预防性应用5-HT_3受体拮抗剂对内脏痛高敏感幼鼠痛敏感性及结肠P物质表达的影响
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摘要
目的采用行为学和电生理学评价方法,探讨预防性应用5-HT3受体拮抗剂对新生期反复结直肠刺激(Colorectal Irritation,CI)建立内脏痛觉高敏感性模型幼鼠内脏痛觉敏感性影响;比较各组幼鼠结肠P物质(substance P,SP)表达,探讨结肠SP异常表达在幼鼠内脏痛觉高敏形成中作用,为临床上采取有效防治措施及开发治疗药物提供理论依据。
方法①32只SD新生大鼠按2×2析因设计分成4组,每组8只,A1B1组:新生期反复CI,建立幼鼠内脏痛觉高敏感模型,15～21d腹腔注射雷莫司琼;A1B2组:新生期反复CI,建立幼鼠内脏痛觉高敏感模型,15～21d腹腔注射生理盐水;A2B1组:新生期未接受CI,15～21d腹腔注射雷莫司琼;A2B2组:新生期未接受CI,15～21d腹腔注射生理盐水。常规饲养到幼鼠期(6周龄),通过观察大鼠在不同压力结直肠扩张(Colorectal Distension ,CRD)刺激后的腹壁撤退反射(AWR)评分、内脏痛阈和腹外斜肌放电测量进行内脏痛觉敏感性评价,选取降结肠进行病理学检查。②32只SD新生大鼠按2×2析因设计分成4组,每组8只,A1B1组:新生期反复CI,建立幼鼠内脏痛觉高敏感模型,15～21d腹腔注射雷莫司琼;A1B2组:新生期反复CI,建立幼鼠内脏痛觉高敏感模型,15～21d腹腔注射生理盐水;A2B1组:新生期未接受CI,15～21d腹腔注射雷莫司琼;A2B2组:新生期未接受CI,15～21d腹腔注射生理盐水。常规饲养到幼鼠期(6周龄),应用免疫组织化学染色及计算机图像分析系统对结肠进行积分光密度值半定量分析。采用SPSS13.0软件包进行统计分析,α=0.05为显著性检验标准。
结果①幼鼠6周龄时,新生期CI建立幼鼠内脏痛觉高敏感性模型可使痛阈降低,新生期CI建立幼鼠内脏痛觉高敏感性模型的使AWR评分升高,新生期CI建立幼鼠内脏痛觉高敏感性模型对于AWR评分的主效应在各个CRD压力下都有统计学意义(F值分别是47.79、6.61、26. 30、4.84,均P<0.05);预防性应用雷莫司琼对于AWR评分降低,预防性应用雷莫司琼对于AWR评分的主效应在各个CRD压力下也都有统计学意义(F值分别是23.74、11.88、4.74、4.20、4.76,均P<0.05)。新生期CI建立幼鼠内脏痛觉高敏感性模型可使幼鼠腹外斜肌放电幅值在各个压力下均升高,新生期CI建立幼鼠内脏痛觉高敏感性模型对幼鼠腹外斜肌放电幅值主效应在各不同CRD压力下均有显著意义(F值分别为9.00、6.50、8.99、4.02、4.98,均P≤0.05);降结肠未见明显病理组织损伤。②幼鼠6周龄时,A1B2组中结肠黏膜层、粘膜下层、肌层内均出现密集棕黄色免疫阳性产物,SP阳性细胞多;A1B1组、A2B1组及A2B2组,结肠黏膜层、粘膜下层、肌层内仅有极少量SP阳性细胞,免疫阳性产物着色浅淡,SP积分光密度值A1B1组肌层大于粘膜下层、粘膜层,差别有统计学意义,A1B2、A2B1、A2B2组各层积分光密度值均未见明显差别。进一步对新生期CI及预防性应用雷莫司琼对于幼鼠结肠各层积分光密度值的主效应值进行随机区组的方差分析,结果表明:粘膜层与肌层的的SP积分光密度值差别有统计学意义(P=0.002),粘膜下层与肌层的SP积分光密度值差别也有统计学意义(P=0.004),粘膜层与粘膜下层的SP积分光密度值差别没有统计学意义(P=0.139);幼鼠结肠粘膜层、粘膜下层、肌层SP积分光密度值均受到新生期CI建立幼鼠内脏痛觉高敏感性模型和预防性应用雷莫司琼影响,新生期CI建立幼鼠内脏痛觉高敏感性模型,其结肠各层SP积分光密度值均明显增加,预防性应用雷莫司琼其结肠粘膜SP积分光密度值均明显减少。
结论①新生期持续CI会造成幼鼠痛阈下降,出现慢性内脏高敏感性,且没有明确的组织病理学改变;预防性应用5-HT3受体拮抗剂雷莫司琼能够降低幼鼠内脏痛觉的高敏感性。②该模型内脏痛觉高敏感性发生机制可能与SP表达增高有关。
Prophylactic use of 5-HT3 receptor antagonist to the visceral pain hypersensitivity and the colon substance P expression in developing rat
Objective To explore the effect of prophylactic use of 5-HT3 receptor antagonist to the visceral sensitivity and the colon substance P expression in detrimental colorectal irritation (CI) stimulation in neonatal period on developing rat by the method of behavior and electrophysiology research. Compare with the colon substance P expression in different group. To explore the effort of abnormal expression of colon substance P expression in the formation of rats’visceral pain hypersensitivity. This study can provide the theoretical basis for taking the preventive measures and the development of therapeutic drugs in clinic.
Method①32 neonatal rats were divided into four groups by 2×2 factorial design with each 8. Group A1B1 imposed on CI at neonatal period and imposed on ramosetron intraperitoneal injection in 15～21day; Group A1B2:imposed on CI at neonatal period and not imposed on ramosetron intraperitoneal injection in 15～21day; Group A2B1:not imposed on CI at neonatal period and imposed on ramosetron intraperitoneal injection in 15～21day; Group A2B2: not imposed on CI at neonatal period and not imposed on ramosetron intraperitoneal injection in 15～21day. Then, conventionally breeding till the young period (6-week age), the following study was implemented:by the method of abdonminal withdrawal reflex (AWR),pain thresholds and electrophysiological study on external oblique to evaluate visceral algesthesia of intestinal tract. To select descending colon to do patholigical examination.②32 neonatal rats were divided into four groups by 2×2 factorial design with each 8. Group A1B1 imposed on CI at neonatal period and imposed on ramosetron intraperitoneal injection in 15～21day; Group A1B2:imposed on CI at neonatal period and not imposed on ramosetron intraperitoneal injection in 15～21day; Group A2B1:not imposed on CI at neonatal period and imposed on ramosetron intraperitoneal injection in 15～21day; Group A2B2: not imposed on CI at neonatal period and not imposed on ramosetron intraperitoneal injection in 15～21day. Then, conventionally breeding till the young period (6-week age), colons were analyzed through immunohisrochemical coloration and computer image analyzing system. SPSS 13.0 software for Windows was used in all statistical tests. The value ofα=0.05 was considered significant.
Result①When imposed on CI at neonatal period for building visceral hypersensitivity model,the pain thresholds were decreased at 6-week age. The AWR scores were increased. There were a significant main effect for AWR scores at different pressures (F=47.79,6.61,26. 30,4.84,all P < 0.05). Prophylactic use of 5-HT3 receptor antagonist ramosetron in developing rat ,the AWR scores were decreased. There were a significant main effect for AWR scores at different pressures(F=23.74,11.88,4.74,4.20,4.76,all P<0.05). When imposed on CI at neonatal period, the amplitudes of spike EOMA were increased at different CRD pressures. There were a significant main effect for the amplitudes of spike EOMA at different pressures(F=9.00,6.50,8.99,4.02,.98,all P≤0.05).Four groups of rats did not any pathological lesion in descending colon.②At 6-week age,there were many immune positive brown-yellow granules in mucous layers,submucosa layers and muscular layers of group A1B2.There are farthing immune positive brown-yellow granules in mucous layers,submucosa layers and muscular layers of group A1B1,. In group A1B1,integral optical density values of substance p were significantly higher in muscular layers than mucous and submucosa layers.In group A1B2 ,group A2B1 and group A2B2,integral optical density values of substance p were no significantly different among different layers. Furthermore take random analysis of main effect value for integral optical density values of substance p in different colon layers.The main effect is imposed on CI at neonatal period and prophylactic use of ramosetron. They were significantly different between mucous layers and muscular layers(P=0.002).And they were significantly different between submucosa layers and muscular layers(P=0.004).They were no significantly different between mucous layers and submucosa layers(P=0.139). Integral optical density values of substance p were effected by CI at neonatal period and prophylactic use of 5-HT3 receptor antagonist ramosetron in developing rat. By CI at neonatal period, the SP immunohistochemistry integral optical density values of different colon layers were increased. Integral optical density values were increased more significantly in mucous and submucosa layers than muscular layers. Prophylactic use of ramosetron, different colon layers of SP integral optical density values were decreased.
Conclusion①The persistent CI in neonatal period can result in low pain threshold and chronic visceral hypersensitivity in developing rats, histological change was not found in colorectal tissue. Prophylactic use of 5-HT3 receptor antagonist can decrease visceral hypersensitivity in developing rat.②The occurrence mechanism of visceral pain hypersensitivity in this model may be related to the increase expression of SP.
方法①32只SD新生大鼠按2×2析因设计分成4组,每组8只,A1B1组:新生期反复CI,建立幼鼠内脏痛觉高敏感模型,15～21d腹腔注射雷莫司琼;A1B2组:新生期反复CI,建立幼鼠内脏痛觉高敏感模型,15～21d腹腔注射生理盐水;A2B1组:新生期未接受CI,15～21d腹腔注射雷莫司琼;A2B2组:新生期未接受CI,15～21d腹腔注射生理盐水。常规饲养到幼鼠期(6周龄),通过观察大鼠在不同压力结直肠扩张(Colorectal Distension ,CRD)刺激后的腹壁撤退反射(AWR)评分、内脏痛阈和腹外斜肌放电测量进行内脏痛觉敏感性评价,选取降结肠进行病理学检查。②32只SD新生大鼠按2×2析因设计分成4组,每组8只,A1B1组:新生期反复CI,建立幼鼠内脏痛觉高敏感模型,15～21d腹腔注射雷莫司琼;A1B2组:新生期反复CI,建立幼鼠内脏痛觉高敏感模型,15～21d腹腔注射生理盐水;A2B1组:新生期未接受CI,15～21d腹腔注射雷莫司琼;A2B2组:新生期未接受CI,15～21d腹腔注射生理盐水。常规饲养到幼鼠期(6周龄),应用免疫组织化学染色及计算机图像分析系统对结肠进行积分光密度值半定量分析。采用SPSS13.0软件包进行统计分析,α=0.05为显著性检验标准。
结果①幼鼠6周龄时,新生期CI建立幼鼠内脏痛觉高敏感性模型可使痛阈降低,新生期CI建立幼鼠内脏痛觉高敏感性模型的使AWR评分升高,新生期CI建立幼鼠内脏痛觉高敏感性模型对于AWR评分的主效应在各个CRD压力下都有统计学意义(F值分别是47.79、6.61、26. 30、4.84,均P<0.05);预防性应用雷莫司琼对于AWR评分降低,预防性应用雷莫司琼对于AWR评分的主效应在各个CRD压力下也都有统计学意义(F值分别是23.74、11.88、4.74、4.20、4.76,均P<0.05)。新生期CI建立幼鼠内脏痛觉高敏感性模型可使幼鼠腹外斜肌放电幅值在各个压力下均升高,新生期CI建立幼鼠内脏痛觉高敏感性模型对幼鼠腹外斜肌放电幅值主效应在各不同CRD压力下均有显著意义(F值分别为9.00、6.50、8.99、4.02、4.98,均P≤0.05);降结肠未见明显病理组织损伤。②幼鼠6周龄时,A1B2组中结肠黏膜层、粘膜下层、肌层内均出现密集棕黄色免疫阳性产物,SP阳性细胞多;A1B1组、A2B1组及A2B2组,结肠黏膜层、粘膜下层、肌层内仅有极少量SP阳性细胞,免疫阳性产物着色浅淡,SP积分光密度值A1B1组肌层大于粘膜下层、粘膜层,差别有统计学意义,A1B2、A2B1、A2B2组各层积分光密度值均未见明显差别。进一步对新生期CI及预防性应用雷莫司琼对于幼鼠结肠各层积分光密度值的主效应值进行随机区组的方差分析,结果表明:粘膜层与肌层的的SP积分光密度值差别有统计学意义(P=0.002),粘膜下层与肌层的SP积分光密度值差别也有统计学意义(P=0.004),粘膜层与粘膜下层的SP积分光密度值差别没有统计学意义(P=0.139);幼鼠结肠粘膜层、粘膜下层、肌层SP积分光密度值均受到新生期CI建立幼鼠内脏痛觉高敏感性模型和预防性应用雷莫司琼影响,新生期CI建立幼鼠内脏痛觉高敏感性模型,其结肠各层SP积分光密度值均明显增加,预防性应用雷莫司琼其结肠粘膜SP积分光密度值均明显减少。
结论①新生期持续CI会造成幼鼠痛阈下降,出现慢性内脏高敏感性,且没有明确的组织病理学改变;预防性应用5-HT3受体拮抗剂雷莫司琼能够降低幼鼠内脏痛觉的高敏感性。②该模型内脏痛觉高敏感性发生机制可能与SP表达增高有关。
Prophylactic use of 5-HT3 receptor antagonist to the visceral pain hypersensitivity and the colon substance P expression in developing rat
Objective To explore the effect of prophylactic use of 5-HT3 receptor antagonist to the visceral sensitivity and the colon substance P expression in detrimental colorectal irritation (CI) stimulation in neonatal period on developing rat by the method of behavior and electrophysiology research. Compare with the colon substance P expression in different group. To explore the effort of abnormal expression of colon substance P expression in the formation of rats’visceral pain hypersensitivity. This study can provide the theoretical basis for taking the preventive measures and the development of therapeutic drugs in clinic.
Method①32 neonatal rats were divided into four groups by 2×2 factorial design with each 8. Group A1B1 imposed on CI at neonatal period and imposed on ramosetron intraperitoneal injection in 15～21day; Group A1B2:imposed on CI at neonatal period and not imposed on ramosetron intraperitoneal injection in 15～21day; Group A2B1:not imposed on CI at neonatal period and imposed on ramosetron intraperitoneal injection in 15～21day; Group A2B2: not imposed on CI at neonatal period and not imposed on ramosetron intraperitoneal injection in 15～21day. Then, conventionally breeding till the young period (6-week age), the following study was implemented:by the method of abdonminal withdrawal reflex (AWR),pain thresholds and electrophysiological study on external oblique to evaluate visceral algesthesia of intestinal tract. To select descending colon to do patholigical examination.②32 neonatal rats were divided into four groups by 2×2 factorial design with each 8. Group A1B1 imposed on CI at neonatal period and imposed on ramosetron intraperitoneal injection in 15～21day; Group A1B2:imposed on CI at neonatal period and not imposed on ramosetron intraperitoneal injection in 15～21day; Group A2B1:not imposed on CI at neonatal period and imposed on ramosetron intraperitoneal injection in 15～21day; Group A2B2: not imposed on CI at neonatal period and not imposed on ramosetron intraperitoneal injection in 15～21day. Then, conventionally breeding till the young period (6-week age), colons were analyzed through immunohisrochemical coloration and computer image analyzing system. SPSS 13.0 software for Windows was used in all statistical tests. The value ofα=0.05 was considered significant.
Result①When imposed on CI at neonatal period for building visceral hypersensitivity model,the pain thresholds were decreased at 6-week age. The AWR scores were increased. There were a significant main effect for AWR scores at different pressures (F=47.79,6.61,26. 30,4.84,all P < 0.05). Prophylactic use of 5-HT3 receptor antagonist ramosetron in developing rat ,the AWR scores were decreased. There were a significant main effect for AWR scores at different pressures(F=23.74,11.88,4.74,4.20,4.76,all P<0.05). When imposed on CI at neonatal period, the amplitudes of spike EOMA were increased at different CRD pressures. There were a significant main effect for the amplitudes of spike EOMA at different pressures(F=9.00,6.50,8.99,4.02,.98,all P≤0.05).Four groups of rats did not any pathological lesion in descending colon.②At 6-week age,there were many immune positive brown-yellow granules in mucous layers,submucosa layers and muscular layers of group A1B2.There are farthing immune positive brown-yellow granules in mucous layers,submucosa layers and muscular layers of group A1B1,. In group A1B1,integral optical density values of substance p were significantly higher in muscular layers than mucous and submucosa layers.In group A1B2 ,group A2B1 and group A2B2,integral optical density values of substance p were no significantly different among different layers. Furthermore take random analysis of main effect value for integral optical density values of substance p in different colon layers.The main effect is imposed on CI at neonatal period and prophylactic use of ramosetron. They were significantly different between mucous layers and muscular layers(P=0.002).And they were significantly different between submucosa layers and muscular layers(P=0.004).They were no significantly different between mucous layers and submucosa layers(P=0.139). Integral optical density values of substance p were effected by CI at neonatal period and prophylactic use of 5-HT3 receptor antagonist ramosetron in developing rat. By CI at neonatal period, the SP immunohistochemistry integral optical density values of different colon layers were increased. Integral optical density values were increased more significantly in mucous and submucosa layers than muscular layers. Prophylactic use of ramosetron, different colon layers of SP integral optical density values were decreased.
Conclusion①The persistent CI in neonatal period can result in low pain threshold and chronic visceral hypersensitivity in developing rats, histological change was not found in colorectal tissue. Prophylactic use of 5-HT3 receptor antagonist can decrease visceral hypersensitivity in developing rat.②The occurrence mechanism of visceral pain hypersensitivity in this model may be related to the increase expression of SP.
引文
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[27]Suzuki R, Morcuende S, Webber M, et al. Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways. Nat Neurosci. 2002,5(12): 1319-1326.
[28]Laporte AM, Koscielniak T, Ponchant M, et al. Quantitative autoradiographic mapping of 5-HT3 receptors in the rat CNS using [125I]iodo-zacopride and [3H]zaco-pride as radioligands. Synapse,1992,10(4):271-281.
[29]Miura M, Lawson DC, Clary EM, et al. Central modulation of rectal distension-induced blood pressure changes by alosetron, a 5-HT3 receptor antagonist. Dig Dis Sci,1999,44(1):20 -24.
[30]Giordano J, Gerstmann H. Patterns of serotonin- and 2-methylserotonin-induced pain may reflect 5-HT3 receptor sensitization. Eur J Pharmacol,2004,483(2-3):267-269.
[1]李枫,图像分析中光密度参数物理意义的正确理解和使用.解剖学杂志,2009,32(2): 271- 274
[2]Vanderah TW. Pathophysiology of Pain. Med Clin N Am, 2007,91:1-12.
[3]章菲菲,莫剑忠.降钙素基因相关肽在内脏敏感性改变机制中的作用.胃肠病学和肝病学杂志,2005,14(2):200-202.
[4]Cervero F, Laird JM. Understanding the signaling and transmission of visceral noci- ceptive events. J Neurobiol,2004,61(1):45-54.
[5]Buéno L, Fioramonti J, Garcia-Villar R. Pathobiology of Visceral Pain: Molecular Me- chanisms and Therapeutic ImplicationsⅢ. Visceral afferent pathways: a source of new therapeutic targets for abdominal pain. Am J Physiol Gastrointest Liver Physiol,2000,278(5): 670-676.
[6]Severini C, Improta G, Falconieri-Erspamer G, et al. The tachykinin peptide family. Pharmacol Rev. 2002,54(2):285-322.
[7]Regoli D, Boudon A, Fauchére JL. Receptors and antagonists for substance P and related peptides. Pharmacol Rev,1994,46(4):551-599.
[8]Maggi CA. The mammalian tachykinin receptors, Gen Pharmacol,1995,26(5):911-944.
[9]Mayer EA, Loo DD, Kodner A, et al. Differential modulation of Ca2(+)-activated K+ channels by substance P. Am J Physiol,1989 257(6 Pt 1):G887-897.
[10] Skidgel RA, Jackman HL, Erd?s EG.. Metabolism of substance P and bradykinin by human neutrophils. Biochem Pharmacol. 1991,41(9):1335-1344.
[11]Almeida TA, Rojo J, Nieto PM, et al. Tachykinins and tachykinin receptors: structure and activity relationships. Curr Med Chem,2004,11(15):2045-2081.
[12]Quartara L, Maggi CA. The tachykinin NK1 receptor. Part I: ligands and mechanisms of cellular activation. Neuropeptides,1997,31(6):537-563.
[13] Fiebich BL, Schleicher S, Butcher RD The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF-kappa B. J Immunol. 2000,165(10):5606-5611.
[14]H?kfelt T, Pernow B, Wahren J. Substance P: a pioneer amongst neuropeptides. J Intern Med. 2001,249(1):27-40.
[15] Holzer P, Lippe IT, Heinemann A, Bartho L. Tachykinin NK1 and NK2 receptor-mediated control of peristaltic propulsion in the guinea pig small intestine in vitro. Neuropharmacology ,1998;37:131-138.
[16]Kirkup AJ, Brunsden AM, Grundy D. Receptors and transmission in the brain-gut axis: potential for novel therapies. I. Receptors on visceral afferents. Am J Physiol Gastrointest Liver Physiol,2001 ,280(5):G787-794.
[17]Okano S, Nagaya H, Ikeura Y. Effects of TAK-637, a Novel Neurokinin-1 Receptor An on Colonic Function in Vivo. J Pharmacol Exp Ther,2001,298(2):559-564.
[18]陈晓敏,张燕华,毛峻岭,等.肠易激综合征患者结肠黏膜P物质、血管活性肠肽和肥大细胞的变化.胃肠病学,2008,13(4): 228-230.
[19]Xiao-Peng Ma, Lin-Ying Tan, Yun Yang , et al. Effect of electro-acupuncture on substance P, its receptor and corticotropin-releasing hormone in rats with irritable bowel syndrome.World J Gastroenterol,2009,15(41): 5211–5217.
[20]孙怡宁,罗金燕,兰莉,等.替加色罗对结肠炎大鼠内脏敏感性的影响及其与结肠内P物质和降钙素基因相关肽表达的关系.西安交通大学学报(医学版), 2007,28(5):506- 510.
[21]Bennett MR. The concept of long term potentiation of transmission at synapses. Prog Neurobiol. 2000,60(2):109-137.
[22]Musial F, H?user W, Langhorst J. Psychophysiology of visceral pain in IBS and health. J Psychosom Res. 2008,64(6):589-597..
[23]杜立峰,展淑琴,郭新奎. P物质、血管活性肠肽与异常胃肠通过的关系.西安交通大学学报(医学版), 2003,24(4):363-364+376.
[1]Rasquin A, Di Lorenzo C, Forbes D, et a1. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006 130(5):1527-1537.
[2]李定国,刘栋,许小幸,陆汉明.青少年儿童肠易激综合征的流行病学调查.中华消化杂志, 2005,25(5):266-269.
[3]Spiller RC. Post infectious irritable bowel syndrome. Gastroenterology, 2003,124(6):1662 -1671.
[4]Bishwa RT, Lanbo G, Robert JN. 5-HT7 receptors mediate the inhibitory effect of 5-HT on peristalsis in the isolated guinea-pig ileum. Br J Pharmacol, 2003,138(7): 1210–1214.
[5]Monnikes H, Ruter J, Konig M, et a1. Differential induction of c-fos expression in brain nuclei by noxious and non-noxious colonic distension: role of afferent C-fibers and 5-HT3 receptors. Brain Res, 2003,966(2):253-264.
[6]De Ponti F, Tonini M. Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. Drugs, 2001,61(3):317-332.
[7]Ruch M, Hamelin B, Rhss K, et al. The effect of mosapride, a novel prokinetic,on acid reflux variables in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther,1998,12(1): 35-40.
[8]Camilleri M. Management of the irritable bowel syndrome. Gastroentero, 2001,120(3):652–668.
[9]Glatzle J, Sternini C, Robin C, et a1. Expression of 5-HT3 receptors in the rat gastrointestinal tract. Gastroentero,2002,123(1):217-226.
[10]Davies PA, Pistis M, Hanna MC, et a1. The 5-HT3B subunit is a major determinant of serotonin- receptor function. Nature,1999,397(6717):359-363.
[11]Niesler B, Walstab J, Combrink S, et a1. Characterization of the novel human serotoni n receptor subunits 5-HT3C, 5-HT3D, and 5-HT3E. Mol Pharmacol,2007,72(1):8-17.
[12]Michel K, Zeller F, Langer R, et al. Serotonin excites neurons in the human submucous plexus via 5-HT3 receptors. Gastroenterology, 2005,128(5):1317-1326.
[13]Van Lelyveld N, Ter Linde J, Schipper M, et al. Serotonergic signalling in the stomachand duodenum of patients with gastroparesis. Neurogastroenterol Motil, 2008,20(5):448–455.
[14]Niesler B, Walstab J, Combrink S, et al. Characterization of the novel human serotonin receptor subunits 5-HT3C, 5-HT3D, and 5-HT3E. Mol Pharmacol, 2007,72(1):8–17.
[15]Johannes K, Lesley AH, Hubert M, et al. First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. Human Molecular Genetics, 2008,17(19):2967-2977.
[16]Ouyang A,Wrzos, H.F. Contribution of gender to pathophysiology and clinical presentation of IBS: should management be different in women?Am.J.Gastroenterol,2006,101(12Suppl):S602 -S609.
[17]Keating E, Lemos C, Monteiro R , et al. The effect of a series of organic cations upon the plasmalemmal serotonin transporter, SERT, Life Sci,2004,76(1):103-119.
[18]Camilleri M, Atanasova E, Carlson PJ, et al. Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome. Gastroentero,2002,123(2): 425-432.
[19]Camilleri M, Northcutt AR, Kong S, et al. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet,2000,355 (9209):1035-1040.
[20]Friedel D, Thomas R, Fisher RS. Ischemic colitis during treatment with alosetron. Gastroentero. 2001,21(1):231-232.
[21]Moynihan R. Alosetron: a case study in regulatory capture, or a victory for patients' rights? BMJ, 2002,325(7364):592-595.
[22]Chang L, Chey WD, Harris L, et al. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am J Gastroenterol, 2006,101(5):1069-1079.
[23]Rahimi R, Nikfar S, Abdollahi M. Efficacy and tolerability of alosetron for the treatmentof irritable bowel syndrome in women and men: A meta-analysis of eight randomized, placebo- controlled, 12-week trials. Clin Ther,2008,30(5):884-901.
[24]Hirata T, Funatsu T, Keto Y, et al. Pharmacological profle of ramosetron, a novel therapeutic agent for IBS. Inflammopharmacology, 2007 15(1):5-9.
[25]Hirata T, Keto Y, Funatsu T, et al. Evaluation of the pharmacological profile of ramosetron, a novel therapeutic agent for irritable bowel syndrome. J Pharmacol Sci, 2007,104(3):263-273.
[26]Funatsu T, Takeuchi A, Hirata T, et al. Effect of ramosetron on conditioned emotional stress- induced colonic dysfunction as a model of irritable bowel syndrome in rats. Eur J Pharmacol, 2007, 573(1-3):190-195.
[27]Matsueda K, Harasawa S, Hongo M, et al. A phase II trial of the novel serotonin type 3 receptor antagonist ramosetron in Japanese male and female patients with diarrhea- predominant irritable bowel syndrome. Digestion, 2008,77(3-4):225-235.
[28]Matsueda K, Harasawa S, Hongo M, et al. A randomized, double-blind, placebo-controlled clinical trial of the effectiveness of the novel serotonin type 3 receptor antagonist ramosetron in both male and female Japanese patients with diarrhea-predominant irritable bowel syndrome. Scand J Gastroenterol, 2008,43(10):1202-1211.
[29]Hirata T, Keto Y, Nakata M, et al. Effects of serotonin 5-HT3 receptor antagonists on stress-induced colonic hyperalgesia and diarrhoea in rats: a comparative study with opioid receptor agonists, a muscarinic receptor antagonist and a synthetic polymer. Neurogastroenterol Motil,2008,20(5):557-565.
[30]Berman SM, Chang L, Suyenobu B, et al. Condition-specific deactivation of brain regions by 5-HT3 receptor antagonist Alosetron. Gastroentero,2002,123(4):969-977.
[2]Frank L,Kleinman L,Rentz A, et al. Health-related quality of life associated with irritable bowel syndrome:comparison with other chronic diseases. Clin Ther, 2002,24(4):675-689.
[3]Boekema PJ,van Dam van Isselt EF, Bots ML, et al. Functional bowel symptoms in a general Dutch population and associations with common stimulants. Neth J Med, 2001,59(1): 23-30.
[4]Varni JW, Lane MM, Burwinkle TM, et al. Health-related quality of life in pediatric patients with irritable bowel syndrome: a comparative analysis. J Dev Behav Pediatr, 2006,27(6):451-458.
[5]肖英莲陈旻湖.功能性胃肠病的药物治疗进展.中国处方药, 2005 (11):41-43.
[6]Ford AC, Brandt LJ, Young C, et al. Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol,2009,104 (7):1831-1843.
[7]Bremner AR, Sandhu BK. Recurrent abdominal pain in childhood: the functional element. Indian Pediatr,2009,46(5):375-379.
[8]Huertas-Ceballos A, Logan S, Bennett C, et al. Pharmacological interventions for recurrent abdominal pain (RAP) and irritable bowel syndrome (IBS) in childhood. Cochrane Database Syst Rev. 2008 ,23;(1):CD003017.
[9]Al-chaer ED, Kawasaki M, Pasricha PJ. A new model of chronic visceral hypersensitivity in adu1t rats induces by colon irritation during postnata1 development. Gastroentero, 2000, 119(5):1276-1285.
[10]张睿,吴斌,林国威,等.新生期结肠刺激及性别对幼鼠内脏痛敏感性的影响.中国疼痛医学杂志,2008,14(3):167-171.
[11]Hirata T, Keto Y, Nakata M, et al. Effects of serotonin 5-HT3 receptor antagonists on stress-induced colonic hyperalgesia and diarrhoea in rats: a comparative study with opioid receptor agonists, a muscarinic receptor antagonist and a synthetic polymer. Neurogastro- enterol Motil,2008,20(5):557-565.
[12]Vanhatalo S, van Nieuwenhuizen O. Fetal pain? Brain & Development 2000,22:145-150.
[13]Anand KS, Coskun V, Thrivikraman KV, et al. Long-term behavioral effects of repetitive pain in neonatal rat pups. Physiol Behav,1999,66:627-637.
[14]Roozendaal B, Okuda S, VanderZee EA, et al. Glucocorticoid enhancement of memory requires arousal-induced noradrenergic activation in the basolateral amygdala. Proc Natl Acad Sci USA,2006,103:6741-6746.
[15]杨燕珍,吴斌,张睿,等.腹外斜肌放电测量在幼鼠内脏痛觉高敏感模型评价中的应用.中国当代儿科杂志,2008,10(5):637-641.
[16]Spiller RC. Post infectious irritable bowel syndrome. Gastroentero, 2003,124(6):1662- 1671.
[17]Tack J, Müller-Lissner S, Bytzer P.A randomised controlled trial assessing the efficacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation. Gut, 2005,54(12):1707-1713.
[18]Bradesi S, Lao L, McLean PG, et al. Dual role of 5-HT3 receptors in a rat model ofdelayed stress-induced visceral hyperalgesia. Pain, 2007,130(1-2):56-65.
[19]Choi YD, Sung TS, Kim HJ, et al. Increased 5-hydroxytryptamine mediates post- inflammatory visceral hypersensitivity via the 5-hydroxytryptamine 3 receptor in rats. 2008 ,53(11):2909-2916.
[20]Hirata T, Funatsu T, Keto Y, et al. Pharmacological profle of ramosetron, a novel therapeutic agent for IBS. Inflammopharmacology, 2007,15(1):5-9.
[21]Hirata T, Keto Y, Funatsu T, et al. Evaluation of the pharmacological profile of ramosetron, a novel therapeutic agent for irritable bowel syndrome. J Pharmacol Sci, 2007, 104(3):263-273.
[22]Rahimi R, Nikfar S, Abdollahi M. Efficacy and tolerability of alosetron for the treatment of irritable bowel syndrome in women and men: A meta-analysis of eight randomized, placebo- controlled, 12-week trials. Clin Ther,2008,30(5):884-901.
[23]Matsueda K, Harasawa S, Hongo M, et al. A phase II trial of the novel serotonin type 3 receptor antagonist ramosetron in Japanese male and female patients with diarrhea- predominant irritable bowel syndrome. Digestion,2008,77(3-4):225-235.
[24]卓玲,吴斌,张睿,等.幼鼠内脏痛觉高敏感性模型的建立及电生理学评价.实用儿科临床杂志,2009,24(19):1487-1489.
[25]Crowell MD. Role of serotonin in the pathophysiology of the irritable bowel syndrome. Br J Pharmacol,2004,141(8):1285-1293.
[26]Mawe GM, Coates MD, Moses PL. Review article: intestinal serotonin signalling in irritable bowel syndrome. Aliment Pharmacol Ther, 2006,23(8):1067-1076.
[27]Suzuki R, Morcuende S, Webber M, et al. Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways. Nat Neurosci. 2002,5(12): 1319-1326.
[28]Laporte AM, Koscielniak T, Ponchant M, et al. Quantitative autoradiographic mapping of 5-HT3 receptors in the rat CNS using [125I]iodo-zacopride and [3H]zaco-pride as radioligands. Synapse,1992,10(4):271-281.
[29]Miura M, Lawson DC, Clary EM, et al. Central modulation of rectal distension-induced blood pressure changes by alosetron, a 5-HT3 receptor antagonist. Dig Dis Sci,1999,44(1):20 -24.
[30]Giordano J, Gerstmann H. Patterns of serotonin- and 2-methylserotonin-induced pain may reflect 5-HT3 receptor sensitization. Eur J Pharmacol,2004,483(2-3):267-269.
[1]李枫,图像分析中光密度参数物理意义的正确理解和使用.解剖学杂志,2009,32(2): 271- 274
[2]Vanderah TW. Pathophysiology of Pain. Med Clin N Am, 2007,91:1-12.
[3]章菲菲,莫剑忠.降钙素基因相关肽在内脏敏感性改变机制中的作用.胃肠病学和肝病学杂志,2005,14(2):200-202.
[4]Cervero F, Laird JM. Understanding the signaling and transmission of visceral noci- ceptive events. J Neurobiol,2004,61(1):45-54.
[5]Buéno L, Fioramonti J, Garcia-Villar R. Pathobiology of Visceral Pain: Molecular Me- chanisms and Therapeutic ImplicationsⅢ. Visceral afferent pathways: a source of new therapeutic targets for abdominal pain. Am J Physiol Gastrointest Liver Physiol,2000,278(5): 670-676.
[6]Severini C, Improta G, Falconieri-Erspamer G, et al. The tachykinin peptide family. Pharmacol Rev. 2002,54(2):285-322.
[7]Regoli D, Boudon A, Fauchére JL. Receptors and antagonists for substance P and related peptides. Pharmacol Rev,1994,46(4):551-599.
[8]Maggi CA. The mammalian tachykinin receptors, Gen Pharmacol,1995,26(5):911-944.
[9]Mayer EA, Loo DD, Kodner A, et al. Differential modulation of Ca2(+)-activated K+ channels by substance P. Am J Physiol,1989 257(6 Pt 1):G887-897.
[10] Skidgel RA, Jackman HL, Erd?s EG.. Metabolism of substance P and bradykinin by human neutrophils. Biochem Pharmacol. 1991,41(9):1335-1344.
[11]Almeida TA, Rojo J, Nieto PM, et al. Tachykinins and tachykinin receptors: structure and activity relationships. Curr Med Chem,2004,11(15):2045-2081.
[12]Quartara L, Maggi CA. The tachykinin NK1 receptor. Part I: ligands and mechanisms of cellular activation. Neuropeptides,1997,31(6):537-563.
[13] Fiebich BL, Schleicher S, Butcher RD The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF-kappa B. J Immunol. 2000,165(10):5606-5611.
[14]H?kfelt T, Pernow B, Wahren J. Substance P: a pioneer amongst neuropeptides. J Intern Med. 2001,249(1):27-40.
[15] Holzer P, Lippe IT, Heinemann A, Bartho L. Tachykinin NK1 and NK2 receptor-mediated control of peristaltic propulsion in the guinea pig small intestine in vitro. Neuropharmacology ,1998;37:131-138.
[16]Kirkup AJ, Brunsden AM, Grundy D. Receptors and transmission in the brain-gut axis: potential for novel therapies. I. Receptors on visceral afferents. Am J Physiol Gastrointest Liver Physiol,2001 ,280(5):G787-794.
[17]Okano S, Nagaya H, Ikeura Y. Effects of TAK-637, a Novel Neurokinin-1 Receptor An on Colonic Function in Vivo. J Pharmacol Exp Ther,2001,298(2):559-564.
[18]陈晓敏,张燕华,毛峻岭,等.肠易激综合征患者结肠黏膜P物质、血管活性肠肽和肥大细胞的变化.胃肠病学,2008,13(4): 228-230.
[19]Xiao-Peng Ma, Lin-Ying Tan, Yun Yang , et al. Effect of electro-acupuncture on substance P, its receptor and corticotropin-releasing hormone in rats with irritable bowel syndrome.World J Gastroenterol,2009,15(41): 5211–5217.
[20]孙怡宁,罗金燕,兰莉,等.替加色罗对结肠炎大鼠内脏敏感性的影响及其与结肠内P物质和降钙素基因相关肽表达的关系.西安交通大学学报(医学版), 2007,28(5):506- 510.
[21]Bennett MR. The concept of long term potentiation of transmission at synapses. Prog Neurobiol. 2000,60(2):109-137.
[22]Musial F, H?user W, Langhorst J. Psychophysiology of visceral pain in IBS and health. J Psychosom Res. 2008,64(6):589-597..
[23]杜立峰,展淑琴,郭新奎. P物质、血管活性肠肽与异常胃肠通过的关系.西安交通大学学报(医学版), 2003,24(4):363-364+376.
[1]Rasquin A, Di Lorenzo C, Forbes D, et a1. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006 130(5):1527-1537.
[2]李定国,刘栋,许小幸,陆汉明.青少年儿童肠易激综合征的流行病学调查.中华消化杂志, 2005,25(5):266-269.
[3]Spiller RC. Post infectious irritable bowel syndrome. Gastroenterology, 2003,124(6):1662 -1671.
[4]Bishwa RT, Lanbo G, Robert JN. 5-HT7 receptors mediate the inhibitory effect of 5-HT on peristalsis in the isolated guinea-pig ileum. Br J Pharmacol, 2003,138(7): 1210–1214.
[5]Monnikes H, Ruter J, Konig M, et a1. Differential induction of c-fos expression in brain nuclei by noxious and non-noxious colonic distension: role of afferent C-fibers and 5-HT3 receptors. Brain Res, 2003,966(2):253-264.
[6]De Ponti F, Tonini M. Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. Drugs, 2001,61(3):317-332.
[7]Ruch M, Hamelin B, Rhss K, et al. The effect of mosapride, a novel prokinetic,on acid reflux variables in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther,1998,12(1): 35-40.
[8]Camilleri M. Management of the irritable bowel syndrome. Gastroentero, 2001,120(3):652–668.
[9]Glatzle J, Sternini C, Robin C, et a1. Expression of 5-HT3 receptors in the rat gastrointestinal tract. Gastroentero,2002,123(1):217-226.
[10]Davies PA, Pistis M, Hanna MC, et a1. The 5-HT3B subunit is a major determinant of serotonin- receptor function. Nature,1999,397(6717):359-363.
[11]Niesler B, Walstab J, Combrink S, et a1. Characterization of the novel human serotoni n receptor subunits 5-HT3C, 5-HT3D, and 5-HT3E. Mol Pharmacol,2007,72(1):8-17.
[12]Michel K, Zeller F, Langer R, et al. Serotonin excites neurons in the human submucous plexus via 5-HT3 receptors. Gastroenterology, 2005,128(5):1317-1326.
[13]Van Lelyveld N, Ter Linde J, Schipper M, et al. Serotonergic signalling in the stomachand duodenum of patients with gastroparesis. Neurogastroenterol Motil, 2008,20(5):448–455.
[14]Niesler B, Walstab J, Combrink S, et al. Characterization of the novel human serotonin receptor subunits 5-HT3C, 5-HT3D, and 5-HT3E. Mol Pharmacol, 2007,72(1):8–17.
[15]Johannes K, Lesley AH, Hubert M, et al. First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. Human Molecular Genetics, 2008,17(19):2967-2977.
[16]Ouyang A,Wrzos, H.F. Contribution of gender to pathophysiology and clinical presentation of IBS: should management be different in women?Am.J.Gastroenterol,2006,101(12Suppl):S602 -S609.
[17]Keating E, Lemos C, Monteiro R , et al. The effect of a series of organic cations upon the plasmalemmal serotonin transporter, SERT, Life Sci,2004,76(1):103-119.
[18]Camilleri M, Atanasova E, Carlson PJ, et al. Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome. Gastroentero,2002,123(2): 425-432.
[19]Camilleri M, Northcutt AR, Kong S, et al. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet,2000,355 (9209):1035-1040.
[20]Friedel D, Thomas R, Fisher RS. Ischemic colitis during treatment with alosetron. Gastroentero. 2001,21(1):231-232.
[21]Moynihan R. Alosetron: a case study in regulatory capture, or a victory for patients' rights? BMJ, 2002,325(7364):592-595.
[22]Chang L, Chey WD, Harris L, et al. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am J Gastroenterol, 2006,101(5):1069-1079.
[23]Rahimi R, Nikfar S, Abdollahi M. Efficacy and tolerability of alosetron for the treatmentof irritable bowel syndrome in women and men: A meta-analysis of eight randomized, placebo- controlled, 12-week trials. Clin Ther,2008,30(5):884-901.
[24]Hirata T, Funatsu T, Keto Y, et al. Pharmacological profle of ramosetron, a novel therapeutic agent for IBS. Inflammopharmacology, 2007 15(1):5-9.
[25]Hirata T, Keto Y, Funatsu T, et al. Evaluation of the pharmacological profile of ramosetron, a novel therapeutic agent for irritable bowel syndrome. J Pharmacol Sci, 2007,104(3):263-273.
[26]Funatsu T, Takeuchi A, Hirata T, et al. Effect of ramosetron on conditioned emotional stress- induced colonic dysfunction as a model of irritable bowel syndrome in rats. Eur J Pharmacol, 2007, 573(1-3):190-195.
[27]Matsueda K, Harasawa S, Hongo M, et al. A phase II trial of the novel serotonin type 3 receptor antagonist ramosetron in Japanese male and female patients with diarrhea- predominant irritable bowel syndrome. Digestion, 2008,77(3-4):225-235.
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