Electroacupuncture ameliorates visceral hypersensitivity and negative emotions by regulating paraventricular hypothalamic nucleus and colonic corticotropin-releasing factor signaling

BACKGROUND Visceral hypersensitivity is the core pathogenesis of irritable bowel syndrome (IBS) and is often accompanied by negative emotions such as anxiety or depression. Paraventricular hypothalamic nucleus (PVN) corticotropin-releasing factor (CRF) is involved in the stress-related gastrointestinal dysfunction. Electroacupuncture (EA) has unique advantages for the treatment of visceral hypersensitivity and negative emotions in IBS patients. However, the underlying mechanisms remain unclear. AIM To investigate the pathological mechanisms visceral hypersensitivity and negative emotions in IBS, as well as the effect mechanism of EA. METHODS A model of diarrhoeal IBS (IBS-D) with negative emotions was prepared by chronic restraint combined with glacial acetic acid enema. The effect of EA was verified by abdominal withdrawal reflex and open-field test. PVN CRF-colonic mast cell (MC)/transient potential receptor vanilloid type 1 (TRPV1) pathway was detected by immunofluorescence, Western blot, ELISA, and toluidine blue staining. Moreover, PVN CRFergic neurons were activated or inhibited by chemogenetical technique to observe the changes of effect indicator. RESULTS In the model group, IBS-D symptoms and negative emotions were successfully induced. Notably, the combination of Baihui (GV20) with Tianshu (ST25) and Dachangshu (BL25) acupoints showed the greatest efficacy in improving the negative emotions and visceral hypersensitivity in model mice. Furthermore, we found that EA inhibited overactivated PVN CRFergic neurons and the overexpression of serum CRF, colonic CRF, CRF-receptor 1 (CRF-R1), mast cell tryptase (MCT), protease-activated receptor 2 and TRPV1 in model mice. Moreover, we found that activating PVN CRFergic neurons induced negative emotions and visceral hypersensitivity in normal mice; however, inhibiting PVN CRFergic neurons alleviated negative emotions and intestinal symptoms in model mice and decreased the expression of colonic CRF-R1, MCT, and TRPV1. CONCLUSION This research highlights the key role of PVN CRF-MC CRF-R1 and the downstream MC/TRPV1 pathway in the pathological process of IBS-D and the mechanism of the effect of EA.