Mao Yuqing, Li Zhengyang, Chen Kan, Yu Huafang, Zhang Shaoren, Jiang Miao, Ma Yuanhua, Liang Chunli, Liu Hongyan, Li Huanqing, Hua Qian, Zhou Hao, Sun Yonghong, Fan Xiaoming
Department of Gastroenterology and Hepatology, Jinshan Hospital of Fudan University, Shanghai, China.
Department of Gastroenterology and Hepatology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
Cell Physiol Biochem. 2017;43(2):518-530. doi: 10.1159/000480478. Epub 2017 Sep 20.
BACKGROUND/AIMS: Irritable bowel syndrome (IBS), defined as recurrent abdominal pain and changes in bowel habits, seriously affects quality of life and ability to work. Ghrelin is a brain-gut hormone, which has been reported to show antinociceptive effects in peripheral pain. We investigated the effect of ghrelin on visceral hypersensitivity and pain in a rat model of IBS.
Maternal deprivation (MD) was used to provide a stress-induced model of IBS in Wistar rats. Colorectal distension (CRD) was used to detect visceral sensitivity, which was evaluated by abdominal withdrawal reflex (AWR) scores. Rats that were confirmed to have visceral hypersensitivity after MD were injected with ghrelin (10 µg/kg) subcutaneously twice a week from weeks 7 to 8. [D-Lys3]-GHRP-6 (100 nmol/L) and naloxone (100 nmol/L) were administered subcutaneously to block growth hormone secretagogue receptor 1α (GHS-R1α) and opioid receptors, respectively. Expression of transient receptor potential vanilloid type 1 (TRPV1) and µ and κ opioid receptors (MOR and KOR) in colon, dorsal root ganglion (DRG) and cerebral cortex tissues were detected by western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemical analyses and immunofluorescence.
Ghrelin treatment increased expression of opioid receptors and inhibited expression of TRPV1 in colon, dorsal root ganglion (DRG) and cerebral cortex. The antinociceptive effect of ghrelin in the rat model of IBS was partly blocked by both the ghrelin antagonist [D-Lys3]-GHRP-6 and the opioid receptor antagonist naloxone.
The results indicate that ghrelin exerted an antinociceptive effect, which was mediated via TRPV1/opioid systems, in IBS-induced visceral hypersensitivity. Ghrelin might potentially be used as a new treatment for IBS.
背景/目的：肠易激综合征（IBS）表现为反复腹痛和排便习惯改变，严重影响生活质量和工作能力。胃饥饿素是一种脑肠肽，据报道其在外周疼痛中具有抗伤害感受作用。我们在IBS大鼠模型中研究了胃饥饿素对内脏超敏反应和疼痛的影响。
采用母婴分离（MD）法建立Wistar大鼠应激诱导的IBS模型。采用结直肠扩张（CRD）检测内脏敏感性，通过腹部撤回反射（AWR）评分进行评估。MD后确认有内脏超敏反应的大鼠，在第7至8周每周皮下注射两次胃饥饿素（10μg/kg）。分别皮下注射[D-Lys3]-GHRP-6（100nmol/L）和纳洛酮（100nmol/L）以阻断生长激素促分泌素受体1α（GHS-R1α）和阿片受体。通过蛋白质免疫印迹法、定量实时聚合酶链反应（qRT-PCR）、免疫组织化学分析和免疫荧光检测结肠、背根神经节（DRG）和大脑皮质组织中瞬时受体电位香草酸亚型1（TRPV1）以及μ和κ阿片受体（MOR和KOR）的表达。
胃饥饿素治疗增加了结肠、背根神经节（DRG）和大脑皮质中阿片受体的表达，并抑制了TRPV1的表达。胃饥饿素拮抗剂[D-Lys3]-GHRP-6和阿片受体拮抗剂纳洛酮均可部分阻断胃饥饿素在IBS大鼠模型中的抗伤害感受作用。
结果表明，胃饥饿素在IBS诱导的内脏超敏反应中发挥抗伤害感受作用，其作用通过TRPV1/阿片系统介导。胃饥饿素可能有望成为IBS的一种新的治疗方法。
