TRPV1 receptor signaling mediates afferent nerve sensitization during colitis-induced motility disorders in rats
TRPV1 receptor signaling mediates afferent nerve sensitization during colitis-induced motility disorders in rats
复制标题
DOI：
10.1152/ajpgi.00351.2007
复制
发表时间：
2008-01-01
影响因子：
4.5
通讯作者：
De Winter, B. Y.
中科院分区：
文献类型：
--
作者：
De Schepper, H. U.;De Man, J. G.;De Winter, B. Y.
患有实验性结肠炎的大鼠胃排空（GE）受损。我们之前表明这种现象涉及骨盆神经内的传入神经元。在这项研究中，我们的目的是确定参与这种传入过度激活的介质。通过硫酸三硝基苯(TNBS)滴注诱发结肠炎。胃内给予半液体伊文思蓝溶液 30 分钟后，我们测定了肠道运输的 GE、远端前端和几何中心 (GC)。我们评估了瞬时受体电位香草酸 1 型 (TRPV1) 拮抗剂辣椒西平 (5-10 mg/kg) 和 N-(4-叔丁基苯基)-4-(3-氯吡啶-2-基)四氢吡嗪-1(2H)甲酰胺 (BCTC；1-10 mg/kg) 和降钙素基因相关肽 (CGRP) 受体拮抗剂 CGRP-(8-37) 的作用(150μg/kg)。为了确定 TRPV1 受体拮抗剂的敏感性，我们检查了它们对辣椒素诱导的离体胃底肌肉条松弛的影响。在背根神经节 (DRG) L6-S1 中进行 TRPV1 的免疫细胞化学染色和 TRPV1 mRNA 的 RT-PCR 分析。 TNBS 诱导的结肠炎降低了 GE，但对肠道蠕动没有影响。辣椒西平可降低对照组大鼠的 GE，但对患有结肠炎的大鼠没有影响。在对对照组没有影响的剂量下，BCTC 和 CGRP-(8-37) 显着改善结肠炎引起的胃轻瘫。 Capsazepine 可抑制辣椒素引起的松弛 35%，而 BCTC 则完全消除它们。 TNBS诱导的结肠炎增加了DRG L6-S1盆腔传入神经元细胞体中的TRPV1样免疫反应性和TRPV1 mRNA含量。总之，大鼠远端结肠炎通过敏感的盆腔传入神经元损害 GE。我们提供了药理学、免疫细胞化学和分子生物学证据，证明这种致敏作用是由 TRPV1 受体介导的，并涉及 CGRP 释放。
Rats with experimental colitis suffer from impaired gastric emptying (GE). We previously showed that this phenomenon involves afferent neurons within the pelvic nerve. In this study, we aimed to identify the mediators involved in this afferent hyperactivation. Colitis was induced by trinitrobenzene sulfate (TNBS) instillation. We determined GE, distal front, and geometric center (GC) of intestinal transit 30 min after intragastric administration of a semiliquid Evans blue solution. We evaluated the effects of the transient receptor potential vanilloid type 1 (TRPV1) antagonists capsazepine (5-10 mg/kg) and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide (BCTC; 1-10 mg/kg) and the calcitonin generelated peptide (CGRP) receptor antagonist CGRP-(8-37) (150 mu g/kg). To determine TRPV1 receptor antagonist sensitivity, we examined their effect on capsaicin-induced relaxations of isolated gastric fundus muscle strips. Immunocytochemical staining of TRPV1 and RT-PCR analysis of TRPV1 mRNA were performed in dorsal root ganglion (DRG) L6-S1. TNBS-induced colitis reduced GE but had no effect on intestinal motility. Capsazepine reduced GE in controls but had no effect in rats with colitis. At doses that had no effects in controls, BCTC and CGRP-(8-37) significantly improved colitis-induced gastroparesis. Capsazepine inhibited capsaicin-induced relaxations by 35% whereas BCTC completely abolished them. TNBS-induced colitis increased TRPV1-like immunoreactivity and TRPV1 mRNA content in pelvic afferent neuronal cell bodies in DRG L6-S1. In conclusion, distal colitis in rats impairs GE via sensitized pelvic afferent neurons. We provided pharmacological, immunocytochemical, and molecular biological evidence that this sensitization is mediated by TRPV1 receptors and involves CGRP release.