Peripheral a-helical CRF (9-41) does not reverse stress-induced mast cell dependent visceral hypersensitivity in maternally separated rats

Background Acute stress-induced hypersensitivity to colorectal distention was shown to depend on corticotropin releasing factor (CRF)-induced mast cell degranulation. At present it remains unclear whether CRF also induces chronic poststress activation of these cells. Accordingly, the objective of this study was to compare pre- and poststress CRF-receptor antagonist treatment protocols for their ability to, respectively, prevent and reverse mast cell dependent visceral hypersensitivity in a rat model of neonatal maternal separation. Methods The visceromotor response to colonic distention was assessed in adult maternally separated and non-handled rats before and at different time points after 1 h of water avoidance (WA). Rats were treated with the mast cell stabilizer doxantrazole and the CRF receptor-antagonist a-helical- CRF (9-41). Western blotting was used to assess mucosal protein levels of the mast cell protease RMCP-2 and the tight junction protein occludin. Key Results In maternally separated, but not in nonhandled rats, WA induced chronic hypersensitivity (up to 30 days) to colorectal distention. Visceral hypersensitivity was prevented, but could not be reversed by administration of a-helical-CRF (9-41). In contrast, however, the mast cell stabilizer doxantrazole reversed visceral hypersensitivity. Compared with vehicle-treated rats, pre-WA a-helical-CRF (9-41) treated animals displayed higher mucosal RMCP-2 and occludin levels. Conclusions & Inferences Water avoidance-stress leads to persistent mast cell dependent visceral hypersensitivity in maternally separated rats, which can be prevented, but not reversed by blockade of peripheral CRF-receptors. We conclude that persistent poststress mast cell activation and subsequent visceral hypersensitivity are not targeted by CRF-receptor antagonists.