MOLECULAR MECHANISMS OF PAEDIATRIC PAIN: A SYSTEMATIC REVIEW OF TRANSLATIONAL EVIDENCE

Abstract

Background: Paediatric pain is increasingly recognized as a biologically distinct phenomenon shaped by developmental maturation of nociceptive, neuroimmune, and neuroplastic pathways. Unlike adult pain physiology, the immature nervous system exhibits age-dependent molecular and cellular mechanisms that may influence acute pain responses and predispose to pain chronification. This systematic review synthesized current translational evidence regarding the molecular mechanisms underlying paediatric pain.

Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. PubMed, Scopus, and Web of Science were searched from inception to March 2026 for original translational preclinical and clinical studies investigating molecular, genetic, epigenetic, neuroimmune, or neurodevelopmental mechanisms of pain in paediatric populations or developmentally relevant animal models. Study selection, data extraction, and quality appraisal were performed independently by two reviewers using the SYRCLE Risk of Bias Tool and Newcastle–Ottawa Scale. Owing to methodological heterogeneity, findings were synthesized qualitatively.

Results: Eighteen studies met inclusion criteria from 90 initially identified records. Evidence consistently demonstrated that paediatric pain is mediated by developmentally regulated mechanisms distinct from adult nociception. Key pathways implicated included enhanced peripheral and central excitability, ion channel dysregulation (Nav1.7, Nav1.8, Nav1.9, TRPV1, TRPA1), augmented glutamatergic/NMDA receptor signaling, persistent dorsal horn sensitization, and neuroimmune activation involving microglial and astrocytic release of pro-inflammatory cytokines. Genetic polymorphisms in CACNG2, P2RX7, BDNF, and COMT were associated with altered pain susceptibility and chronic pain risk. Epigenetic mechanisms—including DNA methylation, microRNA dysregulation, and MeCP2-mediated transcriptional modulation—emerged as significant regulators of nociceptive plasticity. Early-life painful experiences were consistently associated with nociceptive priming and long-term enhancement of pain vulnerability.

Conclusions: Paediatric pain is governed by dynamic developmental molecular mechanisms that differ substantially from adult pain biology. Neuroimmune activation, ion channel dysregulation, genetic susceptibility, and epigenetic remodelling appear central to paediatric nociceptive sensitization and pain chronification. These findings support the need for developmentally tailored, mechanism-based paediatric analgesic strategies and highlight the importance of early pain prevention to mitigate long-term neurobiological consequences.