Abstract

Understanding mechanisms associated with chronic or persistent pain is important in developing therapeutic strategies. PSD-93/chapsyn-110 is a neuronal PDZ domain-containing protein that binds to and clusters NMDA receptors at synapses, and assembles a specific set of signaling proteins around the NMDA receptors. This proposal is focused on the interaction between the PSD-93/chapsyn-110 PDZ domain and NMDA receptors in central mechanisms of chronic or persistent pain. We have made the novel discoveries that 1) PSD-93/chapsyn-110 is expressed mainly in the superficial dorsal horn of spinal cord, where it co-localizes and interacts with NMDA receptors, and 2) targeted disruption of the PSD-93/chapsyn-110 gene significantly attenuates NMDA receptor-mediated excitatory postsynaptic currents in spinal dorsal horn neurons and reduces pain hypersensitivity triggered via NMDA receptor activation. This proposal seeks to further determine the role of PSD-93/chapsyn-110 in chronic or persistent pain, and explores cellular and molecular mechanisms of antinociception resulting from the deletion ofPSD-93/chapsyn-110 in chronic pain states. We will define whether knockout and knockdown of the PSD-93/chapsyn-110 affect thermal and mechanical pain hypersensitivity in complete Freund's adjuvant-induced inflammatory and nerve injury-induced neuropathic pain models. We will determine, in chronic pain states, the effect of PSD-93/chapsyn-110 deletion on NMDA receptor mediated excitatory sensory synaptic potentials, and on NMDA receptor-mediated response to peripheral noxious stimulation and to electrical stimulation-induced wind-up in spinal dorsal horn neurons. In wild type and PSD- 93/chapsyn-110 knockout mice, we will compare surface expression and synaptic localization of NMDA receptors in spinal cord neurons. These studies will provide a novel insight to the mechanisms of chronic pain and a new and potential biochemical target for the prevention and therapy of chronic pain. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044219-02
Application #
6703159
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Porter, Linda L
Project Start
2003-03-01
Project End
2008-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
2
Fiscal Year
2004
Total Cost
$388,313
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Tao, Feng; Johns, Roger A (2010) Tat-Mediated Peptide Intervention in Analgesia and Anesthesia. Drug Dev Res 71:99-105
Tao, Feng; Su, Qingning; Johns, Roger A (2008) Cell-permeable peptide Tat-PSD-95 PDZ2 inhibits chronic inflammatory pain behaviors in mice. Mol Ther 16:1776-82
Sato, Y; Tao, Y-X; Su, Q et al. (2008) Post-synaptic density-93 mediates tyrosine-phosphorylation of the N-methyl-D-aspartate receptors. Neuroscience 153:700-8
Tao, Feng; Johns, Roger A (2008) Effect of disrupting N-methyl-d-aspartate receptor-postsynaptic density protein-95 interactions on the threshold for halothane anesthesia in mice. Anesthesiology 108:882-7
Tao, Feng; Skinner, John; Su, Qingning et al. (2006) New role for spinal Stargazin in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated pain sensitization after inflammation. J Neurosci Res 84:867-73
Chu, Ya-Chun; Guan, Yun; Skinner, John et al. (2005) Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain. Pain 119:113-23
Liaw, Wen-Jinn; Stephens Jr, Robert L; Binns, Brian C et al. (2005) Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain 115:60-70
Tao, F; Tao, Y-X; Zhao, C et al. (2004) Differential roles of neuronal and endothelial nitric oxide synthases during carrageenan-induced inflammatory hyperalgesia. Neuroscience 128:421-30
Tao, Yuan-Xiang; Johns, Roger A (2004) Neuronal PDZ domains: a promising new molecular target for inhaled anesthetics? Mol Interv 4:215-21
Liaw, W-J; Zhang, B; Tao, F et al. (2004) Knockdown of spinal cord postsynaptic density protein-95 prevents the development of morphine tolerance in rats. Neuroscience 123:11-5

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