Topography and time course of changes in spinal neuropeptide Y immunoreactivity after spared nerve injury.

We used a new computer-assisted method to precisely localize and efficiently quantify increases in neuropeptide Y immunoreactivity (NPY-ir) along the mediolateral axis of the L4 dorsal horn (DH) 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 nerves 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 weeks, both NPY-ir upregulation in the DH 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 weeks. Over this time course, the average cross-sectional area of NPY-immunoreactive DRG neurons increased by 151 mum(2). We conclude that the upregulation of NPY after SNI is restricted to medial zones of the DH, 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 DH tonically inhibits hypersensitivity by interrupting mechanisms of central sensitization and integration of sensory signals at the spinal and supraspinal levels.

Intrathecal neuropeptide Y reduces behavioral and molecular markers of inflammatory or neuropathic pain.

Our previous work indicates that the intrathecal administration of neuropeptide Y (NPY) acts at its cognate receptors to reduce behavioral signs of nociception in several models of inflammatory pain, including the formalin test. The present study extends these findings to a rat model of peripheral neuropathic pain, and then evaluates the hypothesis that NPY inhibits inflammation- and nerve injury-induced activation of spinal nociceptive transmission. Here we show that NPY dose-dependently reduced behavioral signs of mechanical and cold hypersensitivity in the spared nerve injury (SNI) model. Intrathecal administration of either a Y1 (BIBO3304) or a Y2 (BIIE0246) receptor antagonist dose-dependently reversed the anti-allodynic actions of NPY. To monitor the effects of NPY on the stimulus-induced activation of spinal nociresponsive neurons, we quantified protein expression of the immediate-early gene c-fos in lamina I-VI of the L4-L5 dorsal horn, with special attention to the mediolateral pattern of Fos immunohistochemical staining after SNI. Either tactile stimulation of the hindpaw ipsilateral to nerve injury, or intraplantar injection of noxious formalin, increased the number of Fos-like immunoreactive profiles. Tactile stimulation evoked a mediolateral pattern of Fos expression corresponding to the innervation territory of the uninjured (sural) nerve. We found that intrathecal NPY reduced both formalin- and SNI-induced Fos expression. NPY inhibition of SNI-induced Fos expression was localized to the sural (uninjured) innervation territory, and could be blocked by intrathecal BIBO3304 and BIIE0246. We conclude that NPY acts at spinal Y1 and Y2 receptors to reduce spinal neuron activity and behavioral signs of inflammatory or neuropathic pain.