The role of peripheral corticotropin-releasing factor signaling in a rat model of stress-induced gastric hyperalgesia

Functional dyspepsia (FD) is a common gastrointestinal disorder associated with persistent or recurrent upper gastrointestinal tract symptoms such as pain without any obvious pathological changes. Psychological and psychiatric factors might have a pathogenic role in FD. Changes in the sensation of stomach pain were determined after application of stress to adult rats. The involvement of corticotropin-releasing factor (CRF), Type 2 CRF receptor (CRF2) and inflammatory cytokine interleukin-6 (IL-6) was also investigated in the gastric hyperalgesia observed in this model.Repeated water avoidance stress (WA-S) produced gastric hyperalgesia, with no obvious lesions in the gastric mucosa. Gastric hyperalgesia was inhibited by CRF and CRF2 antagonists, suggesting their involvement in gastric hyperalgesia observed after application of stress. Gastric hyperalgesia was inhibited by IL-6 neutralizing antibody. Immunofluorescence staining demonstrated CRF, CRF2, urocortin (Ucn)1, and Ucn2-positive cells in the gastric mucosa. CRF2-positive cells increased after WA-S, compared to sham stress. CRF2 and Ucn2 were expressed in the mast cells in the gastric mucosa.CRF2 plays an important role in gastric hyperalgesia produced by stress. CRF2 signaling may be a useful therapeutic target for functional dyspepsia.