NMDA Receptor Phosphorylation and Trafficking after Pain

描述（由申请方提供）：中枢致敏，即由C-传入输入产生的背角神经元兴奋性的活性依赖性增加，被认为是导致病理性疼痛状态产生的主要机制。脊髓背角N-甲基-D-天冬氨酸（NMDA）受体活性的增强与中枢敏感化的发展有关。这个建议的中心假设是，外周伤害性输入可以导致中枢敏化至少部分通过改变磷酸化和细胞内运输的背角NMDA受体。 本研究的目的是探讨在中枢致敏过程中背角NMDA受体亚单位磷酸化和亚细胞分布的变化。此外，这些伤害性刺激诱导的NMDA受体亚单位的变化所涉及的细胞内信号通路将被调查，并与疼痛行为。 本实验将验证以下几个假设：1）足以引起中枢敏化的外周伤害性刺激改变脊髓背角神经元NMDA受体亚单位的磷酸化。2)足以产生中枢敏化的外周伤害性刺激改变脊髓背角神经元NMDA受体亚单位的运输。3)外周伤害性刺激诱导的NMDA受体亚单位磷酸化和转运的变化与中枢致敏的行为测量在时间上相关。 虽然翻译后的NMDA受体的变化被认为是至关重要的突触可塑性，中枢敏化的基础，很少有直接的体内研究的假设。背角神经元中NMDA受体的磷酸化和从细胞内储存到突触后位点的运输将被研究，因为它们与中枢疼痛超敏反应有关。

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 .