Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
Int J Neuropsychopharmacol. 2011 Jun;14(5):666-83. doi: 10.1017/S1461145710000994. Epub 2010 Sep 22.
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 raphé 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.
临床证据表明抑郁和肠易激综合征（IBS）之间存在共病现象。生命早期的压力和遗传易感性是 IBS 和抑郁病理生理学的关键因素。因此，新生期母鼠分离（MS）和 Wistar-Kyoto（WKY）大鼠，一种遗传上对压力敏感的大鼠品系，是两种具有增加内脏敏感性和下丘脑-垂体-肾上腺轴改变的抑郁动物模型。促肾上腺皮质释放因子（CRF）是调节该轴的主要肽，通过两种受体起作用：CRF1 和 CRF2。中枢 CRF 系统也是应激反应的关键调节剂。然而，目前关于成年 MS 或 WKY 动物中枢 CRF 系统改变的研究很少。通过原位杂交，我们发现在 WKY 大鼠的室旁核（PVN）和 MS 动物的背中缝核（DRN）中，CRF mRNA 增加，而在 Sprague-Dawley 和未分离对照中则减少。此外，在两种动物模型的 PVN、杏仁核和 DRN 中，CRF1 mRNA 水平升高，而 WKY 动物的海马体中 CRF1 mRNA 水平较高。最后，MS 和 WKY 大鼠的 DRN 中 CRF2 mRNA 水平低于对照组，MS 大鼠的海马体和杏仁核中 CRF2 mRNA 水平也较低。这些结果表明，中枢 CRF 系统在两种动物模型中均发生改变。这种改变可能会影响 HPA 轴的调节，导致与应激相关障碍相关的行为变化，并改变内脏疼痛调节的情感成分，而这在 IBS 患者中增强。
