Role of corticotropin-releasing factor pathways in stress-related alterations of colonic motor function and viscerosensibility in female rodents

Abstract

Clinical reports have shown that irritable bowel syndrome (IBS) is comorbid with anxiety/depression and stress-related events, and that the disorder is more prevalent among women than among men. In rodents, colorectal distention (CRD) induces abdominal contractions, and this visceromotor response is used to assess visceral pain. The activation of brain corticotropin-releasing factor (CRF) pathways has a key role in the behavioral and visceral responses to stress. In this review of experimental studies that delineate the underlying mechanisms of the stress response, we focused on CRF signaling pathways and sex hormones in modulating visceral hypersensitivity induced by CRD in rodents. The findings of our recent research on the development of an experimental model of visceral pain in female rats and the modulation of the hyperalgesic response to CRD by CRF antagonists were integrated with those of the published literature. A MEDLINE search of the years 1981 to 2005 was conducted using the key words stress, CRF, CRH, CRF1 receptor, IBS, CRD, female rat, visceral pain, estrogen, and anxiety. CRF and other related mammalian peptides (urocortins) interact with the distinct CRF subtype 1 and 2 receptors. Well-documented preclinical studies have established the role of brain CRF1 receptors in mediating stress-related anxiogenic and visceral (stimulation of colonic motor function and sensitization to repeated CRD) responses in male rodents, whereas more limited studies have been performed in female rats. Our recent study indicated that the CRF1 antagonist antalarmin prevents visceral hypersensitivity induced by 2 sets of CRD in female rats. In several models of visceral pain induced by CRD, sex differences and a sensitization action of estrogen were reported. Our preliminary evidence indicated a potentiating interaction between CRF-CRF1 pathways and estrogen in the stimulation of colonic motor responses that may take place within the enteric neurons of the colon, where both CRF1 and estrogen receptors are present. The results of this review suggest that overactivity of CRF1 signaling in the brain and the gut may have relevance in understanding the comorbidity of anxiety/depression and IBS in diarrhea-predominant female patients. Targeting these mechanisms with CRF1 antagonists may provide a novel therapeutic strategy.