Neuropathic pain (NeP) is a chronic pain disorder caused by damage to the somatosensory system, often presenting with long-lasting symptoms and limited efficacy of standard pharmacological treatments. Recent evidence indicates that the microglial activation exists on a dynamic and environment-dependent continuum and this plasticity critically influences the development and maintenance of neuropathic pain. During the polarization process, microglia can release different mediators, and these functional states dynamically regulate neuroinflammation and central sensitization, thereby exerting a profound impact on the occurrence and persistence of NeP. Among these phenotypes, dynamic functional transitions play a critical role in shaping pain outcomes. By releasing pro-inflammatory cytokines such as TNF-α and IL-1β, pain is intensified, whereas anti-inflammatory signaling contributes to protective and reparative effects. This review highlights the critical molecular mechanisms underlying microglial differentiation, including the P2X7, TLR4/NF-κB, and USP19/FOXO1 signaling pathways. It also discusses how these pathways influence the regulation of pain circuits. We also discuss intervention strategies targeting polarization balance, including the potential and challenges of emerging therapeutic approaches such as small-molecule inhibitors, biologics, natural products, and nano-delivery systems. Upcoming studies need to look beyond the M1/M2 dichotomy and explore the complexity of microglial behavior, decode the phenotypic spectrum of microglia at different stages of pain by means of multi-omics technologies, and pay attention to gender differences and translational bottlenecks, so as to promote the development of novel precision analgesic strategies based on neuroimmune regulation.
Mao et al. (Tue,) studied this question.