Unraveling the emerging role of glial heterogeneity in neuropathic pain: from pathological mechanisms to therapeutic Frontiers

Neuropathic pain (NP) arises from injury or dysfunction within the somatosensory nervous system and represents a major clinical challenge due to its complex and multifactorial pathogenesis. Emerging evidence underscores that the onset and maintenance of NP are not solely governed by neuronal mechanisms but are critically shaped by the persistent activation and inherent heterogeneity of glial cells. Glial heterogeneity encompasses diverse molecular phenotypes, functional states, and distinct spatial distributions. Within the central nervous system (CNS), microglia and astrocytes undergo dynamic phenotypic transitions, contributing to both neurotoxic and neuroprotective effects by modulating neuroinflammatory cascades. In the peripheral nervous system, satellite glial cells actively sensitize sensory neurons through enhanced intercellular communication and the release of specific mediators, thereby facilitating the development and persistence of NP. The coordinated actions of heterogeneous glial populations drive key pathological processes—including synaptic remodeling, sustained neuroinflammation, and dysregulation of ion channels—ultimately promoting peripheral and central sensitization. Importantly, emerging therapeutic strategies targeting distinct glial subpopulations or their specific activation states, such as P2X4 receptor antagonists or NF-κB inhibitors, have shown promise beyond conventional neuron-centric approaches. This review synthesizes current insights into glial heterogeneity in NP, addressing a critical gap in the literature and providing a framework for advancing mechanism-based clinical interventions.