Abstract: Neuropathic pain manifests as a variety of symptoms resulting from multiple pathologies. Current treatment options for this disease produce mixed results, with no drug providing reliable anti-allodynia or anti-hyperalgesia. Earlier work has suggested that Neuropeptide Y (NPY) modulates neuropathic pain; however, its exact mechanism(s) of action have not been elucidated. To address this question, we performed behavioral and immunohistochemical studies in the Spared Nerve Injury (SNI) model. We show that NPY dose-dependently reduced behavioral signs of mechanical and cold hypersensitivity. Intrathecal administration of either a Y1 (BIBO3304) or a Y2 (BIIE0246) receptor antagonist dose-dependently reversed the anti-allodynic actions of NPY. In addition to inhibiting behavioral signs of both formalin and neuropathic pain, we found that NPY can also reduce increases in Fos expression in the dorsal horn (DH) after formalin injection or reversibly after non-noxious stimulation in nerve-injured rats. To better understand how nerve injury affects NPY and Y1 receptor expression, we quantified NPY and Y1R staining at 2 weeks post-SNI in the DH, dorsal root ganglia (DRG) and nucleus gracilis (NG). We observed an increase in NPY-LI, accompanied by a decrease in Y1R-LI in the DH and DRG. In the DH, these changes are localized to the area innervated by the injured nerves. In the DRG, we saw NPY-LI appear in large diameter neurons, and Y1R-LI decrease in small diameter neurons. To further characterize Y1R-LI expression after SNI, we co-localized it with markers of primary afferents in the DRG, and found that Y1R-LI expression almost completely co-localizes with CGRP-LI (peptidergic C-fibers). To elucidate the plasticity potential of NPY-LI and Y1R-LI, we examined behavior and protein expression at 6 months after SNI variations and found that if the tibial nerve was transected, mechanical hyperalgesia and cold allodynia largely recovered, but mechanical allodynia persisted. In the DH, NPY-LI and Y1R-LI recovered, but in the DRG and nucleus gracilis (NG), neither NPY-LI nor Y1R-LI completely returned to baseline. Taken together, our results provide evidence that spinal NPY plays an antinociceptive role in neuropathic pain, acting via both Y1 and Y2 receptors.
Keywords: Health and environmental sciences, Neuropathic pain, Neuropeptide Y, Y1 and Y2 receptors