A Multidimensional Mechanistic Framework for Central Sensitization: A Four-Pathway Model Resolving 30 Years of Conceptual Fragmentation
Year: 2025
Type: preprint
Abstract: A Multidimensional Mechanistic Framework for Central Sensitization (CS)This preprint proposes a unified mechanistic architecture for central sensitization, resolving decades of conceptual fragmentation across immunological, neurological, psychosocial, and nociceptive research. Rather than viewing CS or fibromyalgia as single, uniform disorders, the model conceptualizes them as multidimensional end-states emerging from four distinct excitatory pathways: (A) neuroimmune histamine–microglia activation, (B) glutamate/GABA dysregulation, (C) stress–CRH–HPA-axis disturbance, (D) persistent peripheral nociceptive input. Each pathway can independently generate CS through its own self-sustaining loop. Their interactions, overlaps, and shifting dominance explain the heterogeneity seen across nociplastic conditions. Fibromyalgia is reframed as a convergent phenotype of central sensitization, and the term Central Sensitization Spectrum Disorder (CSSD) is proposed to better reflect its dimensional, mechanism-based nature. Version 2.0 expands the model with a defined pre-CS phase, integration of dimensional metrics (WPI/SSS/PSD), deeper analysis of route overlap, and enhanced diagnostic and research implications. The framework supports precision diagnostics, mechanistically targeted treatment, and stratified clinical trial design.
Author: Eshuis, Erik
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7106249053
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