Zielińska Marta, Jarmuż Agata, Wasilewski Andrzej, Cami-Kobeci Gerta, Husbands Stephen, Fichna Jakub
Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.
Pharmacol Rep. 2017 Apr;69(2):350-357. doi: 10.1016/j.pharep.2016.12.001. Epub 2016 Dec 5.
Diarrhea-predominant irritable bowel syndrome (IBS-D) is a functional disorder of the gastrointestinal (GI) tract. The major IBS-D symptoms include diarrhea, abdominal pain and discomfort. High density of opioid receptors (ORs) in the GI tract and their participation in the maintenance of GI homeostasis make ORs ligands an attractive option for developing new anti-IBS-D treatments. The aim of this study was to characterize the effect of methyl-orvinol on the GI motility and secretion and in mouse models mimicking symptoms of IBS-D.
In vitro, the effects of methyl-orvinol on electrical field stimulated smooth muscle contractility and epithelial ion transport were characterized in the mouse colon. In vivo, the following tests were used to determine methyl-orvinol effect on mouse GI motility: colonic bead expulsion, whole GI transit and fecal pellet output. An antinociceptive action of methyl-orvinol was assessed in the mouse model of visceral pain induced by mustard oil.
Methyl-orvinol (10 to 10M) inhibited colonic smooth muscle contractions in a concentration-dependent manner. This effect was reversed by naloxone (non-selective opioid antagonist) and β-funaltrexamine (selective MOP antagonist). Experiments with a selective KOP receptor agonist, U50488 revealed that methyl-orvinol is a KOP receptor antagonist in the GI tract. Methyl-orvinol enhanced epithelial ion transport. In vivo, methyl-orvinol inhibited colonic bead expulsion and prolonged GI transit. Methyl-orvinol improved hypermotility and reduced abdominal pain in the mouse models mimicking IBS-D symptoms.
Methyl-orvinol could become a promising drug candidate in chronic therapy of functional GI diseases such as IBS-D.
腹泻型肠易激综合征（IBS-D）是一种胃肠道功能性疾病。IBS-D的主要症状包括腹泻、腹痛和不适。胃肠道中阿片受体（ORs）的高密度表达及其在维持胃肠道内环境稳定中的作用，使得ORs配体成为开发新型抗IBS-D治疗药物的一个有吸引力的选择。本研究的目的是在模拟IBS-D症状的小鼠模型中，表征甲基奥诺醇对胃肠动力和分泌的影响。
在体外，在小鼠结肠中表征甲基奥诺醇对电场刺激的平滑肌收缩性和上皮离子转运的影响。在体内，采用以下试验来确定甲基奥诺醇对小鼠胃肠动力的影响：结肠珠排出、全胃肠转运和粪便颗粒输出。在芥子油诱导的内脏痛小鼠模型中评估甲基奥诺醇的镇痛作用。
甲基奥诺醇（10至10M）以浓度依赖性方式抑制结肠平滑肌收缩。这种作用被纳洛酮（非选择性阿片受体拮抗剂）和β-芬太尼透胺（选择性MOP拮抗剂）逆转。用选择性KOP受体激动剂U50488进行的实验表明，甲基奥诺醇是胃肠道中的KOP受体拮抗剂。甲基奥诺醇增强上皮离子转运。在体内，甲基奥诺醇抑制结肠珠排出并延长胃肠转运时间。甲基奥诺醇改善了模拟IBS-D症状的小鼠模型中的运动亢进并减轻了腹痛。
甲基奥诺醇可能成为治疗IBS-D等功能性胃肠疾病的有前景的候选药物。
