Chronic or persistent pain is a major health problem in the United States, which results in medical care and productivity losses in the billions of dollars. Two symptoms of chronic or persistent pain, which result in the greatest number of complaints from sufferers, are allodynia (pain to normally non-painful stimuli) and hyperalgesia (enhanced sensation of pain in response to painful stimuli). Recent work with antagonists for the N-methyl-D-aspartate (NMDA) receptor demonstrates that a significant proportion of allodynia and hyperalgesia is mediated by spinal cord NMDA receptors. This work suggests that there is a functional change in the activity of the spinal cord NMDA receptors in response to persistent nociceptive stimuli. NMDA receptors are regulated by a number of factors, including phosphorylation. Phosphorylation of the receptors results in an increase in the activity of the receptors. The two subunits of the NMDA receptor (NR1 and NR2) have consensus sites for several kinases, and activity from some of these kinases in the spinal cord has been associated with allodynia and hyperalgesia. Thus, the major hypothesis of this project is that NMDA receptors are phosphorylated by persistent nociception. To test this hypothesis, however, the PI, who is a new investigator, needs to develop new techniques in his laboratory. Because of the need to develop new techniques, the scope of this application has been narrowed to testing the hypothesis that the NR1 subunit of the NMDA receptor is phosphorylated during persistent nociception. This small grant application will: 1) allow the PI to develop and test the specificity of immunoprecipitation techniques on NR1 subunits transfected into HEK-293 cells, 2) transfer these techniques to the study of NR1 subunits in vivo, and 3) evaluate changes in NR1 phosphorylation in response to nociceptive stimuli. A complete understanding of the dynamics of NMDA receptor phosphorylation in response to pain is the ultimate goal of this project. This knowledge should lead to valuable insights into spinal cord pain processing and, hopefully, to new effective therapies.
| Caudle, Robert M; Perez, Federico M; King, Christopher et al. (2003) N-methyl-D-aspartate receptor subunit expression and phosphorylation following excitotoxic spinal cord injury in rats. Neurosci Lett 349:37-40 |
