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

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).

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.

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.

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.