Hypermethylation of OPRM1: Deregulation of Endogenous Opioid Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome & Fibromyalgia, 2025, Wyns

[Dolphin]

https://www.mdpi.com/1422-0067/27/2/826

Hypermethylation of OPRM1: Deregulation of the Endogenous Opioid Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia​

Arne Wyns1,2,
Jolien Hendrix1,2,3,
Jente Van Campenhout1,
Yanthe Buntinx1,
Huan-Yu Xiong1,3,
Elke De Bruyne4,
Lode Godderis2,5,
Jo Nijs1,6,7,
David Rice8,9 …
Andrea Polli1,2,3,*
1
Pain in Motion (PiM) International Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Rehabilitation Sciences & Physiotherapy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Belgium
2
Department of Public Health and Primary Care, Centre for Environment & Health, KU Leuven, Kapucijnenvoer 35, 3000 Leuven, Belgium
3
Flanders Research Foundation—FWO, 1000 Brussels, Belgium
4
Translational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit Brussel, 1090 Jette, Belgium
5
External Service for Prevention and Protection at Work, IDEWE, 3001 Heverlee, Belgium
6
Department of Physical Medicine and Physiotherapy, University Hospital Brussels, 1000 Jette, Belgium
7
Institute of Neuroscience and Physiology, University of Gothenburg, 405 30 Gothenburg, Sweden
8
Health and Rehabilitation Research Institute, Auckland University of Technology, Auckland 1023, New Zealand
9
Department of Anaesthesiology, Perioperative & Pain Medicine, Health New Zealand, Te Whatu Ora Waitemata, Auckland 0620, New Zealand
10
Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine and Health Science, University of Auckland, Auckland 1023, New Zealand
11
Department of Anaesthesiology, Faculty of Medicine and Health Science, University of Auckland, Auckland 1023, New Zealand
*
Author to whom correspondence should be addressed.
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Int. J. Mol. Sci.2026, 27(2), 826;https://doi.org/10.3390/ijms27020826
This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics

Abstract​

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are debilitating disorders with overlapping symptoms such as chronic pain and fatigue.

Dysregulation of the endogenous opioid system, particularly µ-opioid receptor function, may contribute to their pathophysiology.

This study examined whether epigenetic modifications, specifically µ-opioid receptor 1 gene (OPRM1) promoter methylation, play a role in this dysfunction.

Using a repeated-measures design, 28 ME/CFS/FM patients and 26 matched healthy controls visited the hospital twice within four days.

Assessments included blood sampling for epigenetic analysis, a clinical questionnaire battery, and quantitative sensory testing (QST).

Global DNA (hydroxy)methylation was quantified via liquid chromatography–tandem mass spectrometry, and targeted pyrosequencing was performed on promoter regions of OPRM1, COMT, and BDNF.

ME/CFS/FM patients reported significantly worse symptom outcomes.

No differences in global (hydroxy)methylation were found.

Patients showed significantly higher OPRM1 promoter methylation, which remained after adjusting for symptom severity and QST findings.

Across timepoints, OPRM1 methylation consistently correlated with BDNF Promoter I and Exon III methylation.

This is, to the best of our knowledge, the first study examining OPRM1 methylation in ME/CFS/FM.

Increased OPRM1 methylation in patients, independent of symptoms or pain sensitivity measures, supports the hypothesis of dysregulated opioidergic signaling in these conditions.

Keywords:
myalgic encephalomyelitis/chronic fatigue syndrome; fibromyalgia; opioids; OPRM1; descending modulation; epigenetics; bisulfite conversion

 

[Jonathan Edwards]

I know very little about epigenetics methodology of this sort. The question comes up in my mind as to whether this would be upstream or downstream of the disease. Maybe the controls should be equally disabled and disheartened people with some other disease like Parkinsonism or diabetes.

 

[V.R.T.]

The question comes up in my mind as to whether this would be upstream or downstream of the disease.

Could something like this account for any part of the core symptoms of MECFS? And/or contribute to an immune-brain signalling loop?

 

[forestglip]

Some of the references seem to be numbered wrong, since these seem unrelated to the sentences:

Patients with a clear diagnosis of ME/CFS, according to the Centre for Disease Control and Prevention Criteria, and FM, according to the American College of Rheumatology Criteria (ACR-2011), were enrolled in this study [31,32]. [...] Only female participants were included in this study due to the higher prevalence of ME/CFS and FM in the female sex and important sex-related differences in pain and immune regulation [33,34].

31. Carneiro, A.M.; de Goes Salvetti, M.; Dale, C.S.; da Silva, V.A. Quantitative Sensory Testing in Fibromyalgia Syndrome: A Scoping Review. Biomedicines 2025, 13, 988. [Google Scholar] [CrossRef]

32. Xiong, H.Y.; Hendrix, J.; Schabrun, S.; Wyns, A.; Campenhout, J.V.; Nijs, J.; Polli, A. The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation. Biomolecules 2024, 14, 71. [Google Scholar] [CrossRef] [PubMed]

33. Sun, N.; Yu, L.; Gao, Y.; Ma, L.; Ren, J.; Liu, Y.; Gao, D.S.; Xie, C.; Wu, Y.; Wang, L.; et al. MeCP2 Epigenetic Silencing of Oprm1 Gene in Primary Sensory Neurons Under Neuropathic Pain Conditions. Front. Neurosci. 2021, 15, 743207. [Google Scholar] [CrossRef] [PubMed]

34. Mo, K.; Wu, S.; Gu, X.; Xiong, M.; Cai, W.; Atianjoh, F.E.; Jobe, E.E.; Zhao, X.; Tu, W.-F.; Tao, Y.-X. MBD1 Contributes to the Genesis of Acute Pain and Neuropathic Pain by Epigenetic Silencing of Oprm1 and Kcna2 Genes in Primary Sensory Neurons. J. Neurosci. 2018, 38, 9883–9899. [Google Scholar] [CrossRef]

 

[arachel]

Multiple testing correction was not performed, none of the p-values would remain significant after adjusting for this, so wouldn't read too much into it