Alterations in the central CRF system of two different rat models of comorbid depression and functional gastrointestinal disorders

Clinical evidence suggests comorbidity between depression and irritable bowel syndrome (IBS). Early-life stress and genetic predisposition are key factors in the pathophysiology of both IBS and depression. Thus, neonatal maternal separation (MS), and the Wistar-Kyoto (WKY) rat, a genetically stress-sensitive rat strain, are two animal models of depression that display increased visceral hypersensitivity and alterations in the hypothalamic-pituitary-adrenal axis. Corticotrophin-releasing factor (CRF) is the primary peptide regulating this axis, acting through two receptors : CRF1 and CRF2. The central CRF system is also a key regulator in the stress response. However, there is a paucity of studies investigating alterations in the central CRF system of adult MS or WKY animals. Using in-situ hybridization we demonstrate that CRF mRNA is increased in the paraventricular nucleus (PVN) of WKY rats and the dorsal raphe nucleus (DRN) of MS animals, compared to Sprague-Dawley and non-separated controls, respectively. Additionally, CRF1 mRNA was higher in the PVN, amygdala and DRN of both animal models, along with high levels of CRF1 mRNA in the hippocampus of WKY animals compared to control animals. Finally, CRF2 mRNA was lower in the DRN of MS and WKY rats compared to control animals, and in the hippocampus and amygdala of MS rats. These results show that the central CRF system is altered in both animal models. Such alterations may affect HPA axis regulation, contribute to behavioural changes associated with stress-related disorders, and alter the affective component of visceral pain modulation, which is enhanced in IBS patients.