Importance of epigenetic mechanisms in visceral pain induced by chronic water avoidance stress
Importance of epigenetic mechanisms in visceral pain induced by chronic water avoidance stress
复制标题
DOI：
10.1016/j.psyneuen.2012.09.016
复制
发表时间：
2013-06-01
影响因子：
3.7
通讯作者：
Van-Meerveld, B. Greenwood
中科院分区：
文献类型：
--
作者：
Tran, L.;Chaloner, A.;Van-Meerveld, B. Greenwood
表观遗传分子机制，包括DNA甲基化和组蛋白去乙酰化，与下丘脑-垂体-肾上腺（HPA）轴的失调有关。在此之前，我们证明了反复的避水应激（WAS），一种经过验证的慢性心理应激模型，会引起类似肠易激综合征（IBS）后遗症的啮齿动物内脏疼痛行为的增加。然而，表观遗传分子机制在应激性内脏疼痛病理生理中的作用尚未得到探讨。我们的假设是中枢神经系统（CNS）内的表观遗传机制对慢性应激性内脏超敏反应很重要。成年雄性F-344大鼠脑室内（i.c.v）插管暴露于7天的重复WAS。对照组接受假性应激。在每日1小时的应激源后，通过静脉插管给药曲古斯汀A (TSA, 100 ng/ml)，一种有效的组蛋白去乙酰化酶抑制剂，或载体（VEH， 0.1% DMSO/生理盐水）作为对照。在最终was后24小时评估内脏敏感性，并通过记录结肠直肠膨胀（CRD）分级压力（20-60 mmHg）下腹部收缩的次数来量化内脏运动反应（VMR）。从暴露于重复WAS或SHAM应激的另一组大鼠中分离出杏仁核，通过亚硫酸盐测序和焦磷酸测序来评估糖皮质激素受体（GR）和促肾上腺皮质激素释放因子（CRF）基因的甲基化状态。采用qRT-PCR法检测GR和CRF基因的表达。应激大鼠表现出内脏超敏反应，TSA显著减轻了这种反应。与SHAM对照组相比，was后GR基因的甲基化增加，而GR基因的表达减少。was降低了CRF启动子的甲基化，同时增加了CRF的表达。本研究证明了中枢表观遗传机制参与调节应激诱导的内脏超敏反应，为探索可能导致ibs样症状的表观遗传机制奠定了基础。(C) 2012 Elsevier Ltd.版权所有。
Epigenetic molecular mechanisms, which include DNA methylation and histone deacetylation, are implicated in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Previously, we demonstrated that repeated water avoidance stress (WAS), a validated model of chronic psychological stress, induces heightened visceral pain behaviors in rodents that resemble irritable bowel syndrome (IBS) sequelae. However, the involvement of epigenetic molecular mechanisms in the pathophysiology of stress-induced visceral pain has not been explored. Our hypothesis is that epigenetic mechanisms within the central nervous system (CNS) are important to chronic stress-induced visceral hypersensitivity. Adult male F-344 rats with intracerebroventricular (i.c.v.) cannulae were exposed to 7 days of repeated WAS. Controls received a SHAM stress. Following the daily 1 h stressor, trichostatin A (TSA; 100 ng/ml), a potent histone deacetylase inhibitor, or vehicle (VEH; 0.1% DMSO/saline,) as control was administered via the i.c.v. cannula. Visceral sensitivity was assessed 24 h after the final WAS and quantified the visceromotor response (VMR) by recording the number of abdominal contractions in response to graded pressures (20-60 mmHg) of colorectal distensions (CRD). From a separate group of rats that were exposed to repeated WAS or SHAM stress, the amygdala was isolated to assess the methylation status of glucocorticoid receptor (GR) and corticotropin releasing-factor (CRF) genes via bisulfite sequencing and verified by pyrosequencing. GR and CRF gene expression was quantified via qRT-PCR. Stressed rats exhibited visceral hypersensitivity that was significantly attenuated by TSA. Compared to SHAM controls, methylation of the GR gene was increased following WAS while expression of the GR gene was decreased. Methylation of the CRF promoter was decreased with WAS with a concomitant increase in CRF expression. This study demonstrates the involvement of central epigenetic mechanisms in regulating stress-induced visceral hypersensitivity and provides a foundation for exploring the epigenetic mechanisms that may contribute to IBS-like symptomatology. (C) 2012 Elsevier Ltd. All rights reserved.