title: Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system.
abstract: OBJECTIVE
  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.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. Electronic address: hongss@med.umich.edu.
authors.forename: Shuangsong
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Gen
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: John W
authors.initials: JW
authors.lastname: Wiley
mesh_terms: D015746:Abdominal Pain / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D000107:Acetylation; D000818:Animals; D002908:Chronic Disease; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation; D006657:Histones; D006930:Hyperalgesia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D008297:Male; D010147:Pain Measurement; D017288:Pain Threshold; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D059265:Visceral Pain / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology
chemical_list: C543264:Cnr1 protein, rat; D006657:Histones; C542344:NR3C1 protein, rat; D043884:Receptor, Cannabinoid, CB1; D011965:Receptors, Glucocorticoid; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619382:Dnmt1 protein, rat; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat
keywords: Epigenetic Modification; HPA; Pain Sensitivity; Visceral Hyperalgesia