Department of Regional Medicine and Education, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
Department of General Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
J Gastroenterol. 2017 Jan;52(1):72-80. doi: 10.1007/s00535-016-1208-y. Epub 2016 Apr 13.
Lipopolysaccharide (LPS) induces visceral hypersensitivity, and corticotropin-releasing factor (CRF) also modulates visceral sensation. Besides, LPS increases CRF immunoreactivity in rat colon, which raises the possibility of the existence of a link between LPS and the CRF system in modulating visceral sensation. The present study tried to clarify this possibility.
Visceral sensation was assessed by abdominal muscle contractions induced by colonic balloon distention, i.e., visceromotor response, electrophysiologically in conscious rats. The threshold of visceromotor response was measured before and after administration of drugs.
LPS at a dose of 1 mg/kg subcutaneously (sc) decreased the threshold at 3 h after the administration. Intraperitoneal (ip) administration of anakinra (20 mg/kg), an interleukin-1 (IL-1) receptor antagonist, or interleukin-6 (IL-6) antibody (16.6 µg/kg) blocked this effect. Additionally, IL-1β (10 µg/kg, sc) or IL-6 (10 µg/kg, sc) induced visceral allodynia. Astressin (200 µg/kg, ip), a non-selective CRF receptor antagonist, abolished the effect of LPS, but astressin-B (200 µg/kg, ip), a CRF receptor type 2 (CRF2) antagonist, did not alter it. Peripheral CRF receptor type 1 (CRF1) stimulation by cortagine (60 µg/kg, ip) exaggerated the effect of LPS, but activation of CRF2 by urocortin 2 (60 µg/kg, ip) abolished it.
LPS induced visceral allodynia possibly through stimulating IL-1 and IL-6 release. In addition, this effect was mediated through peripheral CRF signaling. Since the LPS-cytokine system is thought to contribute to altered visceral sensation in the patients with irritable bowel syndrome, these results may further suggest that CRF plays a crucial role in the pathophysiology of this disease.
脂多糖（LPS）可诱导内脏敏感性，促肾上腺皮质释放因子（CRF）也可调节内脏感觉。此外，LPS 增加大鼠结肠中 CRF 的免疫反应性，这增加了 LPS 和 CRF 系统在调节内脏感觉方面存在联系的可能性。本研究试图阐明这种可能性。
通过对清醒大鼠进行结肠球囊扩张引起的腹肌收缩（即内脏运动反应）来评估内脏感觉。在给予药物之前和之后测量内脏运动反应的阈值。
皮下（sc）给予 LPS1mg/kg 可降低给药后 3 小时的阈值。腹腔内（ip）给予白细胞介素-1（IL-1）受体拮抗剂 anakinra（20mg/kg）或白细胞介素-6（IL-6）抗体（16.6μg/kg）可阻断此作用。此外，IL-1β（sc10μg/kg）或 IL-6（sc10μg/kg）可引起内脏痛觉过敏。非选择性 CRF 受体拮抗剂 astressin（200μg/kg，ip）可消除 LPS 的作用，但 CRF2 受体拮抗剂 astressin-B（200μg/kg，ip）则没有改变。外周 CRF 受体 1（CRF1）刺激通过 cortagine（ip60μg/kg）增强 LPS 的作用，但通过 urocortin 2（ip60μg/kg）激活 CRF2 则消除了这种作用。
LPS 诱导内脏痛觉过敏可能是通过刺激白细胞介素-1 和白细胞介素-6 的释放。此外，这种作用是通过外周 CRF 信号传递的。由于 LPS-细胞因子系统被认为有助于肠易激综合征患者内脏感觉的改变，这些结果可能进一步表明 CRF 在该疾病的病理生理学中起着关键作用。
