(660): Contribution of endogenous NPY signaling to chronic pain: A transgenic approach

Abstract

Nerve injury increases NPY expression in large primary afferents and lamina II/III. Although exogenous NPY reduces behavioral signs of inflammatory and neuropathic pain1Taiwo Pain. 2002Google Scholar, 2Intondi IASP abstract. 2005Google Scholar, the contribution of endogenous NPY is unclear. We determined that NPY knockout mice3Erickson Science. 1996Google Scholar exhibited normal inflammatory (capsaicin, formalin, carrageenan, or CFA models) and neuropathic pain. Developmental compensatory responses may cause such discrepancies between the pharmacological and genetic data. Therefore, we used a conditional knockout mouse (NPYtet) that contains a doxycycline (Dox)-regulated cassette at the NPY locus4Ste. Marie PNAS. 2005Google Scholar. NPYtet express 3-4 times more NPY than genetic controls, while doxycycline (in drinking water) reduces hypothalamic NPY 20-fold. We transected the tibial and common peroneal nerves under isoflurane anesthesia, leaving the sural branch of the sciatic nerve intact (spared nerve injury, SNI). This decreased tactile threshold, and increased responsiveness to both pinprick and cold stimuli in C57Bl/6 or SVJ-129 controls. SNI produced less allodynia and hyperalgesia in NPYtet mice -- we speculate that NPY over-expression tonically inhibits neuropathic pain. To evaluate the contribution of NPY to the development of neuropathic pain, NPYtet mice were treated with Dox for 10d, followed by SNI. Dox increased mechanical allodynia, mechanical hyperalgesia, and cold allodynia beginning at 7d after SNI and lasting for at least 8wk. To evaluate the contribution of endogenous NPY to the maintenance of neuropathic pain, SNI was performed, and Dox was provided 14d later. Dox rapidly (within 4d) increased allodynia and hyperalgesia. Dox and/or saccharin in the drinking water of C57Bl/6 controls (saccharin adds palatability) did not change allodynia and hyperalgesia. These studies demonstrate that endogenous NPY inhibits not only the development, but also the maintenance of neuropathic pain. Current IHC studies are ongoing to examine NPY expression in DRG, spinal cord, and hypothalamus. Supported by NIH NS45954 (BKT).