From the Enteric Neurosciences Program, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, MN, USA.
Neurogastroenterol Motil. 2010 Mar;22(3):227-31. doi: 10.1111/j.1365-2982.2009.01465.x.
Ongoing clinical trials suggest that linaclotide, a first-in-class, 14-amino acid peptide guanylate cyclase-C (GC-C) receptor agonist and intestinal secretagogue is an effective treatment for chronic constipation. A study in this issue of the Journal suggests that linaclotide also has antihyperalgesic effects in three common rat models of inflammation- and stress-induced hypersensitivity (i.e., acute trinitrobenzene sulfonic acid colitis, water avoidance stress [WAS], and restraint-induced stress) but not in naïve animals. In mice, linaclotide at least partly reduces hyperalgesia via GC-C receptors. Dose-effect relationships of linaclotide were complicated and non-linear. This viewpoint discusses human clinical trials with linaclotide and the results of this study. Potential mechanisms and clinical significance of these findings are explored. Collectively, these data suggest that GC-C receptors exert other, as yet poorly understood, effects on gastrointestinal sensitivity in conditions associated with inflammation and/or stress-induced increased intestinal permeability. However, the data need to be confirmed in humans and in long-term animal models. Further studies are also necessary to elucidate the mechanisms as these effects cannot be explained by linaclotide's known effects on epithelial GC-C receptors.
正在进行的临床试验表明，作为首个 14 个氨基酸的肽类肠上皮细胞 GC-C 受体激动剂和肠分泌剂，利那洛肽对于慢性便秘是一种有效的治疗药物。本期杂志中的一项研究表明，利那洛肽对于三种常见的炎症和应激诱导性敏感性的大鼠模型（即急性三硝基苯磺酸结肠炎、水回避应激和束缚应激）也具有抗痛觉过敏作用，但对于正常动物没有作用。在小鼠中，利那洛肽至少部分通过 GC-C 受体减轻了痛觉过敏。利那洛肽的剂量-效应关系复杂且非线性。本文观点讨论了利那洛肽的人体临床试验及该研究的结果。探索了这些发现的潜在机制和临床意义。总的来说，这些数据表明，在与炎症和/或应激诱导的肠道通透性增加相关的条件下，GC-C 受体对胃肠道敏感性产生了其他尚未完全了解的影响。然而，这些数据需要在人类和长期动物模型中得到证实。还需要进一步的研究来阐明这些作用的机制，因为这些作用不能用利那洛肽对上皮 GC-C 受体的已知作用来解释。
