Patterns of nerve injury and neuropathic pain in ischemic neuropathy after ligation-reperfusion of femoral artery in mice

Ischemia is an important etiology of painful neuropathies. We generated a mouse system of ischemic neuropathy by ligation-reperfusion of the femoral artery to mimic neuropathic pain and nerve injury patterns observed clinically. Mice exhibited spontaneous neuropathic pain behaviors, which were most obvious after ischemia for 5 h. Mechanical and cold allodynia developed by post-operative day (POD) 7 and persisted through the experimental period up to POD 56. Neuropathic pain behaviors were alleviated with intraperitoneal gabapentin (50 and 100 mg/kg) in a dose-dependent manner. Large-fiber deficit assessed with nerve conduction studies was demonstrated by reduced amplitudes of the compound muscle action potential (CMAP) on POD 7 (48.4% of the control side, p < 0.001). Small-fiber impairment was demonstrated by decreased epidermal nerve density (END) on POD 7 (29.1% of the control side, p < 0.001). Reductions in CMAP amplitudes and ENDs persisted through POD 56. Our system replicated the clinical manifestations of ischemic neuropathy: (1) neuropathic pain with cold and mechanical allodynia and (2) nerve injury to both large and small fibers with pathologic and physiologic evidence. This system produced by a simple procedure provides an opportunity to investigate mechanisms and further treatments of ischemic neuropathy on genetically engineered mice.