Inflammation or peripheral nerve injury increases neuropeptide Y (NPY) expression in pain-relevant areas of the nervous system, such as large primary afferents and lamina l/ll of the dorsal horn of the spinal cord. However, the contribution of endogenous NPY to chronic pain is unclear. This NRSA proposes to test the overall hypothesis that NPY tonically inhibits nociceptive signaling in the spinal cord and brain following inflammation or nerve injury.
Specific Aim #1 will test the hypothesis that genetic knockdown of NPY increases allodynia and/or hyperalgesia associated with nerve injury and inflammation.
Aim #1 experiments utilize a conditional knockout mouse (Npytet) that contains a doxycycline (Dox)-regulated cassette (tTA) upstream of Npy exons to evaluate the contribution of NPY to the development (Aim 1 A) and maintenance (Aim 1B) of chronic pain, and correlate these changes with NPY expression using immunohistochemistry and western blot (Aim 1C).
While Aim #1 establishes a contribution of NPY inhibition to behavioral manifestations of chronic pain, Specific Aim #2 uses direct microinjection techniques to investigate the site of action of NPY. NPY Y1 and NPY Y2 receptors decorate lamina l/ll of the dorsal horn. I propose to target these receptors with intrathecal injection of selective Y1 or Y2 receptor antagonists (Aim 2A). Previous studies indicate that inflammation up-regulates the expression of NPY and Y1 in the arcuate nucleus of the hypothalamus (ARC), and that microinjection of NPY into the ARC attenuated behavioral signs of heat hypersensitivity.
In Aim 2 B, I propose to microinject Y1 or Y2 antagonists into the ARC, and predict that this will exacerbate allodynia and hyperalgesia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS057928-03
Application #
7620109
Study Section
Special Emphasis Panel (ZRG1-F02B-G (20))
Program Officer
Porter, Linda L
Project Start
2008-01-01
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
3
Fiscal Year
2009
Total Cost
$26,976
Indirect Cost
Name
University of Kentucky
Department
Type
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Solway, Brian; Bose, Soma C; Corder, Gregory et al. (2011) Tonic inhibition of chronic pain by neuropeptide Y. Proc Natl Acad Sci U S A 108:7224-9