Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system.
Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system.
复制标题
DOI：
10.1053/j.gastro.2014.09.032
复制
发表时间：
2015-01
期刊：
影响因子：
29.4
通讯作者：
Wiley JW
中科院分区：
文献类型：
--
作者：
Hong S;Zheng G;Wiley JW
慢性应激改变下丘脑-垂体-肾上腺轴，增加肠道动力，增加内脏疼痛的感知。我们研究了表观遗传机制是否调节大鼠外周神经系统慢性应激诱导的内脏痛。雄性大鼠每天进行1小时的避水应激，或每天皮下注射皮质酮，连续10天。收集L4-L5和L 6-S2背根神经节（DRG），并在应激和对照大鼠之间进行比较（每天在无水的水箱中放置1小时）。大麻素受体1（CNR 1），DNA（胞嘧啶-5-）-甲基转移酶1（DNMT 1），瞬时受体电位香草素1型（TRPV 1）和EP 300的水平被敲低在DRG神经元原位小干扰RNA。我们测量了编码糖皮质激素受体（NR 3C 1）、CNR 1和TRPV 1基因的DNA甲基化和组蛋白乙酰化。内脏疼痛的测量是对结直肠扩张的反应。慢性应激与Nr 3c 1启动子甲基化增加和L 6-S2中该基因表达减少相关，但与L4-L5、DRG无关。应激还与DNMT 1相关的Cnr 1启动子甲基化上调和L 6-S2（而非L4-L5）DRG中糖皮质激素受体介导的CNR 1表达下调相关。同时，慢性应激增加了组蛋白乙酰转移酶EP 300的表达，并增加了L 6-S2 DRG神经元中Trpv 1启动子处的组蛋白乙酰化和TRPV 1受体的表达。敲低大鼠L 6-S2 DRG神经元中的DNMT 1和EP 300分别降低DNA甲基化和组蛋白乙酰化，并防止慢性应激诱导的内脏痛增加。慢性应激增加大鼠外周神经系统内脏痛觉调节基因的DNA甲基化和组蛋白乙酰化。阻断脊髓特定区域的表观遗传调节通路可能被开发用于治疗慢性腹痛患者。
Chronic stress alters the hypothalamic–pituitary–adrenal axis, increases gut motility, and increases perception of visceral pain. We investigated whether epigenetic mechanisms regulate chronic stress-induced visceral pain in the peripheral nervous systems of rats. Male rats were subjected to 1 hr water-avoidance stress each day, or given daily subcutaneous injections of corticosterone, for 10 consecutive days. L4–L5 and L6–S2 dorsal root ganglia (DRG) were collected and compared between stressed and control rats (placed for 1 hour each day in a tank without water). Levels of cannabinoid receptor 1 (CNR1), DNA (cytosine-5-)-methyltransferase 1 (DNMT1), transient receptor potential vanilloid type 1 (TRPV1), and EP300 were knocked down in DRG neurons in situ with small interfering RNAs. We measured DNA methylation and histone acetylation at genes encoding the glucocorticoid receptor (NR3C1), CNR1, and TRPV1. Visceral pain was measured in response to colorectal distention. Chronic stress was associated with increased methylation of the Nr3c1 promoter and reduced expression of this gene in L6–S2, but not L4–L5, DRGs. Stress was also associated with upregulation in DNMT1-associated methylation of the Cnr1 promoter and downregulation of glucocorticoid receptor-mediated expression of CNR1 in L6–S2, but not L4–L5, DRGs. Concurrently, chronic stress increased expression of the histone acetyltransferase EP300 and increased histone acetylation at the Trpv1 promoter and expression of the TRPV1 receptor in L6–S2 DRG neurons. Knockdown of DNMT1 and EP300 in L6–S2 DRG neurons of rats reduced DNA methylation and histone acetylation, respectively, and prevented chronic stress-induced increases in visceral pain. Chronic stress increases DNA methylation and histone acetylation of genes that regulate visceral pain sensation in the peripheral nervous system of rats. Blocking epigenetic regulatory pathways in specific regions of the spinal cord might be developed to treat patients with chronic abdominal pain.
登录
查看更多内容
影响因子：
3
作者：
Carrier, E. J.;Patel, S.;Hillard, C. J.
通讯作者：
Hillard, C. J.
影响因子：
3.5
作者：
Hill, Matthew N.;Carrier, Erica J.;Hillard, Cecilia J.
通讯作者：
Hillard, Cecilia J.
影响因子：
3.7
作者：
Oberlander, Tim F.;Weinberg, Joanne;Devlin, Angela M.
通讯作者：
Devlin, Angela M.
影响因子：
9.8
作者：
Myer, Parvathi A.;Mannalithara, Ajitha;Ladabaum, Uri
通讯作者：
Ladabaum, Uri
影响因子：
3.7
作者：
Tran, L.;Chaloner, A.;Van-Meerveld, B. Greenwood
通讯作者：
Van-Meerveld, B. Greenwood