Keates A C, Castagliuolo I, Qiu B, Nikulasson S, Sengupta A, Pothoulakis C
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston 02215, USA.
Am J Physiol. 1998 Jan;274(1):G196-202. doi: 10.1152/ajpgi.1998.274.1.G196.
We have previously reported that pretreatment of rats with capsaicin (an agent that ablates sensory neurons) or CP-96345 (a substance P receptor antagonist) dramatically inhibits fluid secretion and intestinal inflammation in ileal loops exposed to Clostridium difficile toxin A. The aim of this study was to determine whether calcitonin gene-related peptide (CGRP), a neuropeptide also found in sensory afferent neurons, participates in the enterotoxic effects of toxin A. Administration of toxin A was also found to increase CGRP content in dorsal root ganglia and ileal mucosa 60 min after toxin exposure. Furthermore, immunohistochemical studies demonstrated increased neuronal staining for CGRP 2 h after toxin A treatment. Pretreatment of rats with CGRP-(8-37), a specific CGRP antagonist, before instillation of toxin A into ileal loops significantly inhibited toxin-mediated fluid secretion (by 48%), mannitol permeability (by 83%), and histological damage. We conclude that CGRP, like substance P, contributes to the secretory and inflammatory effects of toxin A via increased production of this peptide from intestinal nerves, including primary sensory afferent neurons.
我们之前曾报道，用辣椒素（一种可消除感觉神经元的药物）或CP - 96345（一种P物质受体拮抗剂）对大鼠进行预处理，可显著抑制暴露于艰难梭菌毒素A的回肠袢中的液体分泌和肠道炎症。本研究的目的是确定降钙素基因相关肽（CGRP），一种在感觉传入神经元中也存在的神经肽，是否参与毒素A的肠毒性作用。毒素A给药后60分钟，还发现其可增加背根神经节和回肠黏膜中的CGRP含量。此外，免疫组化研究表明，毒素A处理2小时后，CGRP的神经元染色增加。在用CGRP -（8 - 37）（一种特异性CGRP拮抗剂）对大鼠进行预处理后，再将毒素A注入回肠袢，可显著抑制毒素介导的液体分泌（降低48%）、甘露醇通透性（降低83%）和组织学损伤。我们得出结论，CGRP与P物质一样，通过包括初级感觉传入神经元在内的肠道神经中该肽产量的增加，促成毒素A的分泌和炎症效应。
