Epigenetic Regulation of Anesthesia and Pain

Introduction

• Perioperative outcomes are influenced not only by genetic sequence variation but also by epigenetic modifications that regulate gene expression.¹
• The influence of epigenetics on anesthetic and analgesic responses, as well as on postoperative recovery, is increasingly recognized.
• Definition: Epigenetic mechanisms refer to nonstructural chemical modifications of deoxyribonucleic acid (DNA) that can affect gene activity.²
• Epigenetic mechanisms are commonly grouped as follows (Figure 1):
  • Histone modifications, including acetylation and methylation, are associated with alterations in chromatin accessibility and gene transcription
  • DNA methylation is characterized by the addition of methyl groups to cytosine residues and is known to be associated with transcriptional repression.
  • Noncoding RNAs (ncRNAs), including microRNAs and long ncRNAs, are capable of post-transcriptional regulation of gene expression.
• Epigenetic modifications are dynamically regulated in response to anesthetic exposure, surgical stress, inflammation, and environmental factors.
• Dietary factors, such as folate and Vitamin B12 deficiencies, as well as chronic stress and environmental pollutants, influence epigenetic modifications. Thus, they play a role in dynamically translating external influences on the genome.
• Clinically relevant consequences of perioperative epigenetic modulation are observed across several domains, with some examples below:³
  • Sensitivity to anesthetic and analgesic agents is altered by epigenetic regulation of pharmacodynamic targets and pharmacokinetic pathways.
  • Emergence times from anesthesia and the risk of immediate perioperative side effects are influenced by epigenetic state.
  • The trajectory of acute postoperative pain and the risk of transition to chronic pain are modified by epigenetic responses to surgical injury and inflammation.
  • Cognitive and functional recovery after surgery is potentially modulated by surgery- and anesthesia-induced epigenetic changes.

Epigenetic Influences on Anesthetic and Analgesic Response

Epigenetic mechanisms are implicated in modulating perioperative drug responses.^4,5

• DNA methylation is known to alter the transcription of genes that encode drug targets and proteins involved in drug handling.
  • OPRM1 promoter: Hypermethylation reduces μ opioid receptor mRNA, leading to diminished opioid efficacy.
  • CYP1A2 exon methylation: methylation of a CpG island in the exon of CYP1A2 causes interindividual differences in expression of CYP1A2, which in turn affects the metabolism of anesthetics like ropivacaine and lidocaine
• Posttranslational histone modifications are known to influence chromatin accessibility and transcription of genes related to anesthesia.
  • HDAC inhibitors: Pharmacologic inhibition of HDACs has been shown in preclinical models to potentiate analgesia.
  • Histone acetyltransferase inhibitors: Inhibition of HAT in the presence of morphine has been shown to reduce the development of OIH.
• ncRNAs are implicated in post-transcriptional and transcriptional regulation of genes that determine anesthetic and analgesic sensitivity.
  • MicroRNAs (miRNAs): miR-23b and miR-107 can downregulate μ-opioid receptor expression and have been shown in cell models to reduce morphine signaling when overexpressed.
  • Long ncRNAs (lncRNAs): They are known to regulate transcription of γ-aminobutyric acid type A (GABA_A) and N-methyl-D-aspartate (NMDA) receptor subunits and are therefore able to fine-tune anesthetic sensitivity

Epigenetic Effects of Anesthetic Agents

Early-Life Anesthesia Exposure

• Exposure to anesthetic agents such as isoflurane, sevoflurane, midazolam, and nitrous oxide during critical periods of brain development induces lasting epigenetic modifications in neural tissue.⁶
• Altered DNA methylation dynamics: Anesthesia can increase or decrease DNMT enzyme activity (DNMT1, DNMT3a, DNMT3b), leading to gene-specific changes in methylation patterns across the developing brain.
  • Hypomethylation of inflammatory genes (Tnf-α, IL-1β, Il-6, MMP9, HMGB1) enhances their expression, promoting neuroinflammation and secondary neuronal stress.
  • Hypermethylation. BDNF promoter hypermethylation and upregulated DNMT1 expression in the hippocampus following neonatal isoflurane exposure, correlating with reduced BDNF expression and memory impairment.
• Histone modification and chromatin remodeling: Early anesthesia disrupts histone acetylation, decreasing H3 acetylation and increasing HDAC2 expression, which further limits transcription of genes required for learning and memory.
  • Propofol application during early gestation affects the offspring’s learning and memory by inhibiting histone acetylation.
• Altered miRNA expression: Neonatal exposure to sevoflurane results in significant differential expression of miRNAs in both the whole brain and hippocampus, which is observed immediately after exposure and persists into adulthood.
  • Sevoflurane-associated miRNA targets are enriched in pathways regulating axon guidance, DNA transcription, protein phosphorylation, and nervous system development, suggesting widespread disruption of neurodevelopmental gene networks.

Adolescent/Adult Exposure⁷

• Sevoflurane-induced DNA methylation changes: Increased DNMT expression in hippocampal pyramidal neurons after sevoflurane exposure.
  • This leads to the hypermethylation of Reelin and BDNF promoters, resulting in reduced transcription and a loss of dendritic spine density, which contributes to postoperative cognitive dysfunction (POCD).
• Isoflurane-induced histone deacetylation and cognitive decline: Isoflurane exposure in aged rats disrupts H3K9 and H4K12 acetylation, key marks of transcriptional activation.
  • This histone hypoacetylation is associated with reduced BDNF expression and suppression of the BDNF–TrkB signaling cascade, impairing learning and memory.
• Propofol-induced miRNA dysregulation and neuronal apoptosis: Exposure to propofol in adult neurons alters miRNA expression profiles, particularly decreasing miR-21 levels.
  • This downregulation of miR-21 upregulates Sprouty 2, activating the STAT3/miR-21/Sprouty 2/Akt signaling pathway and promoting neuronal apoptosis, thereby contributing to anesthetic-induced neurotoxicity.
• Ketamine-induced BDNF-AS upregulation and impaired neurotrophic signaling: Ketamine increases the expression of the long ncRNAs BDNF-AS, which suppresses BDNF transcription and downstream TrkB signaling.
  • This repression reduces neuronal survival and neurite outgrowth, linking lncRNA activation to cognitive impairment following exposure to anesthesia.

The following table summarizes the reported epigenetic changes associated with select anesthetic and analgesic agents in preclinical and translational studies.

Epigenetic Regulation in Postsurgical Pain and Recovery

• Epigenetic alterations in the immune system, nociception, and ion channel pathways are known to contribute to the development and persistence of postsurgical pain.^7,8 Some examples are provided below:
• DNA methylation changes
  • Altered DNA methylation contributes to CPSP: Increased methylation of the OPRM promoter was associated with greater postoperative pain intensity and a higher risk of CPSP in adolescents undergoing spinal fusion surgery.
  • Altered DNA methylation in neural and stress-response pathways contributes to the persistence of CPSP.⁹
    • Genome-wide methylation profiling in pediatric postsurgical cohorts revealed distinct CpG methylation signatures associated with CPSP, indicating stable, systemic epigenetic shifts following surgery.
    • Enriched pathways, including GABAergic receptor activity and dopamine–DARPP32 signaling, suggest that methylation-driven transcriptional dysregulation disrupts inhibitory neurotransmission and the modulation of reward-related pain.
  • Neonatal nociception and stress DNAm changes: Early life pain/stress exposure in neonates has been shown to be associated with increased DNAm in serotonin pathway genes and learning disabilities in childhood.
• Histone acetylation shifts.¹⁰
  • Surgical and inflammatory stress increase acetylation of histones H3 and H4 in spinal neurons, enhancing expression of pro-nociceptive genes and maintaining central sensitization.
  • Histone deacetylase inhibition promotes recovery. Treatment with HDAC inhibitors (e.g., valproic acid, SAHA, or trichostatin A) reverses hyperalgesia, restores BDNF signaling, and supports neuronal plasticity and functional recovery after surgery.
• ncRNAs
  • Dysregulated miRNAs drive prolonged neuroinflammation. Downregulation of anti-inflammatory miRNAs, such as miR-183 and miR-133b-3p, and upregulation of miR-21 enhance the MAPK and autophagy pathways, thereby sustaining postoperative pain hypersensitivity.
  • Epigenetic control via ncRNAs affects neuronal resilience. Changes in miR-124 and BDNF-AS lncRNA expression alter synaptic plasticity and apoptosis signaling in the spinal cord and hippocampus, contributing to cognitive and sensory sequelae after anesthesia or surgery.

Clinical Considerations

Translational and Clinical Implications

• Epigenetic markers are proposed to be useful for patient risk stratification for severe acute and chronic postoperative pain.
  • Patients identified as high risk by epigenetic profiling may be offered early, intensive multimodal analgesia, based on pathways impacted.
• Prehabilitation strategies, including stress reduction, exercise conditioning, nutritional optimization, and sleep hygiene, may modulate stress-responsive epigenetic pathways (e.g., those involving glucocorticoid receptor signaling, inflammation, and neuroplasticity).
  • Integrating prehabilitation programs before surgery could potentially stabilize DNA methylation and histone acetylation patterns associated with stress and pain sensitivity, thereby improving postoperative pain recovery trajectories.

Future Directions

• Integrated epigenomic decision support: Develop point of care tools that aggregate each patient’s genetic-epigenetic data with real time physiologic monitoring to guide anesthetic dosing, analgesic selection, and pre-emptive/rapid identification of at risk individuals.
• Building large pediatric cohorts with genomic and phenotypic depth: Establish multicenter pediatric perioperative biobanks that integrate whole genome sequencing, epigenomic profiling, and detailed pain recovery phenotypes to validate biomarkers and enable machine learning–driven risk stratification.
• Targeted epigenetic therapies for perioperative care: Epigenetic mechanisms are being explored as therapeutic targets, to develop epigenetic modulators (for example, selective histone deacetylase inhibitors) to prevent pain chronification or enhance analgesic efficacy during the perioperative period.
• Randomized clinical trials: Future trials to risk-stratify and test interventions based on impacted genomic pathways.