CXCL12/CXCR4 axis in neuropathic pain: Insights from preclinical models and translational implications

Neuropathic pain affects approximately 7%-10% of the global population, significantly impairing patients' quality of life and placing a substantial burden on public health systems. Current pharmacological treatments have limited efficacy and are often accompanied by notable side effects, highlighting the urgent need for novel therapeutic targets. Increasing evidence supports the important role of chemokines and their receptors in neuro-immune interactions underlying pain sensitization. Among these pathways, the CXCL12/CXCR4 axis has emerged as an important regulator of both the initiation and maintenance of neuropathic pain. Beyond its canonical function in immune cell trafficking, the CXCL12/CXCR4 axis modulates neuronal excitability, glial activation, synaptic plasticity, and nociceptive sensitization. Notably, this axis is frequently upregulated in both peripheral and central neurons, as well as in multiple glial populations, including astrocytes, microglia, and satellite glial cells, across diverse neuropathic pain models. Importantly, CXCR4 is one of the few chemokine receptors with a clinically approved antagonist, highlighting its unique translational potential. This review systematically summarizes the expression patterns, biological functions, and pain-related mechanisms of the CXCL12/CXCR4 axis in preclinical models of neuropathic pain and discusses current limitations and potential future therapeutic strategies targeting this pathway.