Hasegawa Ryoko, Nakaya Kumi, Kanazawa Motoyori, Fukudo Shin
Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba, Sendai, 980-8575, Japan.
Division of Epidemiology, School of Public Health, Tohoku University Graduate School of Medicine, Sendai, Japan.
Biopsychosoc Med. 2025 Mar 28;19(1):5. doi: 10.1186/s13030-025-00324-0.
The prevailing paradigm for the etiology of irritable bowel syndrome is that transient noxious events lead to long-lasting sensitization of the neural pain circuit, despite complete resolution of the initiating event. In this study, we tested the hypotheses that (1) the combination of maternal separation (MS) and previous colorectal inflammation induces extensive visceral hypersensitivity in rats and (2) visceral hypersensitivity induced by maternal separation and previous colorectal inflammation in rats is mediated via the corticotropin-releasing hormone receptor-1 (CRH-R1) pathway.
Male rat pups were separated from their dams from postnatal day 2 to postnatal day 21. Acute colitis was induced by colorectal administration of trinitrobenzene sulfonic acid (TNBS) or vehicle on postnatal day 8. On postnatal day 50, the visceromotor response was evaluated by electromyography of the abdominal muscle in response to graded (10-80 mmHg) and phasic colorectal distention (CRD) one time. The same experiments were repeated after administration of the selective CRH-R1 antagonist CP-154,526 (20 mg/kg) or vehicle at 45 min before CRD.
Compared with control rats, visceral perception was increased in MS + TNBS rats. MS + TNBS rats showed a significantly larger visceromotor response to phasic CRD with 40 mmHg, 60 mmHg, and 80 mmHg. Compared with vehicle administration in MS + TNBS rats, administration of CP-154,526 significantly attenuated this visceromotor response to CRD with 40 mmHg, 60 mmHg, and 80 mmHg.
These findings suggest that the combination of previous colitis and early life stress induce visceral hypersensitivity, and that the CRH-R1 pathway may play a role in this sensitization.
肠易激综合征病因的主流范式是，尽管引发事件已完全消退，但短暂的有害事件会导致神经疼痛回路的长期致敏。在本研究中，我们检验了以下假设：（1）母婴分离（MS）与先前的结肠直肠炎症相结合会在大鼠中诱发广泛的内脏超敏反应；（2）大鼠中由母婴分离和先前的结肠直肠炎症诱发的内脏超敏反应是通过促肾上腺皮质激素释放激素受体-1（CRH-R1）途径介导的。
雄性幼鼠在出生后第2天至第21天与母鼠分离。在出生后第8天，通过结肠直肠给予三硝基苯磺酸（TNBS）或赋形剂诱导急性结肠炎。在出生后第50天，通过腹部肌肉的肌电图评估内脏运动反应，以响应分级（10 - 80 mmHg）和阶段性结肠直肠扩张（CRD）一次。在CRD前45分钟给予选择性CRH-R1拮抗剂CP-154,526（20 mg/kg）或赋形剂后，重复相同实验。
与对照大鼠相比，MS + TNBS大鼠的内脏感觉增强。MS + TNBS大鼠对40 mmHg、60 mmHg和80 mmHg的阶段性CRD表现出明显更大的内脏运动反应。与MS + TNBS大鼠给予赋形剂相比，给予CP-154,526可显著减弱对40 mmHg、60 mmHg和80 mmHg的CRD的这种内脏运动反应。
这些发现表明，先前的结肠炎和早期生活应激相结合会诱发内脏超敏反应，并且CRH-R1途径可能在这种致敏过程中起作用。
