Following peripheral nerve injury, lidocaine application has been demonstrated to suppress injury discharges. However, there is very little information about the effects of lidocaine pre-treatment. The aim of the present study was to examine the effects of pre-treatment with lidocaine on injury discharges of the nerve, and neuropeptide Y (NPY) and c-Fos expression in the cuneate nucleus (CN) after median nerve transection (MNT). Rats received either saline or 1%, 5%, or 10% lidocaine applied topically to the median nerve before nerve transection. Electrophysiological recording was used to examine the changes in injury discharges of the nerve at post-injection, transection, pre- and post-electrical stimulation stages in the different groups. Sequential immunohistochemistry was also used to identify the number of NPY-like immunoreactive (NPY-LI) fibers and c-Fos-LI cells in the corresponding CN. An increasing frequency of injury discharges was observed at all stages in the pre-saline group, which were suppressed by lidocaine pre-treatment in a dose-dependent manner. Lidocaine pre-treatment also attenuated the number of injury-induced NPY-LI fibers and c-Fos-LI neurons within the CN in a dose-dependent manner. Furthermore, expression of c-Fos-LI neurons in the CN was significantly reduced by an NPY receptor antagonist, indicating that NPY modulated c-Fos expression following MNT. These data suggest that preventing injury discharges with lidocaine pre-treatment can effectively attenuate central sensitization following MNT.