Neuropathic pain through the perspective of microglia-neuron interactions: a translational review for clinicians.

Neuropathic pain affects up to 10% of the population and is often refractory to current treatments. Growing evidence implicates neuroimmune interactions, particularly microglia, in the pathophysiology, but their role is underappreciated in clinical practice. To summarize current evidence for microglial contributions to neuropathic pain, emphasizing microglia-neuron interactions and translational implications for clinicians. This narrative review synthesizes preclinical and emerging human data (postmortem histopathology, glial-signal positron emission tomography (PET) imaging, dorsal root ganglion transcriptomics) to examine microglial contributions to pain initiation, maintenance and resolution, sex differences and therapeutic implications. Preclinical evidence demonstrates that microglia are necessary and sufficient for pain initiation. Nerve injury engages central sensitization through colony-stimulating factor 1 (CSF1)-CSF1 receptor (CSF1R), purinergic receptors, damage-associated molecular pattern/Toll-like receptor signaling, cytokine cascades (TNFα, IL-1β, IL-6), prostaglandin E₂, extracellular matrix and synaptic remodeling and brain-derived neurotrophic factor-tropomyosin receptor kinase B-mediated disinhibition. Microglia also contribute to pain resolution via pro-resolving mediators and stimulator of interferon genes (STING)/interferon signaling. Sex differences are prominent: microglial mechanisms predominate in males, whereas T-cell-mediated pathways prevail in females. Human postmortem and glial-signal imaging studies support glial involvement in chronic pain but lack direct validation of specific microglial targets. Microglia coordinate pain initiation and resolution via conserved, drug-addressable pathways. Three translational implications emerge: (1) neuroimmune interventions are most effective early, given that microglia drive initiation more than maintenance; (2) sex-stratified trial designs are warranted given divergent microglial versus T-cell mechanisms by sex and (3) CSF1R-PET imaging may enable mechanism-based patient selection. These implications require prospective clinical validation.