Saito-Nakaya K, Hasegawa R, Nagura Y, Ito H, Fukudo S
Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Neurogastroenterol Motil. 2008 Oct;20(10):1147-56. doi: 10.1111/j.1365-2982.2008.01151.x. Epub 2008 Aug 28.
Gastroenteritis is one of the risk factors for developing irritable bowel syndrome (IBS). However, the precise mechanism of postinfectious IBS is still unknown. We tested the hypothesis that a combination of previous inflammation and repetitive colorectal distention (CRD) makes the colon hypersensitive and that treatment with a corticotropin-releasing hormone receptor 1 (CRH-R1) antagonist blocks this colonic hypersensitivity. Rats were pretreated with vehicle or 2,4,6-trinitrobenzene sulphonic acid (TNBS) 6 weeks before CRD. For the CRD experiment, the colorectum was distended once a day for six consecutive days. The CRH-R1 antagonist (CP-154,526, 20 mg kg(-1)) or vehicle was injected subcutaneously 30 min before CRD. Visceral perception was quantified as visceromotor response (VMR) using an electromyograph. For histological examination, the rats were killed on the last day of CRD experiment, and haematoxylin and eosin-staining of colon segments was performed. Although from the first to the third day of CRD, VMRs increased in both the vehicle-treated rats and TNBS-treated rats, they were significantly higher in TNBS-treated rats than those in vehicle-treated controls. On the fifth day of CRD, however, VMRs in the vehicle-treated rats were significantly greater than those in TNBS-treated rats. Pretreatment of rats with CP-154,526 significantly attenuated the increase in VMR induced by repetitive CRD with previous inflammation. Finally, we found that repetitive CRD and repetitive CRD after colitis induced visceral inflammation. These results indicate that a combination of previous inflammation and repetitive CRD induces visceral hypersensitivity and that a CRH-R1 antagonist attenuates this response in rats.
肠胃炎是发展为肠易激综合征（IBS）的风险因素之一。然而，感染后IBS的确切机制仍不清楚。我们检验了这样一个假设，即先前的炎症和重复性结肠扩张（CRD）共同作用会使结肠变得超敏，而用促肾上腺皮质激素释放激素受体1（CRH-R1）拮抗剂进行治疗可阻断这种结肠超敏反应。在进行CRD实验前6周，用赋形剂或2,4,6-三硝基苯磺酸（TNBS）对大鼠进行预处理。在CRD实验中，连续6天每天对直肠进行一次扩张。在CRD前30分钟皮下注射CRH-R1拮抗剂（CP-154,526，20 mg·kg⁻¹）或赋形剂。使用肌电图将内脏感觉量化为内脏运动反应（VMR）。为进行组织学检查，在CRD实验的最后一天处死大鼠，并对结肠段进行苏木精和伊红染色。尽管在CRD的第一天到第三天，赋形剂处理组大鼠和TNBS处理组大鼠的VMR均增加，但TNBS处理组大鼠的VMR显著高于赋形剂处理组的对照大鼠。然而，在CRD的第五天，赋形剂处理组大鼠的VMR显著大于TNBS处理组大鼠。用CP-154,526对大鼠进行预处理可显著减轻先前炎症状态下重复性CRD诱导的VMR增加。最后，我们发现重复性CRD以及结肠炎后的重复性CRD均可诱导内脏炎症。这些结果表明，先前的炎症和重复性CRD共同作用可诱导内脏超敏反应，且CRH-R1拮抗剂可减轻大鼠的这种反应。
