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Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system.
Gastroenterology. 2015 Jan; 148(1):148-157.e7.G

Abstract

BACKGROUND & AIMS

Chronic stress alters the hypothalamic-pituitary-adrenal axis, increases gut motility, and increases the perception of visceral pain. We investigated whether epigenetic mechanisms regulate chronic stress-induced visceral pain in the peripheral nervous systems of rats.

METHODS

Male rats were subjected to 1 hour of 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.

RESULTS

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 also was associated with up-regulation in DNMT1-associated methylation of the Cnr1 promoter and down-regulation 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.

CONCLUSIONS

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.

Authors+Show Affiliations

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. Electronic address: hongss@med.umich.edu.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25263804

Citation

Hong, Shuangsong, et al. "Epigenetic Regulation of Genes That Modulate Chronic Stress-induced Visceral Pain in the Peripheral Nervous System." Gastroenterology, vol. 148, no. 1, 2015, pp. 148-157.e7.
Hong S, Zheng G, Wiley JW. Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system. Gastroenterology. 2015;148(1):148-157.e7.
Hong, S., Zheng, G., & Wiley, J. W. (2015). Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system. Gastroenterology, 148(1), 148-e7. https://doi.org/10.1053/j.gastro.2014.09.032
Hong S, Zheng G, Wiley JW. Epigenetic Regulation of Genes That Modulate Chronic Stress-induced Visceral Pain in the Peripheral Nervous System. Gastroenterology. 2015;148(1):148-157.e7. PubMed PMID: 25263804.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system. AU - Hong,Shuangsong, AU - Zheng,Gen, AU - Wiley,John W, Y1 - 2014/09/28/ PY - 2014/01/20/received PY - 2014/09/18/revised PY - 2014/09/21/accepted PY - 2014/9/30/entrez PY - 2014/9/30/pubmed PY - 2015/3/7/medline KW - Epigenetic Modification KW - HPA KW - Pain Sensitivity KW - Visceral Hyperalgesia SP - 148 EP - 157.e7 JF - Gastroenterology JO - Gastroenterology VL - 148 IS - 1 N2 - BACKGROUND & AIMS: Chronic stress alters the hypothalamic-pituitary-adrenal axis, increases gut motility, and increases the perception of visceral pain. We investigated whether epigenetic mechanisms regulate chronic stress-induced visceral pain in the peripheral nervous systems of rats. METHODS: Male rats were subjected to 1 hour of 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. RESULTS: 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 also was associated with up-regulation in DNMT1-associated methylation of the Cnr1 promoter and down-regulation 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. CONCLUSIONS: 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. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/25263804/Epigenetic_regulation_of_genes_that_modulate_chronic_stress_induced_visceral_pain_in_the_peripheral_nervous_system_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(14)01186-X DB - PRIME DP - Unbound Medicine ER -