Dorsal Root Ganglion as a Hub for Peripheral Sensitization: A Hierarchical Regulation Model and Translational...

The high attrition rate of analgesic candidates in clinical trials stems largely from a reductionist reliance on rodent models and a neglect of the spatiotemporal complexity of nociception. Positioning the dorsal root ganglion (DRG) as the core computational hub for peripheral sensitization, this review proposes a "Hierarchical Regulation Model" to integrate fragmented mechanisms into a systemic framework. We stratify peripheral sensitization into three interlocking tiers: an acute tier driven by ion channel functional remodeling (eg, Nav1.7/1.8, Transient Receptor Potential (TRP) family); an intermediate tier orchestrated by neuroinflammation and glia-immune networks (eg, Satellite glial cell (SGC) activation, B-cell infiltration); and a long-term tier anchored by epigenetic reprogramming (eg, histone modifications, DNA methylation) that constitutes the "molecular memory" of pain. Crucially, this model reveals that pain chronification arises from the "pathological homeostasis" formed by cross-hierarchical feedback loops. Importantly, we extend this framework to pathology-specific trajectories, highlighting "acute layer jumping" in chemotherapy-induced peripheral neuropathy and "early metabolic solidification" in diabetic peripheral neuropathy. Finally, anchored by the recent breakthrough approval of the selective Nav1.8 inhibitor Suzetrigine (VX-548), we validate the "Human-First" drug development paradigm. We conclude that overcoming translational barriers requires shifting from "one-size-fits-all" approaches to precision strategies stratified by pathological tier, disease stage, and biological sex.