1232.
20.陈洪,段丽萍,朱元莉,等.大鼠肠道一过性线虫感染致持续性肠运动功能紊乱.北京大学学报:医学版2004; 36(2):198-201.
21. Al Chaer ED, Kawasaki M, Pasricha PJ. A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology 2000; 119:1276-1285.
22. Bercík P, Wang L, VerdúEF, et al. Visceral hyperalgesia and intestinal dysmotility in a mouse model of postinfective gut dysfunction. Gastroenterology 2004; 127(1):179-87.
23.董文珠,李兆申,邹多武,等.肠易激综合征患者肠黏膜肥大细胞与P物质的相关性.中华内科杂志2003; 42(9): 611-4.
24. Gwee KA, Collins SM, Read NW, , et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut. 2003; 52(4):523-6.
25. Zhou Q, Caudle RM, Price DD, et al. Selective up-regulation of NMDA-NR1 receptor expression in myenteric plexus after TNBS induced colitis in rats. Mol Pain. 2006; 17(2): 3.
26. Galligan JJ, LePard KJ, Schneider DA, et al. Multiple mechanisms of fast excitatory synaptic transmission in the enteric nervous system. Journal of the Autonomic Nervous System. 2000; 81(1-3):97-103.
27. Sharkey KA, Kroese AB. Consequences of intestinal inflammation on the enteric nervous system: neuronal activation induced by inflammatory mediators. Anat Rec. 2001; 262(1):79-90.
28. Magari?os AM, Verdugo JM, McEwen BS. Chronic stress alters synaptic terminal structure in hippocampus. Proc Natl Acad Sci U S A. 1997; 94(25):14002-8.
29.杨小军,官阳,钱伟,等.突触可塑性在急性束缚应激所致内脏高敏感中的作用.中华消化杂志2007; 27(10):670-674.
30. Calakos N, Scheller RH. Vesicle-associated membrane protein and Synaptophysin are associated on the synaptic vesicle. J. Biol. Chem 1994; 269(40):24534-24537.
31. Edelmann L, Hanson PI, Chapman ER, et al. Synaptobrevin binding to Synaptophysin: a potential mechanism for controlling the exocytotic fusion machine. EMBO J 1995; 14(2):224–231.
32. Dzienis-Koronkiewicz E, Debek W, Chyczewski L. Use of Synaptophysin immunohistochemistry in intestinal motility disorders. Eur J Pediatr Surg 2005; 15(6):392-8.
33. Wiedenmann B, Riedel C, John M,et al. Qualitative and quantitative analysis of synapses in Hirschsprung's disease. Pediatr Surg Int 1998; 13(7):468-73.
34.王晓,尹朝礼.肠动力疾病结肠壁内NOS, AchE及SP阳性神经的分布.中华消化杂志997; 17(4):195-198.
35. Nakao M, Suita S, Taguchi T, et al. Fourteen-year experience of acetylcholinesterase staining for rectal mucosal biopsy in neonatal Hirschsprung's disease. Journal ofPediatric Surgery. 2001; 36(9):1357-63.
36. Collins SM. The immunomodulation of enteric neuromuscular function: implications for motility and inflammatory disorders. Gastroenterology 1996; 111(6):1683-99.
37. Kennedy MB. Signal-Processing Machines at the Postsynaptic Density. Science 2000; 290(5492):750-4.
38. Lin Y, Skeberdis VA, Francesconi A, Bennett MVL, Zukin RS. Postsynaptic density protein-95 regulates NMDA channel gating and surface expression. J Neurosci 2004; 24: 10138–10148.
39. Lavezzari G, McCallum J, Dewey CM, Roche KW. Subunit-specific regulation of NMDA receptor endocytosis. J Neurosci 2004; 24: 6383–6391.
40. Béique JC, Lin DT, Kang MG, Aizawa H, Takamiya K, Huganir RL. Synapse-specific regulation of AMPA receptor function by PSD-95.Proc Natl Acad Sci USA 2006; 103(51):19535-40.
41. Messenger JP, Bornstein JC, Furness JB. Electrophysiological and morphological classification of myenteric neurons in the proximal colon of the guinea-pig. Neuroscience 1994; 60(1):227-44.
42. Chard PS, Jordán J, Marcuccilli CJ, Miller RJ, Leiden JM, Roos RP. Regulation of excitatory transmission at hippocampal synapses by calbindin D28k.Proc Natl Acad Sci USA 1995; 92(11):5144-8.
43. Ribchester RR, Thomson D, Haddow LJ, Ushkaryov YA. Enhancement of spontaneous transmitter release at neonatal mouse neuromuscular junctions by the glial cell line-derived neurotrophic factor (GDNF). J Physiol 1998; 512 (Pt 3):635-41.
44. Focke PJ, Swetlik AR, Schilz JL, Epstein ML. GDNF and insulin cooperate to enhance the proliferation and differentiation of enteric crest-derived cells. J Neurobiol 2003; 55: 151-64.
45. Liou JC, Yang RS, Fu WM. Regulation of quantal secretion by neurotrophic factors at developing motoneurons in Xenopus cell cultures. J Physiol 1997; 503: 129-39.
46. Ribchester RR, Thomson D, Haddow LJ, Ushkaryov YA. Enhancement of spontaneous transmitter release at neonatal mouse neuromuscular junctions by the glial cell line-derived neurotrophic factor (GDNF). J Physiol 1998; 512(Pt 3): 635-641.
47. Wang LJ, Lu YY, Muramatsu S, Ikeguchi K,et al. Neuroprotective effects of glial cellline-derived neurotrophic factor mediated by an adeno-associated virus vector in a transgenic animal model of amyotrophic lateral sclerosis. J Neurosci 2002; 22: 6920-8.
48. von Boyen GB, Reinshagen M, Steinkamp M, Adler G, Kirsch J. Enteric nervous plasticity and development: dependence on neurotrophic factors. J Gastroenterol 2002; 37: 583-8.
1. Verne GN, Robinson ME, Price DD. Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome. Pain 2001; 93(1):7-14.
2. Bouin M, Plourde V, Boivin M, Riberdy M, Lupien F, Laganière M, Verrier P, Poitras P. Rectal distention testing in patients with irritable bowel syndrome: sensitivity,specificity, and predictive values of pain sensory thresholds. Gastroenterology 2002; 122(7):1771-7.
3. Sarkar S, Aziz Q, Woolf CJ, Hobson AR, Thompson DG. Contribution of central sensitization to the development of non-cardiac chest pain. Lancet. 2000 Sep 30; 356(9236):1127-8.
4. Lin C, Al-Chaer ED. Long-term sensitization of primary afferents in adult rats exposed to neonatal colon pain. Brain Res. 2003 May 2; 971(1):73-82.
5. Chan CL, Facer P, Davis JB, Smith GD, Egerton J, Bountra C, Williams NS, Anand P. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet. 2003 Feb 1;361(9355):385-91
6. Schicho R, Donnerer J, Liebmann I, Lippe IT. Nociceptive transmitter release in the dorsal spinal cord by capsaicin-sensitive fibers after noxious gastric stimulation. Brain Res. 2005 Mar 28;1039(1-2):108-15
7. Bueno L, Fioramonti J. Visceral perception: inflammatory and non-inflammatory mediators. Gut. 2002 Jul; 51 Suppl 1:i19-23.
8. Riva MA, Tascedda F, Lovati E, Racagni G. Regulation of NMDA receptor subunit messenger RNA levels in the rat brain following acute and chronic exposure to antipsychotic drugs. Brain Res Mol Brain Res. 1997; 50(1-2):136-42.
9. Little Z, Grover LM, Teyler TJ. Metabotropic glutamate receptor antagonist, (R,S)-alpha-methyl-4-carboxyphenyglycine, blocks two distinct forms of long-term potentiation in area CA1 of rat hippocampus. Neurosci Lett. 1995 Dec 1; 201(1):73-6.
10. Johnston D, Williams S, Jaffe D, Gray R. NMDA-Receptor-Independent Long-Term Potentiation . Annual Review of Physiology1992; 54: 489-505.
11. Sun YN, Luo JY, Shang P, Lan L, Rao ZR. Effects of N-methyl-D-aspartate receptor in visceral, hypersensitivity in rats with colonic inflammation. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005; 30(5):504-9.
12. Cull-Candy SG, Leszkiewicz DN. Role of distinct NMDA receptor subtypes at central synapses. Sci STKE. 2004;(255):re16
13. McRoberts JA, Coutinho SV, Marvizón JC, et al. Role of peripheral N-methyl-D-aspartate (NMDA) receptors in visceral nociception in rats. Gastroenterology 2001; 120(7):1737-48.
14. Saito YA, Schoenfeld P, Locke GR 3rd. The epidemiology of irritable bowel syndrome in North America: a systematic review. Am J Gastroenterol. 2002; 97(8):1910-5.
15. Barbara G, Vallance BA, Collins SM. Persistent intestinal neuromuscular dysfunction after acute nematode infection in mice. Gastroenterology, 1997, 113(4):1224–1232.
16.陈洪,段丽萍,朱元莉,等.大鼠肠道一过性线虫感染致持续性肠运动功能紊乱.北京大学学报:医学版, 2004, 36(2):198-201.
17. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut. 1973; 14(2): 125–132.
18. Brenner GJ, Ji RR, Shaffer S, Woolf CJ. Peripheral noxious stimulation induces phosphorylation of the NMDA receptor NR1 subunit at the PKC-dependent site, serine-896, in spinal cord dorsal horn neurons. Eur J Neurosci. 2004; 20(2):375-84.
19. Cull-Candy SG, Leszkiewicz DN. Role of distinct NMDA receptor subtypes at central synapses. Sci STKE. 2004 Oct 19;2004(255):re16
20. Berman SM, Naliboff BD, Chang L, Fitzgerald L, Antolin T, Camplone A, Mayer EA. Enhanced preattentive central nervous system reactivity in irritable bowel syndrome. Am J Gastroenterol. 2002 Nov;97(11):2791-7
21. Yuan YZ, Tao RJ, Xu B, Sun J, Chen KM, Miao F, Zhang ZW, Xu JY. Functional brain imaging in irritable bowel syndrome with rectal balloon-distention by using fMRI. World J Gastroenterol. 2003;9(6):1356-60
22. Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology. 2000 May; 118(5):842-8.
23. Kirchgessner AL, Gershon MD. Identification of vagal efferent fibers and putative target neurons in the enteric nervous system of the rat. The Journal of Comparative Neurology 1989; 285(1): 38-53.
24. Sjovall H. Sympathetic control of jejunal ?uid and electrolyte transport. Acta Physiol Scand 1984 ;( suppl 535):1–62.
25. Sjovall H, Redfors S, Jodal M, et al. On the mode of action of the sympathetic fibres on intestinal ?uid transport: Evidence for the existence of a glucose stimulated secretory nervous pathway in the intestinal wall. Acta Physiol Scand 1983;119:39–48.
26. Jansson G, Martinson J. Studies on the ganglionic site of action of sympathetic out?owto the stomach. Acta Physiol Scand 1966; 68:184–92.
27.杨小军,官阳,钱伟,沈蕾,侯晓华.突触可塑性在急性束缚应激所致内脏高敏感中的作用.中华消化杂志. 2007,27(10):670-674.
28. Robertson BS, Satterfield BE, Said SI, Dey RD. N-Methyl-d-aspartate receptors are expressed by intrinsic neurons of rat larynx and esophagus Neuroscience Letters 1998; 244(4):77-80.
29. Milusheva EA, Kuneva VI, Itzev DE, Kortezova NI, Sperlagh B, Mizhorkova ZN. Glutamate stimulation of acetylcholine release from myenteric plexus is mediated by endogenous nitric oxide. Brain Res Bull. 2005; 66(3):229-34.
30. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, Wang YT, Salter MW, Tymianski M. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science. 2002; 298(5594):846-50.
31. Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron.1999; 23(3):583-92.
32. Sattler R, Xiong Z, Lu WY, Hafner M, MacDonald JF, Tymianski M. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science. 1999; 284(5421):1845-8.
33. Song XJ, Zhao ZQ. Involvement of NMDA and non-NMDA receptors in transmission of spinal visceral nociception in cat. Zhongguo Yao Li Xue Bao. 1999; 20(4):308-12.
34. Zhou Q, Caudle RM, Price DD, Del Valle-Pinero AY, Verne GN. Selective up-regulation of NMDA-NR1 receptor expression in myenteric plexus after TNBS induced colitis in rats. Mol Pain. 2006;2:3
35. Wilson MA, Kinsman SL, Johnston MV. Expression of NMDA receptor subunit mRNA after MK-801 treatment in neonatal rats. Brain Res Dev Brain Res. 1998; 109(2):211-20.
36. Gaudreau GA, Plourde V. Involvement of N-methyl-d-aspartate (NMDA) receptors in a rat model of visceral hypersensitivity. Behav Brain Res. 2004 Apr 2; 150(1-2):185-9.
37. Lindén AM, V?s?inen J, Wong G, Castrén E. NMDA receptor 2C subunit is selectively decreased by MK-801 in the entorhinal cortex. Eur J Pharmacol. 1997; 319(1):R1-2.
38. Fernández de Sevilla D, Fuenzalida M, Porto Pazos AB, Bu?o W. Selective shunting ofthe NMDA EPSP component by the slow afterhyperpolarization in rat CA1 pyramidal neurons. J Neurophysiol. 2007 May; 97(5):3242-55.
39. Evidence for a role for GABA (A) and NMDA receptors in ethanol inhibition of long-term potentiation.
40. Muller D, Nikonenko I, Jourdain P, Alberi S. LTP, memory and structural plasticity. Curr Mol Med. 2002;2(7):605-11.
41. Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ. Genetic enhancement of learning and memory in mice. Nature. 1999; 401(6748):63-9.
42. Morgan SL, Teyler TJ. VDCCs and NMDARs underlie two forms of LTP in CA1 hippocampus in vivo. J Neurophysiol. 1999 Aug; 82(2):736-40.
43. Greene R. Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia. Hippocampus. 2001; 11(5):569-77.
44. Lomax AE, Fernández E, Sharkey KA. Plasticity of the enteric nervous system during intestinal inflammation. Neurogastroenterol Motil. 2005; 17(1):4-15.
45. Wood JD, Kirchgessner A. Slow excitatory metabotropic signal transmission in the enteric nervous system. Neurogastroenterol Motil. 2004; 16 Suppl 1:71-80.
46. Ferry B, Magistretti PJ, Pralong E. Noradrenaline Modulates GIutamate-mediated Neurotransmission in the Rat Basolateral Amygdala In Vitro. European Journal of Neuroscience. 1997; 9(7): 1356-1364.
47. Aramakis VB, Bandrowski AE, Ashe JH. Muscarinic reduction of GABAergic synaptic potentials results in disinhibition of the AMPA/kainate-mediated EPSP in auditory cortex. Brain Res. 1997 May 30; 758(1-2):107-17.
1 Kaila M, Isolauri E, Saxelin M, et al. Viable versus inactivated lactobacillus strain GG in acute rotavirus diarrhoea. Arch Dis Child. 1995, 72:51–3.
2 Shornikova A-V, Isolauri E, Burnakova L, et al. A trial in the Karelian Republic of oral rehydration and Lactobacillus GG for treatment of acute diarrhoea. Acta Paediatr. 1997,86:460–5.
3 Majamaa M, Isolauri E, Saxelin M, et al. Lactic acid bacteria in the treatment of acute rotavirus gastroenteritis. J Pediatr Gastroenterol Nutr, 1995, 20:333–8.
4 DuPont HL, Ericsson CD. Prevention and treatment of traveler's diarrhea. N Engl J Med. 1993, 328:1821–7.
5 Oksanen PJ, Salminen S, Saxelin M, et al. Prevention of travellers' diarrhoea by Lactobacillus GG. Ann Med, 1990,22:53–6.
6 Bamias G, Nyce MR, De La Rue SA, et al. New concepts in the pathophysiology of infl ammatory bowel disease. Ann Intern Med, 2005, 143: 895-904.
7 Osman N, Adawi D, Molin G, Bifidobacterium infantis strains with and without a combination of oligofructose and inulin (OFI) attenuate inflammation in DSS-induced colitis in rats. BMC Gastroenterol, 2006, 6(1):31.
8 McCarthy J, O’Mahony L, Dunne C, An open trial of a novel probiotic as an alternative to steroids in mild/moderately active Crohn’s disease. Gut, 2001,49: A2447
9 Ishikawa H, Akedo I, Umesaki Y, Randomized controlled trial of the effect of bifidobacterial fermented milk on ulcerative colitis. J Am Coll Nutr, 2003, 22:56-63.
10 Kato K, Mizuno S, Umesaki Y, et al. Randomized placebo-controlled trial assessing the effect of bifidobacteria-fermented milk on active ulcerative colitis. Aliment Pharmacol Ther, 2004, 20: 1133-1141.
11 Zocco MA, dal Verme LZ, Cremonini F, et al. Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther, 2006, 23: 1567-1574.
12 Marteau P, Lemann M, Seksik P, Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn’s disease: a randomised, double blind, placebo controlled GETAID trial. Gut, 2006, 55: 842-847.
13 Mcfarland LV. Epidemiology. risk factor and treatment for antibiotic associated diarrhea. Dig dis sci, 1998, 16:292-307.
14 Levy J. The effects of antibiotic use on gastrointestinal function. Am J Gastroenterol. 2000, 95(1 Suppl):S8-10.
15 Arvola T, Laiho K, Torkkeli S, et al. Prophylactic Lactobacillus GG Reduces Antibiotic-Associated Diarrhea in Children With Respiratory Infections: A Randomized Study. Pediatrics, 1999, 104(5):64.
16 Can M, Besirbellioglu BA, Avci IY, Prophylactic Saccharomyces boulardii in theprevention of antibiotic-associated diarrhea: a prospective study. Med Sci Monit, 2006, 12(4):PI19-22.
17 Barbara G, Stanghellini V, Brandi G, Interactions between commensal bacteria and gut sensorimotor function in health and disease. Am J Gastroenterol, 2005, 100(11):2560-8.
18 Whorwell PJ, Altringer L, Morel J. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006, 101(7):1581-90.
19 Kim HJ, Vazquez Roque MI, Camilleri M, et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil.2005,(5):687-96.
20 Madsen K, Cornish A, Soper P, McKaigney C, Jijon H, Yachimec C, Doyle J, Jewell L, De Simone C. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 2001; 121: 580-591.
21 Llopis M, Antoln M, Guarner F, et al. Mucosal colonisation with Lactobacillus casei mitigates barrier injury induced by exposure to trinitronbenzene sulphonic acid. Gut, 2005,54:955–959.
22 Yan F, Polk DB. Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells. J Biol Chem. 2002, 277: 50959-50965.
23 Resta-Lenert S, Barrett KE. Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut, 2003, 52: 988-997.
24 Mack DR, Ahrne S, Hyde L, et al. Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro. Gut, 2003, 52: 827-833.
25 Li LJ, Wu ZW, Xiao DS, Changes of gut flora and endotoxin in rats with D-galactosamine-induced acute liver failure. World J Gastroenterol, 2004; 10(14): 2087-2090.
26 García-Lafuente A, Antolín M, Guarner F, et al. Modulation of colonic barrier function by the composition of the commensal flora in the rat. Gut,2001,48:503–507.
27 Perdigon G, Maldonado Galdeano C, Valdez JC, et al. Interaction of lactic acid bacteria with the gut immune system. Eur J Clin Nutr, 2002, 56(Suppl 4):S21-6.
2.潘国宗,鲁素彩,柯美云,韩少梅,郭慧平,方秀才.北京地区肠易激综合征的流行病学研究:一个整群、分层、随机的调查.中华流行病学杂志2000;21(1):26-29.
3.周建宁,侯晓华,刘南植,朱尤庆,罗和生,许桦林.武汉地区消化内科就诊患者肠易激综合征的发病情况.胃肠病学2006; 11(6):356-8.
4. Drossman DA.The Functional Gastrointestinal Disorders and the Rome III Process. Gastroenterology 2006; 130:1377–1390.
5.房奇,冯海燕,杨晓云,王炳英,彭娜.井下煤矿工人肠易激综合征患病现状分析.工业卫生与职业病2006; 32(6):351-4
6.陈仕武,侯玉娟.青年士兵肠易激综合征影响因素分析华.北国防医药2007; l9 (3):39-40.
7.沈蕾,孔浩,侯晓华.不同专业硕士研究生肠易激综合征的流行病学调查.胃肠病学2007; l2 (1):14-18.
8. Monnikes H,Tebbe JJ,Hildebrandt M,Arck P,Osmanoglou E,Rose Klapp B,Wiedenmann B,Heymann-Monnikes I. The Role of stress in functional gastrointestinal disorders. Evidence for stress induced alterations in gastrointestinal motility and sensitivity.Dig Dis 2001; 19(3):201-11.
9.孙燕,柳锋霖,宋耿青,汪步海,钱伟,侯晓华.急性和慢性束缚应激对大鼠内脏敏感性和神经内分泌的影响.中华消化杂志2006; 26(1):38-41.
10. Wood JD,Grundy D.Little brain—big brain V. Neurogastroenterol Motil 1998;10 (5) :377-385.
11. Wood JD.Recent advances in understanding molecular mechanisms of primary afferent activation.Gut 2004; 53(Suppl 2):ii9-ii 12.
12.兰玲,陈玉龙.焦虑大鼠内脏敏感性增高以及行直结肠扩张后血清皮质酮的变化及意义.胃肠病学和肝病学杂志2005; l4 (1):125-128.
13. Blomhof S, Jacobsen MB, Vatn M, Malt UF.Intestinal reactivity to words with emotional content and brain information processing in irritable bowel syndrome.Dig Dis Sci 2000;45(6):1160—1165.
14.廖敏,刘能保,张敏海,李宏莲,刘少纯,刘向前,张伟.慢性捆绑应激致大鼠学习记忆受损及海马神经元突触素和突触后致密物-95表达的变化.华中科技大学学报(医学版) 2003; 32(4):367-370.
15. Williams CL, Villar RG, Peterson JM,Burks TF. Stress-induced changes in intestinal transit in the rat: a model for irritable bowel syndrome. Gastroenterology 1988; 94(3):6l-62.
16. Farr M, Mathews J, Zhu DF, Ambron RT. Inflammation Causes a Long-Term Hyperexcitability in the Nociceptive Sensory Neurons of Aplysia. Learning & Memory 1999; 6(3): 331-340.
17. Pan B, Yang DW, Han TZ. Changes of synaptic structure after long-lasting LTP induced by high and low frequency tetanus in slices of the rat visual cortex... Acta Physiologica Sinica 2005; 57(1):77—82.
18. Krauter EM, David R Linden DR, Sharkey KA, Mawe GM. Synaptic plasticity in myenteric neurons of the guinea pig distal colon: Presynaptic mechanisms of inflammation-induced synaptic facilitation. The journal of physiology.
19. Marrone DF, Leboutillier JC, Petit TL. Changes in synaptic ultrastructure during reactive synaptogenesis in the rat dentate gyrus. Brain research 2004; 1005(1-2):124-136.
20.刘劲松,杨菊,侯晓华.寒冷浸水应激对大鼠胃排空及肠肌间神经递质的影响.中华消化杂志2004; 24(8):492-493.
21. Alder J, Kanki H,Valtotta F, et al. Overexpression of Synaptophysin Enhances Neurotransmitter Secretion at Xenopus Neuromuscular Synapses The Journal of Neuroscience, 15(l): 511-519.
22. Thome J, Pesold B, Baader M, et al. Stress differentially regulates synaptophysin and synaptotagmin expression in hippocampus. Biological Psychiatry; 50(10):809-812.
23. El Husseini AE, Schnell E, Chetkovich DM, et al. PSD-95 involvement in maturation of excitatory synapses. Science 2000; 290:1364–1368.
24. Lin Y, Skeberdis VA, Francesconi A, et al. Postsynaptic density protein-95 regulates NMDA channel gating and surface expression. J Neurosci 2004; 24: 10138–10148.
25. Lavezzari G, McCallum J, Dewey CM, et al. Subunit-specific regulation of NMDA receptor endocytosis. J Neurosci 2004; 24: 6383–6391.
26. Bé?que JC, Lin DT, Kang MG, et al.Synapse-specific regulation of AMPA receptor function by PSD-95.Proc Natl Acad Sci USA. 2006,103(51):19535-40.
1.潘国宗,鲁素彩,柯美云,韩少梅,郭慧平,方秀才.北京地区肠易激综合征的流行病学研究:一个整群、分层、随机的调查.中华流行病学杂志2000;21:26-29.
2.王利华,方秀才,潘国宗.肠感染与肠易激综合征.中华内科杂志2002;41:90-93.
3. Wang LH, Fang XC, Pan GZ.Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesisi.Gut 2004; 53: 1096-1101.
4. Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: postal survey of patients. BMJ 1997; 314:77 9—782.
5. Drossman DA. What Does the Future Hold for Irritable Bowel Syndrome and the Functional Gastrointestinal Disorders? J Clin Gastroenterol 2005;(5 Suppl):S251-6.
6. Azpiroz F. Hypersensitivity in functional gastrointestinal disorders. Gut 2002;51(Suppl 1):i25-8.
7. Sharkey KA, Kroese ABA. Consequences of Intestinal In?ammation on the Enteric Nervous System: Neuronal Activation Induced by In?ammatory Mediators. The Anatomical Record 2001; 262:79–90.
8. Park JH, Rhee PL, Kim HS, et al. Mucosal mast cell counts correlate with visceral hypersensitivity in patients with diarrhea predominant irritable bowel syndrome. Journal of Gastroenterology and Hepatology 2006; 21: 71–78.
9. Swidinski A, Klilkin M, Ortner M, et al. Alteration of bacterial concentration in colonic biopsies from patients with irritable bowel syndrome (IBS). Gastroenterology 1999;116:A1.
10. David LM, Douglas GR, Eric AM, Carl DN. The Abdominal Brain and EntericNervous System. The Journal of Alternative and Complementary Medicine 1999; 5(6): 575-586.
11. Gabella G. On the plasticity of form and structure of enteric ganglia. J Auton Nerv Syst 1990; 30:S59–S66.
12. Collins SM. The immunomodulation of enteric neuromuscular function: implications for motility and in?ammatory disorders. Gastroenterology 1996;111:1683–1699.
13. Stead RH. Nerve remodelling during intestinal in?ammation. Ann NY Acad Sci 1992; 664: 443–455.
14. Giaroni C, De Ponti F, Cosentino M, Lecchini S, Frigo G. Plasticity in the enteric nervous system. Gastroenterology 1999;117:1438–1458.
15. Miller MJS, Sadowska-Krowicka H, Jeng AY, et al. Substance P levels in experimental ileitis in guinea pigs: effects of misoprostol. Am J Physiol Gastrointest Liver Physiol 1993; 265:G321–G330.
16. Palmer JM,Wong-RileyM, Sharkey KA . Functional alterations in jejunal myenteric neurons during in?ammation in nematode-infected guinea pigs. Am J Physiol Gastrointest Liver Physiol 1998; 275: G922–G935.
17. Miampamba M, Sharkey KA. c-Fos expression in the myenteric plexus, spinal cord and brainstem following injection of formalin in the rat colonic wall. J Auton Nerv Syst 1999; 77:140–151.
18. Sharkey KA, Parr EJ, Keenan CM. Immediate-early gene expression in the inferior mesenteric ganglion and colonic myenteric plexus of the guinea pig. J Neurosci 1999; 19:2755–2764.
19. Barbara G, Vallance BA, Collins SM. Persistent intestinal neuromuscular dysfunction after acute nematode infection in mice. Gastroenterology 1997; 113(4):1224–1232.
20.陈洪,段丽萍,朱元莉,等.大鼠肠道一过性线虫感染致持续性肠运动功能紊乱.北京大学学报:医学版2004; 36(2):198-201.
21. Al Chaer ED, Kawasaki M, Pasricha PJ. A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology 2000; 119:1276-1285.
22. Bercík P, Wang L, VerdúEF, et al. Visceral hyperalgesia and intestinal dysmotility in a mouse model of postinfective gut dysfunction. Gastroenterology 2004; 127(1):179-87.
23.董文珠,李兆申,邹多武,等.肠易激综合征患者肠黏膜肥大细胞与P物质的相关性.中华内科杂志2003; 42(9): 611-4.
24. Gwee KA, Collins SM, Read NW, , et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut. 2003; 52(4):523-6.
25. Zhou Q, Caudle RM, Price DD, et al. Selective up-regulation of NMDA-NR1 receptor expression in myenteric plexus after TNBS induced colitis in rats. Mol Pain. 2006; 17(2): 3.
26. Galligan JJ, LePard KJ, Schneider DA, et al. Multiple mechanisms of fast excitatory synaptic transmission in the enteric nervous system. Journal of the Autonomic Nervous System. 2000; 81(1-3):97-103.
27. Sharkey KA, Kroese AB. Consequences of intestinal inflammation on the enteric nervous system: neuronal activation induced by inflammatory mediators. Anat Rec. 2001; 262(1):79-90.
28. Magari?os AM, Verdugo JM, McEwen BS. Chronic stress alters synaptic terminal structure in hippocampus. Proc Natl Acad Sci U S A. 1997; 94(25):14002-8.
29.杨小军,官阳,钱伟,等.突触可塑性在急性束缚应激所致内脏高敏感中的作用.中华消化杂志2007; 27(10):670-674.
30. Calakos N, Scheller RH. Vesicle-associated membrane protein and Synaptophysin are associated on the synaptic vesicle. J. Biol. Chem 1994; 269(40):24534-24537.
31. Edelmann L, Hanson PI, Chapman ER, et al. Synaptobrevin binding to Synaptophysin: a potential mechanism for controlling the exocytotic fusion machine. EMBO J 1995; 14(2):224–231.
32. Dzienis-Koronkiewicz E, Debek W, Chyczewski L. Use of Synaptophysin immunohistochemistry in intestinal motility disorders. Eur J Pediatr Surg 2005; 15(6):392-8.
33. Wiedenmann B, Riedel C, John M,et al. Qualitative and quantitative analysis of synapses in Hirschsprung's disease. Pediatr Surg Int 1998; 13(7):468-73.
34.王晓,尹朝礼.肠动力疾病结肠壁内NOS, AchE及SP阳性神经的分布.中华消化杂志997; 17(4):195-198.
35. Nakao M, Suita S, Taguchi T, et al. Fourteen-year experience of acetylcholinesterase staining for rectal mucosal biopsy in neonatal Hirschsprung's disease. Journal ofPediatric Surgery. 2001; 36(9):1357-63.
36. Collins SM. The immunomodulation of enteric neuromuscular function: implications for motility and inflammatory disorders. Gastroenterology 1996; 111(6):1683-99.
37. Kennedy MB. Signal-Processing Machines at the Postsynaptic Density. Science 2000; 290(5492):750-4.
38. Lin Y, Skeberdis VA, Francesconi A, Bennett MVL, Zukin RS. Postsynaptic density protein-95 regulates NMDA channel gating and surface expression. J Neurosci 2004; 24: 10138–10148.
39. Lavezzari G, McCallum J, Dewey CM, Roche KW. Subunit-specific regulation of NMDA receptor endocytosis. J Neurosci 2004; 24: 6383–6391.
40. Béique JC, Lin DT, Kang MG, Aizawa H, Takamiya K, Huganir RL. Synapse-specific regulation of AMPA receptor function by PSD-95.Proc Natl Acad Sci USA 2006; 103(51):19535-40.
41. Messenger JP, Bornstein JC, Furness JB. Electrophysiological and morphological classification of myenteric neurons in the proximal colon of the guinea-pig. Neuroscience 1994; 60(1):227-44.
42. Chard PS, Jordán J, Marcuccilli CJ, Miller RJ, Leiden JM, Roos RP. Regulation of excitatory transmission at hippocampal synapses by calbindin D28k.Proc Natl Acad Sci USA 1995; 92(11):5144-8.
43. Ribchester RR, Thomson D, Haddow LJ, Ushkaryov YA. Enhancement of spontaneous transmitter release at neonatal mouse neuromuscular junctions by the glial cell line-derived neurotrophic factor (GDNF). J Physiol 1998; 512 (Pt 3):635-41.
44. Focke PJ, Swetlik AR, Schilz JL, Epstein ML. GDNF and insulin cooperate to enhance the proliferation and differentiation of enteric crest-derived cells. J Neurobiol 2003; 55: 151-64.
45. Liou JC, Yang RS, Fu WM. Regulation of quantal secretion by neurotrophic factors at developing motoneurons in Xenopus cell cultures. J Physiol 1997; 503: 129-39.
46. Ribchester RR, Thomson D, Haddow LJ, Ushkaryov YA. Enhancement of spontaneous transmitter release at neonatal mouse neuromuscular junctions by the glial cell line-derived neurotrophic factor (GDNF). J Physiol 1998; 512(Pt 3): 635-641.
47. Wang LJ, Lu YY, Muramatsu S, Ikeguchi K,et al. Neuroprotective effects of glial cellline-derived neurotrophic factor mediated by an adeno-associated virus vector in a transgenic animal model of amyotrophic lateral sclerosis. J Neurosci 2002; 22: 6920-8.
48. von Boyen GB, Reinshagen M, Steinkamp M, Adler G, Kirsch J. Enteric nervous plasticity and development: dependence on neurotrophic factors. J Gastroenterol 2002; 37: 583-8.
1. Verne GN, Robinson ME, Price DD. Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome. Pain 2001; 93(1):7-14.
2. Bouin M, Plourde V, Boivin M, Riberdy M, Lupien F, Laganière M, Verrier P, Poitras P. Rectal distention testing in patients with irritable bowel syndrome: sensitivity,specificity, and predictive values of pain sensory thresholds. Gastroenterology 2002; 122(7):1771-7.
3. Sarkar S, Aziz Q, Woolf CJ, Hobson AR, Thompson DG. Contribution of central sensitization to the development of non-cardiac chest pain. Lancet. 2000 Sep 30; 356(9236):1127-8.
4. Lin C, Al-Chaer ED. Long-term sensitization of primary afferents in adult rats exposed to neonatal colon pain. Brain Res. 2003 May 2; 971(1):73-82.
5. Chan CL, Facer P, Davis JB, Smith GD, Egerton J, Bountra C, Williams NS, Anand P. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet. 2003 Feb 1;361(9355):385-91
6. Schicho R, Donnerer J, Liebmann I, Lippe IT. Nociceptive transmitter release in the dorsal spinal cord by capsaicin-sensitive fibers after noxious gastric stimulation. Brain Res. 2005 Mar 28;1039(1-2):108-15
7. Bueno L, Fioramonti J. Visceral perception: inflammatory and non-inflammatory mediators. Gut. 2002 Jul; 51 Suppl 1:i19-23.
8. Riva MA, Tascedda F, Lovati E, Racagni G. Regulation of NMDA receptor subunit messenger RNA levels in the rat brain following acute and chronic exposure to antipsychotic drugs. Brain Res Mol Brain Res. 1997; 50(1-2):136-42.
9. Little Z, Grover LM, Teyler TJ. Metabotropic glutamate receptor antagonist, (R,S)-alpha-methyl-4-carboxyphenyglycine, blocks two distinct forms of long-term potentiation in area CA1 of rat hippocampus. Neurosci Lett. 1995 Dec 1; 201(1):73-6.
10. Johnston D, Williams S, Jaffe D, Gray R. NMDA-Receptor-Independent Long-Term Potentiation . Annual Review of Physiology1992; 54: 489-505.
11. Sun YN, Luo JY, Shang P, Lan L, Rao ZR. Effects of N-methyl-D-aspartate receptor in visceral, hypersensitivity in rats with colonic inflammation. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005; 30(5):504-9.
12. Cull-Candy SG, Leszkiewicz DN. Role of distinct NMDA receptor subtypes at central synapses. Sci STKE. 2004;(255):re16
13. McRoberts JA, Coutinho SV, Marvizón JC, et al. Role of peripheral N-methyl-D-aspartate (NMDA) receptors in visceral nociception in rats. Gastroenterology 2001; 120(7):1737-48.
14. Saito YA, Schoenfeld P, Locke GR 3rd. The epidemiology of irritable bowel syndrome in North America: a systematic review. Am J Gastroenterol. 2002; 97(8):1910-5.
15. Barbara G, Vallance BA, Collins SM. Persistent intestinal neuromuscular dysfunction after acute nematode infection in mice. Gastroenterology, 1997, 113(4):1224–1232.
16.陈洪,段丽萍,朱元莉,等.大鼠肠道一过性线虫感染致持续性肠运动功能紊乱.北京大学学报:医学版, 2004, 36(2):198-201.
17. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut. 1973; 14(2): 125–132.
18. Brenner GJ, Ji RR, Shaffer S, Woolf CJ. Peripheral noxious stimulation induces phosphorylation of the NMDA receptor NR1 subunit at the PKC-dependent site, serine-896, in spinal cord dorsal horn neurons. Eur J Neurosci. 2004; 20(2):375-84.
19. Cull-Candy SG, Leszkiewicz DN. Role of distinct NMDA receptor subtypes at central synapses. Sci STKE. 2004 Oct 19;2004(255):re16
20. Berman SM, Naliboff BD, Chang L, Fitzgerald L, Antolin T, Camplone A, Mayer EA. Enhanced preattentive central nervous system reactivity in irritable bowel syndrome. Am J Gastroenterol. 2002 Nov;97(11):2791-7
21. Yuan YZ, Tao RJ, Xu B, Sun J, Chen KM, Miao F, Zhang ZW, Xu JY. Functional brain imaging in irritable bowel syndrome with rectal balloon-distention by using fMRI. World J Gastroenterol. 2003;9(6):1356-60
22. Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology. 2000 May; 118(5):842-8.
23. Kirchgessner AL, Gershon MD. Identification of vagal efferent fibers and putative target neurons in the enteric nervous system of the rat. The Journal of Comparative Neurology 1989; 285(1): 38-53.
24. Sjovall H. Sympathetic control of jejunal ?uid and electrolyte transport. Acta Physiol Scand 1984 ;( suppl 535):1–62.
25. Sjovall H, Redfors S, Jodal M, et al. On the mode of action of the sympathetic fibres on intestinal ?uid transport: Evidence for the existence of a glucose stimulated secretory nervous pathway in the intestinal wall. Acta Physiol Scand 1983;119:39–48.
26. Jansson G, Martinson J. Studies on the ganglionic site of action of sympathetic out?owto the stomach. Acta Physiol Scand 1966; 68:184–92.
27.杨小军,官阳,钱伟,沈蕾,侯晓华.突触可塑性在急性束缚应激所致内脏高敏感中的作用.中华消化杂志. 2007,27(10):670-674.
28. Robertson BS, Satterfield BE, Said SI, Dey RD. N-Methyl-d-aspartate receptors are expressed by intrinsic neurons of rat larynx and esophagus Neuroscience Letters 1998; 244(4):77-80.
29. Milusheva EA, Kuneva VI, Itzev DE, Kortezova NI, Sperlagh B, Mizhorkova ZN. Glutamate stimulation of acetylcholine release from myenteric plexus is mediated by endogenous nitric oxide. Brain Res Bull. 2005; 66(3):229-34.
30. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, Wang YT, Salter MW, Tymianski M. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science. 2002; 298(5594):846-50.
31. Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron.1999; 23(3):583-92.
32. Sattler R, Xiong Z, Lu WY, Hafner M, MacDonald JF, Tymianski M. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science. 1999; 284(5421):1845-8.
33. Song XJ, Zhao ZQ. Involvement of NMDA and non-NMDA receptors in transmission of spinal visceral nociception in cat. Zhongguo Yao Li Xue Bao. 1999; 20(4):308-12.
34. Zhou Q, Caudle RM, Price DD, Del Valle-Pinero AY, Verne GN. Selective up-regulation of NMDA-NR1 receptor expression in myenteric plexus after TNBS induced colitis in rats. Mol Pain. 2006;2:3
35. Wilson MA, Kinsman SL, Johnston MV. Expression of NMDA receptor subunit mRNA after MK-801 treatment in neonatal rats. Brain Res Dev Brain Res. 1998; 109(2):211-20.
36. Gaudreau GA, Plourde V. Involvement of N-methyl-d-aspartate (NMDA) receptors in a rat model of visceral hypersensitivity. Behav Brain Res. 2004 Apr 2; 150(1-2):185-9.
37. Lindén AM, V?s?inen J, Wong G, Castrén E. NMDA receptor 2C subunit is selectively decreased by MK-801 in the entorhinal cortex. Eur J Pharmacol. 1997; 319(1):R1-2.
38. Fernández de Sevilla D, Fuenzalida M, Porto Pazos AB, Bu?o W. Selective shunting ofthe NMDA EPSP component by the slow afterhyperpolarization in rat CA1 pyramidal neurons. J Neurophysiol. 2007 May; 97(5):3242-55.
39. Evidence for a role for GABA (A) and NMDA receptors in ethanol inhibition of long-term potentiation.
40. Muller D, Nikonenko I, Jourdain P, Alberi S. LTP, memory and structural plasticity. Curr Mol Med. 2002;2(7):605-11.
41. Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ. Genetic enhancement of learning and memory in mice. Nature. 1999; 401(6748):63-9.
42. Morgan SL, Teyler TJ. VDCCs and NMDARs underlie two forms of LTP in CA1 hippocampus in vivo. J Neurophysiol. 1999 Aug; 82(2):736-40.
43. Greene R. Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia. Hippocampus. 2001; 11(5):569-77.
44. Lomax AE, Fernández E, Sharkey KA. Plasticity of the enteric nervous system during intestinal inflammation. Neurogastroenterol Motil. 2005; 17(1):4-15.
45. Wood JD, Kirchgessner A. Slow excitatory metabotropic signal transmission in the enteric nervous system. Neurogastroenterol Motil. 2004; 16 Suppl 1:71-80.
46. Ferry B, Magistretti PJ, Pralong E. Noradrenaline Modulates GIutamate-mediated Neurotransmission in the Rat Basolateral Amygdala In Vitro. European Journal of Neuroscience. 1997; 9(7): 1356-1364.
47. Aramakis VB, Bandrowski AE, Ashe JH. Muscarinic reduction of GABAergic synaptic potentials results in disinhibition of the AMPA/kainate-mediated EPSP in auditory cortex. Brain Res. 1997 May 30; 758(1-2):107-17.
1 Kaila M, Isolauri E, Saxelin M, et al. Viable versus inactivated lactobacillus strain GG in acute rotavirus diarrhoea. Arch Dis Child. 1995, 72:51–3.
2 Shornikova A-V, Isolauri E, Burnakova L, et al. A trial in the Karelian Republic of oral rehydration and Lactobacillus GG for treatment of acute diarrhoea. Acta Paediatr. 1997,86:460–5.
3 Majamaa M, Isolauri E, Saxelin M, et al. Lactic acid bacteria in the treatment of acute rotavirus gastroenteritis. J Pediatr Gastroenterol Nutr, 1995, 20:333–8.
4 DuPont HL, Ericsson CD. Prevention and treatment of traveler's diarrhea. N Engl J Med. 1993, 328:1821–7.
5 Oksanen PJ, Salminen S, Saxelin M, et al. Prevention of travellers' diarrhoea by Lactobacillus GG. Ann Med, 1990,22:53–6.
6 Bamias G, Nyce MR, De La Rue SA, et al. New concepts in the pathophysiology of infl ammatory bowel disease. Ann Intern Med, 2005, 143: 895-904.
7 Osman N, Adawi D, Molin G, Bifidobacterium infantis strains with and without a combination of oligofructose and inulin (OFI) attenuate inflammation in DSS-induced colitis in rats. BMC Gastroenterol, 2006, 6(1):31.
8 McCarthy J, O’Mahony L, Dunne C, An open trial of a novel probiotic as an alternative to steroids in mild/moderately active Crohn’s disease. Gut, 2001,49: A2447
9 Ishikawa H, Akedo I, Umesaki Y, Randomized controlled trial of the effect of bifidobacterial fermented milk on ulcerative colitis. J Am Coll Nutr, 2003, 22:56-63.
10 Kato K, Mizuno S, Umesaki Y, et al. Randomized placebo-controlled trial assessing the effect of bifidobacteria-fermented milk on active ulcerative colitis. Aliment Pharmacol Ther, 2004, 20: 1133-1141.
11 Zocco MA, dal Verme LZ, Cremonini F, et al. Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther, 2006, 23: 1567-1574.
12 Marteau P, Lemann M, Seksik P, Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn’s disease: a randomised, double blind, placebo controlled GETAID trial. Gut, 2006, 55: 842-847.
13 Mcfarland LV. Epidemiology. risk factor and treatment for antibiotic associated diarrhea. Dig dis sci, 1998, 16:292-307.
14 Levy J. The effects of antibiotic use on gastrointestinal function. Am J Gastroenterol. 2000, 95(1 Suppl):S8-10.
15 Arvola T, Laiho K, Torkkeli S, et al. Prophylactic Lactobacillus GG Reduces Antibiotic-Associated Diarrhea in Children With Respiratory Infections: A Randomized Study. Pediatrics, 1999, 104(5):64.
16 Can M, Besirbellioglu BA, Avci IY, Prophylactic Saccharomyces boulardii in theprevention of antibiotic-associated diarrhea: a prospective study. Med Sci Monit, 2006, 12(4):PI19-22.
17 Barbara G, Stanghellini V, Brandi G, Interactions between commensal bacteria and gut sensorimotor function in health and disease. Am J Gastroenterol, 2005, 100(11):2560-8.
18 Whorwell PJ, Altringer L, Morel J. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006, 101(7):1581-90.
19 Kim HJ, Vazquez Roque MI, Camilleri M, et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil.2005,(5):687-96.
20 Madsen K, Cornish A, Soper P, McKaigney C, Jijon H, Yachimec C, Doyle J, Jewell L, De Simone C. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 2001; 121: 580-591.
21 Llopis M, Antoln M, Guarner F, et al. Mucosal colonisation with Lactobacillus casei mitigates barrier injury induced by exposure to trinitronbenzene sulphonic acid. Gut, 2005,54:955–959.
22 Yan F, Polk DB. Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells. J Biol Chem. 2002, 277: 50959-50965.
23 Resta-Lenert S, Barrett KE. Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut, 2003, 52: 988-997.
24 Mack DR, Ahrne S, Hyde L, et al. Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro. Gut, 2003, 52: 827-833.
25 Li LJ, Wu ZW, Xiao DS, Changes of gut flora and endotoxin in rats with D-galactosamine-induced acute liver failure. World J Gastroenterol, 2004; 10(14): 2087-2090.
26 García-Lafuente A, Antolín M, Guarner F, et al. Modulation of colonic barrier function by the composition of the commensal flora in the rat. Gut,2001,48:503–507.
27 Perdigon G, Maldonado Galdeano C, Valdez JC, et al. Interaction of lactic acid bacteria with the gut immune system. Eur J Clin Nutr, 2002, 56(Suppl 4):S21-6.