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.