Our work indicates that intrathecal administration of NPY acts in a dose- and NPY receptor-dependent mannerto reduce the mechanical and thermal hypersensitivity associated with inflammation or nerve injury. Theobjective of the present application is to establish NPY as an intrinsic pain modulator, and to identify themechanisms underlying NPY-mediated inhibition of inflammatory or neuropathic pain. The central hypothesis isthat tissue or nerve injury sensitizes the dorsal horn to the pain inhibitory actions of NPY receptor signaling.Our approach involves transgenic, biochemical, and anatomical methods to determine: the anti-allodynicactions of intrinsic NPY (Aim 1); the effect of injury on the efficacy of NPY receptor stimulation (Aim 2); theeffect of NPY on the release of substance P (Aim 3A); and the effect of NPY on activity of spinal neurons thatexpress the NPY Y1 receptor (Aim 3B). Our long-term goal is to establish the therapeutic potential of NPYreceptor agonists for chronic pain.
AIM #1 tests the hypothesis that intrinsic NPY reduces allodynia. To address the contribution ofendogenous NPY to chronic pain, Aim #1 will utilize transgenic mice (NPYtet) that contain a doxycycline (Dox)-regulated cassette (tetracycline trans-activator, tTA) at the promotor region of the npy locus. We describe dataindicating that inducible NPY depletion increases behavioral signs of tactile and cold allodynia in the sparednerve injury (SNI) model of neuropathic pain. These data lead us to determine the effect of conditional NPYknockdown on the induction, maintenance, and reinstatement of chronic pain. We predict that NPY depletionwill speed the development, increase the intensity, and extend the duration of the allodynia induced by nerveinjury or adjuvant-induced inflammation.
AIM #2 tests the hypothesis that injury increases NPY receptor signaling in the dorsal horn. Todetermine whether injury increases NPY receptor-G protein coupling, we will evaluate Y1- and Y2-agoniststimulatedGTP?S binding after inflammation, nerve injury, or sham surgery in NPYtet mice. Because receptorexpression levels must be taken into account when assessing the efficacy of NPY receptor stimulation, we willalso measure Y1 and Y2 expression after inflammation, nerve injury, or sham surgery.
AIM #3 will test the hypothesis that NPY inhibits spinal pronociceptive neurotransmission. Y1 receptorsdecorate presynaptic terminals in the dorsal horn. Based on our preliminary results, we predict that intrathecalNPY will dose- and receptor-dependently reduce the injury-induced release of SP (using microdialysis andinjury-induced NK1 receptor internalization). Because Y1 receptors also label spinal neurons, we will test forpostsynaptic actions of NPY. We will determine the effect of intrathecal NPY on SP-induced nociceptivebehavior and NK1 receptor internalization. Our preliminary data with the selective neurotoxin NPY-saporinsuggest that Y1-expressing cells in the dorsal horn facilitate pain transmission. We predict that the activity ofthis population of spinal neurons will be decreased by NPY administration, and increased by NPY knockdown.
| Corder, Gregory; Siegel, Andrew; Intondi, Allison B et al. (2010) A novel method to quantify histochemical changes throughout the mediolateral axis of the substantia gelatinosa after spared nerve injury: characterization with TRPV1 and substance P. J Pain 11:388-98 |
| Intondi, A B; Zadina, J E; Zhang, X et al. (2010) Topography and time course of changes in spinal neuropeptide Y immunoreactivity after spared nerve injury. Neuroscience 165:914-22 |
| Gould 3rd, Harry J; Garrett, Colleen; Donahue, Renee R et al. (2009) Ranolazine attenuates behavioral signs of neuropathic pain. Behav Pharmacol 20:755-8 |
| Taylor, Bradley K (2009) Spinal inhibitory neurotransmission in neuropathic pain. Curr Pain Headache Rep 13:208-14 |
