Yang Y, Cui X, Chen Y, Wang Y, Li X, Lin L, Zhang H
Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
J Physiol Pharmacol. 2014 Jun;65(3):349-57.
Glucagon-like peptide-1 (GLP-1) analogue ROSE-010 can provide effective pain relief from irritable bowel syndrome (IBS). However, the underlying biological mechanism is still unknown. Here, we investigate the effect of GLP-1 analogue exendin-4 on visceral hypersensitivity in colonic sensitized rats. Rat models of visceral hypersensitivity were established by intra-colonic infusion of acetic acid in 10-day-old Sprague-Dawley rats. Visceral sensitivity was assessed by measurement of abdominal withdrawal reflex (AWR) and electromyography (EMG). Exendin-4 with doses of 1, 5, and 10 μg/kg were intraperitoneally administered, respectively. The expressions of serotonin transporter (SERT) and tryptophan hydroxylase-1 (TPH-1) in colonic tissues were detected by RT-PCR and Western blot, respectively. The levels of serotonin (5-HT) and GLP-1 were measured by ELISA assay. Visceral hypersensitivity after neonatal colonic sensitization was verified. The colonic sensitized rats showed low levels of GLP-1 in plasma and high levels of 5-HT in plasma and colonic tissue (P<0.05). Exendin-4 dose-dependently reduced visceral hypersensitivity in colonic sensitized rats. The AWR scores in colonic sensitized rats with exendin-4 (5 μg/kg) reduced to 1.56±0.53 (P=0.013 vs. 2.33±0.50), 2.23±0.45 (P=0.008 vs. 3.0±0.5) during CRD at 40, and 60 mmHg, respectively. Similar findings were showed at dose of 10 μg/kg. Exendin-4 (5 μg/kg and 10 μg/kg) reduced the EMG during CRD at 40, 60, 80 mmHg (P<0.01). Exendin-4 (5.0 μg/kg or 10.0 μg/kg) significantly decreased the 5-HT colonic levels (2.343±0.447, 2.175±0.360 ng/100 mg vs. 3.607±0.628 ng/100 mg, P<0.05). The SERT protein expressions in colonic tissues in colonic sensitized rats were significantly increased with exendin-4 at doses of 1, 5 or 10 μg/kg (0.759±0.068, 0.942±0.037, 0.944±0.097 vs. 0.552±0.047, P<0.05, respectively), and the SERT mRNA expression also increased after treatment with exendin-4. The colonic sensitized rats showed lower TPH-1 levels after treatment with exendin-4 (P<0.05). These findings suggest that exendin-4 reduce visceral hypersensitivity and this may be associated with up-regulating SERT expression, and down-regulating TPH-1 expression.
胰高血糖素样肽-1（GLP-1）类似物ROSE-010可有效缓解肠易激综合征（IBS）的疼痛。然而，其潜在的生物学机制仍不清楚。在此，我们研究GLP-1类似物艾塞那肽-4对结肠致敏大鼠内脏超敏反应的影响。通过向10日龄的斯普拉格-道利大鼠结肠内注入乙酸建立内脏超敏反应大鼠模型。通过测量腹部回撤反射（AWR）和肌电图（EMG）评估内脏敏感性。分别腹腔注射剂量为1、5和10μg/kg的艾塞那肽-4。分别通过RT-PCR和蛋白质印迹法检测结肠组织中5-羟色胺转运体（SERT）和色氨酸羟化酶-1（TPH-1）的表达。通过ELISA法检测5-羟色胺（5-HT）和GLP-1的水平。验证了新生大鼠结肠致敏后的内脏超敏反应。结肠致敏大鼠血浆中GLP-1水平较低，血浆和结肠组织中5-HT水平较高（P<0.05）。艾塞那肽-4剂量依赖性地降低结肠致敏大鼠的内脏超敏反应。在40和60 mmHg的结直肠扩张（CRD）期间，注射艾塞那肽-4（5μg/kg）的结肠致敏大鼠的AWR评分分别降至1.56±0.53（与2.33±0.50相比，P=0.013）、2.23±0.45（与3.0±0.5相比，P=0.008）。在10μg/kg剂量时也有类似发现。艾塞那肽-4（5μg/kg和10μg/kg）在40、60、80 mmHg的CRD期间降低了EMG（P<0.01）。艾塞那肽-4（5.0μg/kg或10.0μg/kg）显著降低结肠5-HT水平（2.343±0.447、2.175±0.360 ng/100 mg与3.607±0.628 ng/100 mg相比，P<0.05）。在结肠致敏大鼠中，剂量为1、5或10μg/kg的艾塞那肽-4可显著增加结肠组织中SERT蛋白表达（分别为0.759±0.068、0.942±0.037、0.944±0.097与0.552±0.047相比，P<0.05），且艾塞那肽-4治疗后SERT mRNA表达也增加。结肠致敏大鼠经艾塞那肽-4治疗后TPH-1水平降低（P<0.05）。这些发现表明，艾塞那肽-4可降低内脏超敏反应，这可能与上调SERT表达和下调TPH-1表达有关。
