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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.

SUBMITTER: Crow M

PROVIDER: S-EPMC3706821 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Genes and epigenetic processes as prospective pain targets.

Crow Megan M Denk Franziska F McMahon Stephen B SB

Genome medicine 20130215 2

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 ...[more]

PMID: 23409739

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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.

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Genes and epigenetic processes as prospective pain targets.

Publications

Genes and epigenetic processes as prospective pain targets.

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