Saphenous–sural nerve injury: a sensory-specific rodent model of neuropathic pain without motor deficits

Abstract Clinical neuropathic pain is typically characterized by pain arising from damage or disease affecting the somatosensory system without motor deficits. However, traditional nerve injury–induced neuropathic pain models involve damage to mixed motor-sensory nerves, complicating the assessment of pain behaviors because of motor impairments and limiting their translational relevance to clinical neuropathic pain. To overcome these limitations, we developed the saphenous–sural nerve injury model (SS model), which exclusively targets sensory nerves while sparing motor function. In this model, C57Bl/6 mice underwent ligation and transection of the saphenous and sural nerves, which are pure sensory nerves without motor fibers, resulting in rapid and persistent mechanical hypersensitivity without thermal or cold hypersensitivity. Conditioned place preference testing indicated the presence of ongoing spontaneous pain. Importantly, motor function remained unaffected, with no deficits observed in rotarod performance, paw posture, or foot drop. Cellular analyses confirmed injury-specific ATF3 expression in dorsal root ganglion sensory neurons, accompanied by significant microgliosis and astrogliosis in the ipsilateral spinal dorsal horn. In contrast to traditional models, no ATF3 expression or gliosis was observed in motor neurons or the spinal ventral horn, further reinforcing the model's sensory-specific nature. Thus, the SS model effectively replicates key features of neuropathic pain while eliminating motor confounds, enhancing its translational relevance. Its selective sensory neuron injury and robust glial activation provide a valuable platform for investigating pain mechanisms and evaluating novel therapies.