NMDA Receptor Phosphorylation and Trafficking after Pain

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DESCRIPTION (provided by applicant): Central sensitization, an activity-dependent increase in the excitability of dorsal horn neurons generated by C-afferent input, is thought to be a primary mechanism responsible for the generation of pathological pain states. Enhanced activity of spinal cord dorsal horn N-methyl-D-aspartate (NMDA) receptors has been implicated in the development of central sensitization. The central hypothesis of this proposal is that peripheral nociceptive input can lead to central sensitization at least in part through altered phosphorylation and intracellular trafficking of dorsal horn NMDA receptors. The aim of this proposal is to examine changes in dorsal horn NMDA receptor subunit phosphorylation and subcellular distribution during the generation of central sensitization. In addition, intracellular signaling pathways involved in these noxious stimulus-induced NMDA receptor subunit changes will be investigated and correlated with pain behaviors. The proposed experiments will test several specific hypotheses: 1) Peripheral noxious stimulation sufficient to generate central sensitization alters NMDA receptor subunit phosphorylation in spinal cord dorsal horn neurons. 2) Peripheral noxious stimulation sufficient to generate central sensitization alters NMDA receptor subunit trafficking in spinal cord dorsal horn neurons. 3) Peripheral noxious stimulation induced changes in NMDA receptor subunit phosphorylation and trafficking are temporally related to behavioral measures of central sensitization. Although post-translational changes in the NMDA receptor are believed critical for the synaptic plasticity that underlies central sensitization, there has been little direct in vivo investigation of the hypothesis. Both phosphorylation and trafficking, from intracellular stores to the postsynaptic site, of NMDA receptors in dorsal horn neurons will be investigated as they relate to central pain hypersensitivity .