Dataset Information

Targeting epigenetic mechanisms for chronic visceral pain: A valid approach for the development of novel therapeutics.

ABSTRACT:

Background

Chronic visceral pain is persistent pain emanating from thoracic, pelvic, or abdominal origin that is poorly localized with regard to the specific organ affected. The prevalence can range up to 25% in the adult population as chronic visceral pain is a common feature of many visceral disorders, which may or may not be accompanied by distinct structural or histological abnormalities within the visceral organs. Mounting evidence suggests that changes in epigenetic mechanisms are involved in the top-down or bottom-up sensitization of pain pathways and the development of chronic pain. Epigenetic changes can lead to long-term alterations in gene expression profiles of neurons and consequently alter functionality of peripheral neurons, dorsal root ganglia, spinal cord, and brain neurons. However, epigenetic modifications are dynamic, and thus, detrimental changes may be reversible. Hence, external factors/therapeutic interventions may be capable of modulating the epigenome and restore normal gene expression for extended periods of time.

Purpose

The goal of this review is to highlight the latest discoveries made toward understanding the epigenetic mechanisms that are involved in the development or maintenance of chronic visceral pain. Furthermore, this review will provide evidence supporting that targeting these epigenetic mechanisms may represent a novel approach to treat chronic visceral pain.

SUBMITTER: Louwies T

PROVIDER: S-EPMC7924309 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Targeting epigenetic mechanisms for chronic visceral pain: A valid approach for the development of novel therapeutics.

Louwies Tijs T Ligon Casey O CO Johnson Anthony C AC Greenwood-Van Meerveld Beverley B

Neurogastroenterology and motility 20181104 3

<h4>Background</h4>Chronic visceral pain is persistent pain emanating from thoracic, pelvic, or abdominal origin that is poorly localized with regard to the specific organ affected. The prevalence can range up to 25% in the adult population as chronic visceral pain is a common feature of many visceral disorders, which may or may not be accompanied by distinct structural or histological abnormalities within the visceral organs. Mounting evidence suggests that changes in epigenetic mechanisms are ...[more]

PMID: 30393913

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Project description:Background & aimsChronic 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.MethodsMale 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.ResultsChronic 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.ConclusionsChronic 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.

Project description:Irritable bowel syndrome is a gastrointestinal disorder of unknown etiology characterized by widespread, chronic abdominal pain associated with altered bowel movements. Increasing amounts of evidence indicate that injury and inflammation during the neonatal period have long-term effects on tissue structure and function in the adult that may predispose to gastrointestinal diseases. In this study we aimed to investigate how the epigenetic regulation of DNA demethylation of the p2x7r locus guided by the transcription factor GATA binding protein 1 (GATA1) in spinal astrocytes affects chronic visceral pain in adult rats with neonatal colonic inflammation (NCI). The spinal GATA1 targeting to DNA demethylation of p2x7r locus in these rats was assessed by assessing GATA1 function with luciferase assay, chromatin immunoprecipitation, patch clamp, and interference in vitro and in vivo. In addition, a decoy oligodeoxynucleotide was designed and applied to determine the influence of GATA1 on the DNA methylation of a p2x7r CpG island. We showed that NCI caused the induction of GATA1, Ten-eleven translocation 3 (TET3), and purinergic receptors (P2X7Rs) in astrocytes of the spinal dorsal horn, and demonstrated that inhibiting these molecules markedly increased the pain threshold, inhibited the activation of astrocytes, and decreased the spinal sEPSC frequency. NCI also markedly demethylated the p2x7r locus in a manner dependent on the enhancement of both a GATA1-TET3 physical interaction and GATA1 binding at the p2x7r promoter. Importantly, we showed that demethylation of the p2x7r locus (and the attendant increase in P2X7R expression) was reversed upon knockdown of GATA1 or TET3 expression, and demonstrated that a decoy oligodeoxynucleotide that selectively blocked the GATA1 binding site increased the methylation of a CpG island in the p2x7r promoter. These results demonstrate that chronic visceral pain is mediated synergistically by GATA1 and TET3 via a DNA-demethylation mechanism that controls p2x7r transcription in spinal dorsal horn astrocytes, and provide a potential therapeutic strategy by targeting GATA1 and p2x7r locus binding.

Dataset Information

Targeting epigenetic mechanisms for chronic visceral pain: A valid approach for the development of novel therapeutics.

Background

Purpose

Publications

Targeting epigenetic mechanisms for chronic visceral pain: A valid approach for the development of novel therapeutics.

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