Neuropeptide Y is analgesic in rats after plantar incision

Previous work has demonstrated that neuropeptide tyrosine (NPY), Y1 receptor and Y2 receptor are critical in modulation of pain after nerve injury. We hypothesized that NPY was important for nociception after surgical incision. As a model of postoperative pain, rats underwent a plantar incision in one hindpaw. Western blots were used to quantify changes in protein expression of NPY, Y1 receptor and Y2 receptor after incision in skin, muscle, and dorsal root ganglion (DRG). Pain-related behaviors were tested after incision in rats treated with intrathecal NPY, Y1 receptor antagonist (BIBO3304 - Chemical Name: N-[(1R)-1-[[[[4-[[(Aminocarbonyl)amino]methyl]phenyl]methyl]amino]carbonyl]-4-[(aminoiminomethyl)amino]butyl]-α-phenyl-benzeneacetamide ditrifluoroacetate), Y2 receptor antagonist (BIIE0246 - Chemical Name: N-[(1S)-4-[(Aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide), combined NPY+antagonists, morphine, or vehicle. Pain behaviors were tested after incision in rats treated with locally applied intraplantar injections of NPY, Y1 receptor and Y2 receptor antagonists or vehicle. NPY protein expression was significantly downregulated in muscle for two days after incision. In contrast, Y1 receptor and Y2 receptor protein expression was upregulated in both skin and muscle. A single intrathecal injection of NPY reduced cumulative guarding pain scores, as did morphine. The intrathecal administration of Y2 receptor antagonist also reduced pain scores; findings that were not observed when drugs were administered locally. Intrathecal Y2 receptor antagonists and NPY improved mechanical threshold and heat withdrawal latency 2 h after incision. Intrathecal administration of NPY and/or central blockade of Y2 receptor attenuated pain behaviors early after incision (postoperative day (POD) 1-2). Y1 receptor antagonist administration blocked the anti-hyperalgesic effect of NPY. Together these data suggest a role for spinal NPY in postoperative pain.