Chronic opioid use is associated with increased DNA methylation correlating with increased clinical pain

Abstract

Environmentally caused changes in chromosomes that do not alter the DNA sequence but cause phenotypic changes by altering gene transcription are summarized as epigenetics. A major epigenetic mechanism is methylation or demethylation at CpG-rich DNA islands. DNA methylation triggered by drugs has largely unexplored therapeutic consequences. Here we report increased methylation at a CpG rich island in the OPRM1 gene coding for μ-opioid receptors and at a global methylation site (LINE-1) in leukocytes of methadone-substituted former opiate addicts compared with matched healthy controls. Higher DNA methylation associated with chronic opioid exposure was reproduced in an independent cohort of opioid-treated as compared to non-opioid-treated pain patients. This suggests that opioids may stimulate DNA methylation. The OPRM1 methylation had no immediate effect on μ-opioid receptor transcription and was not associated with opioid dosing requirements. However, the global DNA methylation at LINE-1 was significantly correlated with increased chronic pain. This suggests inhibitory effects on the transcription of still unspecified nocifensive gene products. It further implies that opioids may be causally associated with increased genome-wide DNA methylation, although currently there is no direct evidence of this. This has phenotypic consequences for pain and may provide a new, epigenetics-associated mechanism of opioid-induced hyperalgesia. The results indicate a potential influence of opioid analgesics on the patients' epigenome. They emphasize the need for reliable and cost-effective screening tools and may imply that high-throughput screening for lead compounds in artificial expression systems may not provide the best tools for identifying new pain medications.

Transgenerational modification of hippocampus TNF-α and S100B levels in the offspring of rats chronically exposed to morphine during adolescence

“…Epigenetic mechanisms are suggested to be responsible for this phenomenon (38,39). Although investigations of the effects of these types of opiates are scarce, some recent studies in animal models have shown that the offspring of parents with a background of morphine use demonstrate differences in the expression pattern of opioid receptors in different brain areas (36).…”

Epigenetics in the perioperative period

“…Opiate receptors ↔ development (Hwang et al, 2007) Local anaesthetics ↓ methylation (Lirk et al, 2012(Lirk et al, , 2014 Opiates ↑ methylation (Doehring et al, 2013) Opiate-induced hyperalgesia (Doehring et al, 2013) ↓ MCP3 expression → pain (Imai et al, 2013) ↓ GAD65 expression → pain (Zhang et al, 2013) Prefrontal cortex methylation (Tajerian et al, 2013) TRPA1 methylation ↔ pain (Bell et al, 2014) Transcriptome in inflammation (Bais et al, 2009) Transcriptome in healing (Kruidenier et al, 2012;Barnes et al, 2013;Belkina et al, 2013) Cell migration/prolif, angiogenesis (Rafehi et al, 2011) Heritable response to injury (Zeybel et al, 2012) Wound healing inflammation…”

“…In humans, increased DNA methylation levels in peripheral blood leukocytes have been linked to the severity of chronic pain in patients on long-term treatment using potent opioids (Doehring et al, 2013). A recent investigation in monozygotic twins found that the degree of heat pain sensitivity correlated with the methylation status of the gene that encodes the TRPA-1 ion channel (Bell et al, 2014).…”

“…In the leukocytes of patients treated with various opioids, there was a global increase of DNA methylation at (LINE-1) and also a specific increase of methylation at the μ opioid receptor 1. Interestingly, a positive correlation was described between the methylation levels and pain intensity in patients treated with opiates, but not in patients in control groups receiving other pain medications (Doehring et al, 2013). It should be kept in mind, however, that the opiates constitute a heterogeneous group of drugs with distinct physicochemical properties, and the epigenetic effects of many opiates widely used perioperatively, such as tramadol (Scott and Perry, 2000), have not been investigated.…”

Do Amide Local Anesthetics Play a Therapeutic Role in the Perioperative Management of Cancer Patients?

“…63 Interestingly, this effect is the opposite compared with long-term opioid intake, which leads to hypermethylation. 64 …”