We used a new computer-assisted method to precisely localize and efficiently quantify increases in NPY immunoreactivity (NPY-ir) along the mediolateral axis of the L4 dorsal horn following transection of either the tibial and common peroneal nerves (thus sparing the sural branch, spared nerve injury, SNI), the tibial nerve, or the common peroneal and sural nerves. Two weeks after SNI, NPY-ir increased within the tibial and peroneal innervation territories; however, NPY-ir in the central-lateral region (innervated by the spared sural nerve) was indistinguishable from that of SHAM. Conversely, transection of the sural and common peroneal nerved induced an increase in NPY-ir in the central-lateral region, while leaving the medial region (innervated by the tibial nerve) unaffected. All nerve injuries increased NPY-ir in dorsal root ganglia (DRG) and nucleus gracilis (NG). By 24 wk, both NPY-ir up-regulation in the dorsal horn and hyper-responsivity to cold and noxious mechanical stimuli had resolved. Conversely, NPY-ir in DRG and NG, and hypersensitivity to non-noxious static mechanical stimuli, did not resolve within 24 wk. Over this time course, the average cross-sectional area of NPY-immunoreactive DRG neurons increased by 150 μm 2 . We conclude that the up-regulation of NPY after SNI is restricted to medial zones of the dorsal horn, and therefore cannot act directly upon synapses within the more lateral (sural) zones to control sural nerve hypersensitivity. Instead, we suggest that NPY in the medial dorsal horn tonically inhibits hypersensitivity by interrupting mechanisms of central sensitization and integration of sensory signals at the spinal and supraspinal levels.

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