Epigenetics and the transition from acute to chronic pain

Abstract

Objective: The objective of this study was to review the epigenetic modifications involved in the transition from acute to chronic pain and to identify potential targets for the development of novel, individualized pain therapeutics.

Background: Epigenetics is the study of heritable modifications in gene expression and phenotype that do not require a change in genetic sequence to manifest their effects. Environmental toxins, medications, diet, and psychological stresses can alter epigenetic processes such as DNA methylation, histone acetylation, and RNA interference. As epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, steroid responsiveness, and opioid sensitivity, they are likely key factors in the development of chronic pain. Although our knowledge of the human genetic code and disease-associated polymorphisms has grown significantly in the past decade, we have not yet been able to elucidate the mechanisms that lead to the development of persistent pain after nerve injury or surgery.

Design: This is a focused literature review of epigenetic science and its relationship to chronic pain.

Results: Significant laboratory and clinical data support the notion that epigenetic modifications are affected by the environment and lead to differential gene expression. Similar to mechanisms involved in the development of cancer, neurodegenerative disease, and inflammatory disorders, the literature endorses an important potential role for epigenetics in chronic pain.

Conclusions: Epigenetic analysis may identify mechanisms critical to the development of chronic pain after injury, and may provide new pathways and target mechanisms for future drug development and individualized medicine.

Figure 1. Epigenetic Mechanisms

A) DNA wraps around histone octamers to form a nucleosome, the fundamental building block of chromatin. B) Histone proteins may be modified through several processes, including acetylation. The addition of an acetyl group to histone tails generally opens the chromatin structure and facilitates transcription factor binding, enhancing gene expression. C) Methylation of cytosine nucleotides in C-G rich sequences (“CG Islands”) prevents the binding of transcription factors and generally silences gene expression. These CG Islands are often found near promoter regions and serve a significant role in gene regulation. D) Post-transcriptional regulatory mechanisms include short hairpin RNA (shRNA), small interfering RNA, (siRNA) and micro RNA (miRNA) that bind RNA and induce their degradation.

Figure 2. Laboratory Techniques in Epigenetics

A) In ChIP-Seq analysis, an antibody is used on chromatin to immunoprecipitate and select for acetylation and other histone modifications. The results may then be analyzed through several techniques including genome-wide next generation sequencing. In this manner, the histone acetylation patterns of a particular tissue may be determined. B) The analysis of DNA methylation employs bisulfite sequencing to convert unmethylated cytosines to uracil. This process does not affect the methylated cytosines. The methylation patterns can be calculated by comparing the ratio of cytosine to uracil.

Figure 3. Epigenome and Chronic Pain

Twin A and Twin B demonstrate similar “epigenomes” at birth with few (if any) differences in methylation and acetylation patterns. Environmental factors throughout development affect histone acetylation patterns and cytosine methylation patterns, resulting in phenotypic differences by adulthood. With surgery or nerve injury, these epigenetic differences may result in differing risks of chronic pain.