Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, AB, Canada.
Neurogastroenterol Motil. 2013 Aug;25(8):e550-9. doi: 10.1111/nmo.12158. Epub 2013 May 21.
Constipation-predominant irritable bowel syndrome (IBS-C) is a common functional gastrointestinal (GI) disorder with abdominal pain and decreased motility. Current treatments of IBS-C are insufficient. The aim of this study was to evaluate the potential application of taranabant, a cannabinoid type 1 (CB1) inverse agonist using mouse models mimicking the symptoms of IBS-C.
Changes in intestinal contractile activity were studied in vitro, using isolated mouse ileum and colon and intracellular recordings. In vivo, whole gastrointestinal transit (WGT) and fecal pellet output (FPO) were measured under standard conditions and with pharmacologically delayed GI transit. The antinociceptive effect was evaluated in mustard oil- and acetic acid-induced models of visceral pain. Forced swimming and tail suspension tests were performed and locomotor activity was measured to evaluate potential central side effects.
In vitro, taranabant (10(-10) -10(-7) mol L(-1)) increased contractile responses in mouse ileum and blocked the effect of the CB agonist WIN 55,212-2. Taranabant had no effect on the amplitude of electrical field stimulation (EFS)-evoked junction potentials. In vivo, taranabant (0.1-3 mg kg(-1), i.p. and 3 mg kg(-1), p.o.) increased WGT and FPO in mice and reversed experimental constipation. The effect of taranabant was absent in CB1(-/-) mice. Taranabant significantly decreased the number of pain-related behaviors in animal models. At the doses tested, taranabant did not display mood-related adverse side effects typical for CB1 receptor inverse agonists.
CONCLUSIONS & INFERENCES: Taranabant improved symptoms related to slow GI motility and abdominal pain and may become an attractive template in the development of novel therapeutics targeting IBS-C.
以腹痛和运动减少为特征的便秘型肠易激综合征（IBS-C）是一种常见的功能性胃肠道（GI）疾病。目前对 IBS-C 的治疗效果并不理想。本研究旨在评估大麻素 1 型（CB1）反向激动剂 taranabant 在模拟 IBS-C 症状的小鼠模型中的潜在应用。
使用分离的小鼠回肠和结肠以及细胞内记录研究了肠收缩活性的变化。在体内，在标准条件下和通过药物延迟 GI 转运的情况下测量全胃肠道转运（WGT）和粪便颗粒输出（FPO）。在芥末油和乙酸诱导的内脏疼痛模型中评估了镇痛作用。进行了强迫游泳和悬尾试验，并测量了运动活性以评估潜在的中枢副作用。
在体外，taranabant（10(-10) -10(-7) mol L(-1)）增加了小鼠回肠的收缩反应，并阻断了 CB 激动剂 WIN 55,212-2 的作用。Taranabant 对电刺激（EFS）诱发的结电位幅度没有影响。在体内，taranabant（0.1-3 mg kg(-1)，腹腔注射和 3 mg kg(-1)，口服）增加了小鼠的 WGT 和 FPO，并逆转了实验性便秘。在 CB1(-/-)小鼠中，taranabant 的作用不存在。Taranabant 显著减少了动物模型中与疼痛相关的行为次数。在测试的剂量下，taranabant 没有显示出与 CB1 受体反向激动剂相关的情绪相关的不良反应。
Taranabant 改善了与 GI 运动缓慢和腹痛相关的症状，可能成为治疗 IBS-C 的新型治疗方法的有吸引力的模板。
