Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
J Gastroenterol Hepatol. 2018 Jan;33(1):232-239. doi: 10.1111/jgh.13808.
A glucagon-like peptide-1 analog, liraglutide, has been reported to block inflammatory somatic pain. We hypothesized that liraglutide attenuates lipopolysaccharide (LPS)-induced and repeated water avoidance stress (WAS)-induced visceral hypersensitivity and tested the hypothesis in rats.
The threshold of the visceromotor response induced by colonic balloon distention was measured to assess visceral sensation. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue spectrophotometrically, which was instilled in the proximal colon for 15 min. The interleukin-6 level in colonic mucosa was also quantified using ELISA.
Subcutaneously injected LPS (1 mg/kg) reduced the visceromotor response threshold after 3 h. Liraglutide (300 μg/kg subcutaneously) at 15 h and 30 min before injecting LPS eliminated LPS-induced allodynia. It also blocked the allodynia induced by repeated water avoidance stress for 1 h for three consecutive days. Neither vagotomy nor naloxone altered the antinociceptive effect of liraglutide, but N -nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor, blocked it. LPS increased colonic permeability and the interleukin-6 level, and the analog significantly inhibited these responses.
This study suggests that liraglutide blocked LPS-induced visceral allodynia, which may be a nitric oxide-dependent response, and was probably mediated by inhibiting pro-inflammatory cytokine production and attenuating the increased gut permeability. Because the LPS-cytokine system is considered to contribute to altered visceral sensation in irritable bowel syndrome, these results indicate the possibility that liraglutide can be useful for treating this disease.
胰高血糖素样肽-1 类似物利拉鲁肽已被报道可阻断炎症性躯体疼痛。我们假设利拉鲁肽可减轻脂多糖（LPS）诱导和重复回避水应激（WAS）诱导的内脏高敏，并在大鼠中验证这一假设。
通过测量结肠球囊扩张引起的内脏运动反应阈值来评估内脏感觉。通过定量吸收的 Evans 蓝分光光度法在体内测定结肠通透性，将 Evans 蓝注入近端结肠 15 分钟。还使用 ELISA 定量测定结肠黏膜中的白细胞介素-6 水平。
皮下注射 LPS（1mg/kg）可在 3 小时后降低内脏运动反应阈值。在注射 LPS 前 15 小时和 30 分钟皮下注射利拉鲁肽（300μg/kg）可消除 LPS 诱导的痛觉过敏。它还可阻断连续 3 天每天 1 小时的重复回避水应激引起的痛觉过敏。迷走神经切断术或纳洛酮均不改变利拉鲁肽的镇痛作用，但一氧化氮合酶抑制剂 N-硝基-L-精氨酸甲酯可阻断其作用。LPS 增加结肠通透性和白细胞介素-6 水平，类似物显著抑制这些反应。
本研究表明，利拉鲁肽可阻断 LPS 诱导的内脏痛觉过敏，这可能是一种依赖于一氧化氮的反应，可能是通过抑制促炎细胞因子的产生和减轻增加的肠道通透性来实现的。由于 LPS-细胞因子系统被认为有助于肠易激综合征中内脏感觉的改变，这些结果表明利拉鲁肽有可能用于治疗这种疾病。
