Transient peripheral compression induces persistent central pain: the acute constriction injury model

Traditional neuropathic pain models such as chronic constriction injury (CCI) induce permanent peripheral nerve damage and cannot mimic persistent pain after resolved transient nerve compression. We established an acute constriction injury (ACI) model on male C57BL/6 J mice with 2-h sciatic nerve constriction followed by complete ligature removal, and performed a 250-day multimodal longitudinal comparison of Control, CCI and ACI mice using behavioral pain assays, somatosensory evoked potentials (SEPs), sciatic function index (SFI), nerve histology, muscle atrophy measurement, open field test, and serial 9.4 T pain-evoked BOLD-fMRI. ACI and CCI mice developed comparable long-lasting ipsilateral and delayed contralateral mechanical allodynia and thermal hyperalgesia over the 250-day observation period. Nonetheless, ACI mice achieved robust peripheral nerve structural and functional recovery without muscle atrophy, whereas CCI mice suffered irreversible peripheral nerve lesions. Serial fMRI revealed distinct brain activation trajectories: ACI mice exhibited spatially restricted response reductions relative to Controls and widespread suppression relative to CCI mice at day 3, isolated hypothalamic activation at day 12, and widespread bilateral activation of brainstem descending modulatory networks at day 250; in contrast, CCI mice showed cerebellar and somatosensory cortical activation at early/mid time points and significant deactivation of striatal-limbic circuits at late chronic stages. Anxiety-like behaviors were detected in both CCI and ACI mice at 12 day post-surgery but only in ACI mice at 7 months post-injury. These data support the pain centralization hypothesis: Brief peripheral nerve insult triggers self-maintained central sensitization that sustains chronic pain after peripheral anatomical and functional recovery. The ACI model may facilitate translational research on central-targeted therapeutics for compression-induced persistent neuropathic pain.