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. Long‐term increase of CRF1 induced ICC damage, which may be an indirect effect through enteric neurons to decrease expression of SCF or a direct effect of ICC itself, resulting in colon dysmotility.