Mechanical Compression-Induced Peripheral Neuropathic Pain: From Astrocyte Mechanosensing and Phenotypic Reprogramming to CCL2-CCR2 Axis-Targeted Therapies.

Neuropathic pain (NP) arising from mechanical nerve compression is driven by central sensitization, in which reactive astrocytes and chemokine-mediated neuro-glial crosstalk act as master regulators. Among candidate chemokine axes, the C-C motif chemokine ligand 2 (CCL2) and its receptor, C-C chemokine receptor type 2 (CCR2), most directly couple astrocyte activation to nociceptive signaling, and aberrant activation of this axis is conserved across diverse compression paradigms. This review synthesizes current evidence on how mechanical compression is translated into persistent pain via astrocytes. We first outline the methodological foundations and anatomical diversity of compression models, together with advances and limitations in astrocyte profiling. We then trace how mechanosensitive receptors and ion channels initiate astrocytic activation and examine the multicellular origins of CCL2 and its intracellular and epigenetic regulation. Equally important are single-cell-resolved phenotypic heterogeneity beyond the A1/A2 dichotomy, sexual dimorphism in astrocytic versus microglial pathways and the collapse of homeostatic, non-inflammatory astrocyte functions. Downstream, astrocyte-derived CCL2 engages neuronal and microglial CCR2 and together with interleukin (IL) and tumor necrosis factor-α (TNF-α) cytokine cascades, drives feed-forward glial crosstalk and sensitization of spinal and supraspinal circuits. Building on this framework, we evaluate a range of strategies targeting the axis, spanning small-molecule inhibitors, natural products, gene-silencing and precision-delivery platforms, and combinatorial regimens. We also highlight the clinical translational gap, exemplified by the discontinued anti-CCL2 monoclonal antibody carlumab, the Phase II analgesic failure of the CCR2 antagonist AZD2423, the halted CCR2/CCR5 antagonist PF-04634817, and the absence of JAK inhibitors from pain randomized controlled trials. Finally, we identify three translational bottlenecks: limited tools for resolving astrocyte states in vivo, insufficient large-animal pharmacological validation, and compensatory chemokine-receptor redundancy. We further outline directions for next-generation, multi-modal interventions.