Genetic and epigenetic mechanisms influencing acute to chronic postsurgical pain transitions in pediatrics: Preclinical to clinical evidence

Background Chronic postsurgical pain (CPSP) in children remains an important problem with no effective preventive or therapeutic strategies. Recently, genomic underpinnings explaining additional interindividual risk beyond psychological factors have been proposed. Aims We present a comprehensive review of current preclinical and clinical evidence for genetic and epigenetic mechanisms relevant to pediatric CPSP. Methods Narrative review Results Animal models are relevant to translational research for unraveling genomic mechanisms. For example, Cacng2, p2rx7 and bdnf mutant mice show altered mechanical hypersensitivity to injury, and variants of the same genes have been associated with CPSP susceptibility in humans; similarly, differential DNA methylation (H1SP) and miRNAs (miR-96/7a) have shown translational implications. Animal studies also suggest crosstalk between neurons and immune cells may be involved in nociceptive priming observed in neonates. In children, differential DNA methylation in regulatory genomic regions enriching GABAergic, dopaminergic and immune pathways, as well as polygenic risk scores for enhanced prediction of CPSP, have been described. Genome wide studies in pediatric CPSP are scarce, but pathways identified by adult gene association studies point to potential common mechanisms. Conclusions Bench to bedside genomics research in pediatric CPSP is currently limited. Reverse translational approaches, use of other -omics and inclusion of pediatric/CPSP endophenotypes in large scale biobanks may be potential solutions. Time of developmental vulnerability and longitudinal genomic changes after surgery warrant further investigation. Emergence of promising precision pain management strategies based on gene editing and epigenetic programing emphasize need for further research in pediatric CPSP-related genomics.