Corticotropin-releasing factor receptor agonists decrease interstitial cells of Cajal in murine colon

Background: Peripheral corticotropin-releasing factor (CRF) has been reported to affect gastrointestinal motility through corticotropin-releasing factor receptor located in enteric nervous system (ENS), but less is known about of the relationship between peripheral CRF and interstitial cells of Cajal (ICC).

Methods: Mice were intraperitoneally injected with CRF receptor agonists to determine their effects on colonic ICC. Chronic heterotypic stress (CHeS) was applied to mice to determine endogenous CRF-CRF receptor signaling on colonic ICC.

Results: We found that stressin1, a selective CRF receptor 1 (CRF₁ ) agonist, significantly increased the expression of CRF₁ but had no effect on the expression of CRF₂ in the smooth muscles of murine colon. The protein expression of c-Kit, Anoctamin-1 (ANO1), and stem cell factor (SCF) in the colonic smooth muscles was significantly decreased in stressin1-treated mice. Accordingly, 2-(4-Chloro-2-methylphenoxy)-N'-(2-methoxybenzylidene) acetohydrazide (Ani 9), a selective ANO1 blocker, had a less significant inhibitory effect on CMMC in stressin1-treated mice compared to the saline-treated ones. Similarly, we also found that ICC and ANO1 were reduced in the colonic smooth muscles of mice by treatment with sauvagine (ip), a CRF₂ agonist. However, different with stressin1, sauvagine decreased the expression of CRF₂ besides increasing CRF₁ expression in the colonic smooth muscles. Similar results of CRF₁ and c-Kit expressions were also obtained from the colon of CHeS-treated mice.

Conclusion: All these results suggest that CRF may be involved in the abnormality of colonic motility through peripheral CRF₁ to decrease the number and function of ICC, which provides a potential target for treating stress-induced gastrointestinal motility disorder.