Genes and epigenetic processes as prospective pain targets

Abstract

Chronic pain affects approximately one in five adults, resulting in a greatly reduced quality of life and a higher risk of developing co-morbidities such as depression. Available treatments often provide inadequate pain relief, but it is hoped that through deeper understanding of the molecular mechanisms underlying chronic pain states we can discover new and improved therapies. Although genetic research has flourished over the past decade and has identified many key genes in pain processing, the budding field of epigenetics promises to provide new insights and a more dynamic view of pain regulation. This review gives an overview of basic mechanisms and current therapies to treat pain, and discusses the clinical and preclinical evidence for the contribution of genetic and epigenetic factors, with a focus on how this knowledge can affect drug development.

Figure 1

How polymorphisms can confer risk to pain. Single nucleotide polymorphisms (SNPs) can confer increased risk to pain by causing missense mutations that alter protein function. One of the most dramatic examples of this phenomenon is SNPs in the voltage-gated sodium channel Na_v1.7. In this case, a SNP causing a change from an isoleucine to threonine residue in the loop domain leads to loss of channel inactivation, which is responsible for inherited paroxysmal pain disorder [27]. (a) Structure of Na_v1.7. Arrow indicates the mutation in the loop domain. (b) Human embryonic kidney (HEK) cells transfected with wild-type Na_v1.7 show normal channel inactivation. (c) HEK cells transfected with mutant Na_v1.7 are unable to inactivate. Adapted with permission from [27].

Figure 2

Evidence for epigenetic modulation in pain. Evidence has been obtained for such modulation at four different levels, numbered here in order from peripheral to central. 1, Pain-associated hyperacetylation of MIP2 and CXCR5 in the nerve after partial sciatic nerve ligation (PSL) [86] (shown in yellow). 2, Decreased expression of MeCP2 target genes after CFA [91]; miRNA expression changes [104,106]; intrathecal HDAC inhibitor treatment reduces acute pain after CFA [83] (shown in green). 3, GAD2 hypoacetylation after CFA leads to loss of descending inhibition [84] (shown in pink). 4, Carrageenan-associated miRNA dysregulation in the prefrontal cortex [105] (shown in purple).

Figure 3

How epigenetic mechanisms can influence pain processing. (a) Under normal conditions, histone tails are acetylated at the GAD2 promoter in the nucleus raphe magnus (NRM). (b) After application of complete Freund's adjuvant (CFA), Gad65 expression is suppressed through hypoacetylation of the GAD2 promoter, leading to loss of descending inhibition from the NRM [84]. GABA, γ-aminobutyric acid.