Abstract
BACKGROUND: The pathogenesis of neuropathic pain (NP) is complex and remains incompletely understood, making it essential to establish animal models that can stably and reproducibly recapitulate pain behaviors and functional impairments. The conventional chronic constriction injury (CCI) model of the sciatic nerve is highly operator dependent, resulting in limited reproducibility. This study aimed to establish a NP model with improved stability and reproducibility. METHODS: A NP model was generated by applying sustained and quantifiable mechanical compression to the rat sciatic nerve using a clip device. Pain-related behavioral tests, gait analysis, electrophysiological recordings, and histological and immunofluorescence analyses were conducted to systematically compare and validate the clip-compression model against the CCI model. RESULTS: Quantitative measurements using a thin-film pressure sensor demonstrated that the clip applied a consistent force of 1.75 ± 0.17 N. Behavioral assessments showed that both the CCI and clip-compression models reliably induced pain hypersensitivity; however, the clip-compression model exhibited a more persistent and stable pain phenotype. Gait and electrophysiological evaluations revealed significant ipsilateral hind-limb gait dysfunction, reduced weight-bearing capacity, and impaired peripheral nerve conduction in the clip-compression model. Histological and immunofluorescence analyses indicated that both models caused nerve fascicle disorganization, myelin damage, and axonal degeneration. Notably, the clip-compression model was associated with relatively milder inflammatory cell infiltration, greater early preservation of myelin architecture, and maintained nerve trunk continuity, more closely resembling the pathological features of chronic nerve compression. CONCLUSION: This study establishes and systematically validates a novel clip-based nerve compression model of NP, providing a more stable, reliable, and reproducible animal model for mechanistic studies and therapeutic evaluation in NP research.