UCSF

BACKGROUND/IMPORTANCE: 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. OBJECTIVE: To summarize current evidence for microglial contributions to neuropathic pain, emphasizing microglia-neuron interactions and translational implications for clinicians. EVIDENCE REVIEW: 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. FINDINGS: 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. CONCLUSIONS: 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.