However, the long-lasting modification of colonic epithelial CRF and CRH-1 receptor expression observed in the Paclitaxel CORT-nursed phenotype does not affect the homeostasis capacity of healthy CORT-nursed rats. Conversely, under TNBS colitis, an opposing modification of colonic CRH-1R expression corresponds to the up-regulation in colonic CRF expression, both in CORTnursed and control rats. In particular, in CORT-nursed rats, unlike control rats, the induction of colitis caused the downregulation of epithelial CRH-1R. The fact that the CORT-nursed phenotype, under basal conditions as well as under experimental colitis, shows a difference in expression of the peripheral CRFergic system, supports the involvement of this system in the reduced vulnerability to colitis observed in this model. CORT-nursed rats are more apt to counteract the homeostatic alteration induced by colitis through CRH-1R pathways, which are known to mediate pro-inflammatory processes. The down-regulation of CRH-1R in CORT-nursed rats could promote the reduced susceptibility to TNBS-colitis. The explanation why the differential regulation of CRH-1R expression can determine greater resistance to colitis in CORT-nursed rats, requires further investigations. Among the underlying mechanisms, an improvement in colonic epithelial function could be suggested. In fact, as colonic epithelial CRH-1R are known to mediate increased intestinal permeability, their down regulation, observed in colitic CORT-nursed rats, could result in a more efficacious barrier against luminal proinflammatory antigens. This proposal is in agreement with Soderholm et al., who, in functional studies with CRF antagonists, indicated that CRF is important for early life stress-induced changes in colonic epithelial function and suggested that its effects could be mediated by peripherally located receptors without characterizing their subclasses and location. In this study we clarify that the subclass of CRF receptors mainly involved in modulating CRF-altered intestinal permeability is CRH-1R, located in the colonic epithelium. The hypothesis that colonic epithelial functional improvement plays a pivotal role in the reduced susceptibility to colitis observed in CORT-nursed rats was put in evidence above when we discussed the role of their lower plasma corticosterone level, and it is also supported by another observation reported here. We are referring to the reduced colonic mast cell degranulation shown in colitic CORT-nursed rats, which may have a positive role in the preservation of the intestinal barrier. Mast cell activation increases gut macromolecular permeability following exposure to stress through the release of different mediators that enhance influx, altering trans-epithelial ion transport. The significant decrease in colonic mast cell degranulation observed in colitic CORT-nursed rats with respect to controls is in agreement with mast cell modulation of intestinal permeability, even if indirectly. Altogether, these findings contribute toward the hypothesis that changes in intestinal permeability are the basis for the reduced vulnerability to colitis observed in CORT-nursed rats.