Nozu Tsukasa, Miyagishi Saori, Nozu Rintaro, Takakusaki Kaoru, Okumura Toshikatsu
Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
J Gastroenterol Hepatol. 2017 Dec;32(12):1958-1965. doi: 10.1111/jgh.13787.
Repeated water avoidance stress (WAS) induces visceral hypersensitivity. Additionally, it is also known to activate corticotropin-releasing factor (CRF), mast cells, and pro-inflammatory cytokines systems, but their precise roles on visceral sensation have not been determined definitely. The aim of the study was to explore this issue.
Abdominal muscle contractions induced by colonic balloon distention, that is, visceromotor response (VMR) was detected electrophysiologically in conscious rats. WAS or sham stress as control for 1 h daily was loaded, and the threshold of VMR was determined before and at 24 h after the stress.
Repeated WAS for three consecutive days reduced the threshold of VMR, but sham stress did not induce any change. Astressin, a CRF receptor antagonist (50 μg/kg) intraperitoneally (ip) at 10 min before each WAS session, prevented the visceral allodynia, but the antagonist (200 μg/kg) ip at 30 min and 15 h before measurement of the threshold after completing 3-day stress session did not modify the response. Ketotifen, a mast cell stabilizer (3 mg/kg), anakinra, an interleukin (IL)-1 receptor antagonist (20 mg/kg) or IL-6 antibody (16.6 μg/kg) ip for two times before the measurement abolished the response.
Repeated WAS for three consecutive days induced visceral allodynia, which was mediated through mast cells, IL-1, and IL-6 pathways. Inhibition of peripheral CRF signaling prevented but did not reverse this response, suggesting that peripheral CRF may be an essential trigger but may not contribute to the maintenance of repeated WAS-induced visceral allodynia.
反复水回避应激（WAS）可诱发内脏超敏反应。此外，已知其还会激活促肾上腺皮质激素释放因子（CRF）、肥大细胞和促炎细胞因子系统，但其在内脏感觉中的精确作用尚未明确确定。本研究旨在探讨这一问题。
在清醒大鼠中通过结肠球囊扩张诱发的腹部肌肉收缩，即内脏运动反应（VMR），采用电生理学方法进行检测。每天进行1小时的WAS或假应激作为对照，在应激前和应激后24小时测定VMR阈值。
连续三天反复进行WAS可降低VMR阈值，但假应激未引起任何变化。在每次WAS试验前10分钟腹腔注射（ip）CRF受体拮抗剂阿施他辛（50μg/kg）可预防内脏痛觉过敏，但在完成3天应激试验后，在测量阈值前30分钟和15小时腹腔注射拮抗剂（200μg/kg）并未改变反应。在测量前腹腔注射两次肥大细胞稳定剂酮替芬（3mg/kg）、白细胞介素（IL）-1受体拮抗剂阿那白滞素（20mg/kg）或IL-6抗体（16.6μg/kg）可消除反应。
连续三天反复进行WAS可诱发内脏痛觉过敏，其通过肥大细胞、IL-1和IL-6途径介导。抑制外周CRF信号传导可预防但不能逆转这种反应，表明外周CRF可能是一个重要的触发因素，但可能对反复WAS诱发的内脏痛觉过敏的维持没有作用。
