Activation of guanylate cyclase-C attenuates stretch responses and sensitization of mouse colorectal afferents.
Activation of guanylate cyclase-C attenuates stretch responses and sensitization of mouse colorectal afferents.
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DOI：
10.1523/jneurosci.5114-12.2013
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发表时间：
2013-06-05
期刊：
影响因子：
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通讯作者：
Gebhart GF
中科院分区：
文献类型：
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作者：
Feng B;Kiyatkin ME;La JH;Ge P;Solinga R;Silos-Santiago I;Gebhart GF
肠易激综合征(IBS)的特征是排便习惯改变，持续的疼痛和不适，典型的结直肠过敏。利纳氯肽是一种外周限制性14氨基酸多肽，被批准用于治疗IBS便秘，缓解便秘并减轻这些患者的IBS相关疼痛，可能是通过激活鸟苷环化酶-C(GC-C)，刺激肠道上皮细胞产生和释放环鸟苷一磷酸(CGMP)。我们研究了内源性激动剂尿鸟苷或激活的主要下游效应物cGMP对GC-C的激活是否直接调节机械敏感型大肠初级传入的反应和敏化。取带盆神经的小鼠结肠远端2 cm处，将扁平的粘膜一侧朝上固定，进行体外单纤维记录，研究机械敏感传入(浆膜、粘膜、肌肉和肌肉-粘膜)对探查和周向牵拉的编码特性。CGMP(10-300μM)和尿鸟苷(1-1000 nm)直接作用于大肠感受性末梢可显著降低肌肉和肌肉-粘膜传入对牵张的反应，而对浆膜和粘膜传入无明显影响。CGMP逆转了肌肉和肌肉-粘膜传入的敏化反应(即，对拉伸的反应增加)，使对拉伸的反应恢复到对照。通过对培养的肠道T84细胞的研究证实，丙磺舒阻断大肠上皮细胞中cGMP的转运，消除了尿鸟苷对肌肉-粘膜传入的抑制作用。这些结果表明，GC-C激动剂，如利纳氯肽，通过抑制牵张敏感型传入机械敏感性和正常化传入敏化来减轻结直肠疼痛和超敏反应。
Irritable bowel syndrome (IBS) is characterized by altered bowel habits, persistent pain and discomfort, and typically colorectal hypersensitivity. Linaclotide, a peripherally-restricted 14-amino acid peptide approved for the treatment of IBS with constipation, relieves constipation and reduces IBS-associated pain in these patients presumably by activation of guanylate cyclase-C (GC-C), which stimulates production and release of cyclic guanosine monophosphate (cGMP) from intestinal epithelial cells. We investigated whether activation of GC-C by the endogenous agonist uroguanylin or the primary downstream effector of that activation, cGMP, directly modulates responses and sensitization of mechanosensitive colorectal primary afferents. The distal 2 cm of mouse colorectum with attached pelvic nerve was harvested, pinned flat mucosal side up for in vitro single-fiber recordings and the encoding properties of mechanosensitive afferents (serosal, mucosal, muscular and muscular-mucosal) to probing and circumferential stretch studied. Both cGMP (10–300μM) and uroguanylin (1–1000nM) applied directly to colorectal receptive endings significantly reduced responses of muscular and muscular-mucosal afferents to stretch; serosal and mucosal afferents were not affected. Sensitized responses (i.e., increased responses to stretch) of muscular and muscular-mucosal afferents were reversed by cGMP, returning responses to stretch to control. Blocking the transport of cGMP from colorectal epithelia by probenecid, a mechanism validated by studies in cultured intestinal T84 cells, abolished the inhibitory effect of uroguanylin on muscular-mucosal afferents. These results suggest that GC-C agonists like linaclotide alleviate colorectal pain and hypersensitivity by dampening stretch-sensitive afferent mechanosensitivity and normalizing afferent sensitization.