Department of Neurological Sciences, University of Vermont, Burlington, VT, USA.
Department of Surgery, University of Vermont Medical Center, Burlington, VT, USA.
Neurogastroenterol Motil. 2021 Apr;33(4):e14026. doi: 10.1111/nmo.14026. Epub 2020 Nov 12.
5-HT receptor (5-HT R) agonists exert prokinetic actions in the GI tract, but non-selective actions and potential for stimulation of non-target 5-HT Rs have limited their use. Since 5-HT Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5-HT R agonists promote intestinal motility.
Non-absorbed 5-HT R agonists, based on prucalopride and naronapride, were assessed for potency at the 5-HT R in vitro, and for tissue and serum distribution in vivo in mice. In vivo assessment of prokinetic potential included whole gut transit, colonic motility, fecal output, and fecal water content. Colonic motility was also studied ex vivo in mice treated in vivo. Immunofluorescence was used to evaluate receptor distribution in human intestinal mucosa.
Pharmacological screening demonstrated selectivity and potency of test agonists for 5-HT R. Bioavailability studies showed negligible serum detection. Gavage of agonists caused faster whole gut transit and colonic motility, increased fecal output, and elevated fecal water content. Prokinetic actions were blocked by a 5-HT R antagonist and were not detected in 5-HT R knockout mice. Agonist administration promoted motility in models of constipation. Evaluation of motility patterns ex vivo revealed enhanced contractility in the middle and distal colon. Immunoreactivity for 5-HT R is present in the epithelial layer of the human small and large intestines.
These findings demonstrated that stimulation of epithelial 5-HT Rs can potentiate propulsive motility and support the concept that mucosal 5-HT Rs could represent a safe and effective therapeutic target for the treatment of constipation.
5-羟色胺受体（5-HT R）激动剂在胃肠道中发挥促动力作用，但由于非选择性作用和潜在的非靶标 5-HT R 刺激，其应用受到限制。由于 5-HT R 在结肠上皮细胞中表达，其刺激可在体外加速结肠推进，因此我们测试了腔内作用的 5-HT R 激动剂是否能促进肠道运动。
基于普卡必利和那罗普肽的非吸收性 5-HT R 激动剂，在体外评估其对 5-HT R 的效力，以及在体内评估其在小鼠中的组织和血清分布。体内评估促动力潜能包括全肠道转运、结肠动力、粪便排出量和粪便含水量。在体内治疗后，还在体外研究了结肠动力。免疫荧光用于评估人类肠黏膜中受体的分布。
药物筛选显示测试激动剂对 5-HT R 的选择性和效力。生物利用度研究表明血清检测可忽略不计。激动剂灌胃导致全肠道转运和结肠动力加快，粪便排出量增加，粪便含水量升高。5-HT R 拮抗剂可阻断促动力作用，在 5-HT R 敲除小鼠中未检测到。激动剂给药可促进便秘模型中的动力。对离体运动模式的评估显示，中、远端结肠的收缩力增强。5-HT R 免疫反应性存在于人类小肠和大肠的上皮层中。
这些发现表明，刺激上皮 5-HT R 可以增强推进性运动，并支持黏膜 5-HT R 可能是治疗便秘的安全有效治疗靶点的概念。
