Pharmacoepigenetics of the Role of DNA Methylation in μ-Opioid Receptor Expression in Different Human Brain Regions

Abstract

Aim: Exposure to opioids has been associated with epigenetic effects. Studies in rodents suggested a role of varying degrees of DNA methylation in the differential regulation of μ-opioid receptor expression across the brain. Methods: In a translational investigation, using tissue acquired postmortem from 21 brain regions of former opiate addicts, representing a human cohort with chronic opioid exposure, μ-opioid receptor expression was analyzed at the level of DNA methylation, mRNA and protein. Results & conclusion: While high or low μ-opioid receptor expression significantly correlated with local OPRM1 mRNA levels, there was no corresponding association with OPRM1 methylation status. Additional experiments in human cell lines showed that changes in DNA methylation associated with changes in μ-opioid expression were an order of magnitude greater than differences in brain. Hence, different degrees of DNA methylation associated with chronic opioid exposure are unlikely to exert a major role in the region-specificity of μ-opioid receptor expression in the human brain.

Keywords::

• DNA methylation
• human brain
• μ-opioid receptor regulation
• OPRM1 methylation

Acknowledgements

The HEK-293 cell line was kindly provided by I Tegeder, Institute of Clinical Pharmacology, Goethe – University, Frankfurt am Main, Germany. The authors thank M Parnham, Fraunhofer Project Group Translational Medicine and Pharmacology TMP, Frankfurt am Main, Germany, for language editing.

Financial & competing interests disclosure

The work has been supported by the Else Kröner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation – Pharma (TRIP, G Geisslinger, J Lötsch) and the Landesoffensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz (LOEWE), LOEWE-Zentrum für Translationale Medizin und Pharmakologie (G Geisslinger, J Lötsch). Additional support of the analytical environment was gained form the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 602919 (GLORIA, J Lötsch). The funders had no role in method design, data selection and analysis, decision to publish or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No funded writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

The work has been supported by the Else Kröner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation – Pharma (TRIP, G Geisslinger, J Lötsch) and the Landesoffensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz (LOEWE), LOEWE-Zentrum für Translationale Medizin und Pharmakologie (G Geisslinger, J Lötsch). Additional support of the analytical environment was gained form the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 602919 (GLORIA, J Lötsch). The funders had no role in method design, data selection and analysis, decision to publish or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No funded writing assistance was utilized in the production of this manuscript.