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.

Keywords: acetylation; brain; gastrointestinal; methylation; spinal cord; stress.

Figure 1:. Common Visceral Pain Disorders.

Left side: Visceral pain disorders associates with overt tissue inflammation, which may or may not be due to an infection. Right side: Visceral pain disorders with no identified pathological marker. Visceral pain is typically diffuse and may be referred to somatic structures (muscle, skin, joints) within the same or adjacent dermatomes or to other visceral organs. The location of selected organs is approximate. The name of the disorder has been illustrated near the affected organ. GERD, gastroesophageal reflux disease; IBD, inflammatory bowel disease; BPS, bladder pain syndrome; IC, interstitial cystitis; IBS, irritable bowel syndrome; NBS, narcotic bowel syndrome. This composite image was assembled from individual public domain images available from Wikimedia Commons.

Figure 2:. Epigenetic Modifications.

A) Nucleosomes are composed of an octamer of histones H2A, H2B, H3, and H4 (two dimers of 2A/2B and two dimers of H3/H4) with 146 base pairs of DNA wrapped around the complex (drawn as black double line). The H1 histone may also be attached as a linker to stabilize the DNA (not shown). Several epigenetically regulated modifications to the n-terminal tails of the histones influence DNA accessibility to transcription machinery including acetylation (red circles), methylation (gray circles), phosphorylation (purple circles), or ADP ribosylation (blue circles). The single letter abbreviation was used for each amino acid, with spaces after every ten, and subscript numbers indicating location. Multiple circles on a single amino acid represent alternative modifications. N-terminal sequences were based on consensus sequences for human histones at uniport.org: H2A - P0C0S8, H2B - P62807, H3 - P68431, H4 – P62805. B) DNA methyl transferases (DNMT) target cytosine residues immediately upstream of guanosine residues (CpG sites) within DNA to form 5-methylcytosine (5mC), which typically represses transcription. Ten-eleven-translocation (TET) proteins participate in demethylation by converting 5mC to 5-hydroxymethylcytosine (5hmC), which has also been demonstrated to participate in epigenetic regulation of gene expression. Further oxidation by TET proteins changes 5hmC to 5-formylcytosine (5fC) and subsequently 5-carboxylcytosine (5caC), which can then be converted back to cytosine (not pictured). The role of 5fC and 5caC in modulation of gene expression is uncertain due to the recent development of tools that can distinguish between 5mC, 5hmC, 5fC, and 5caC. For each structure, R is the sugar (deoxyribose)-phosphate group that forms the DNA nucleotide.