NMDA Receptor Phosphorylation and Trafficking after Pain

疼痛后 NMDA 受体磷酸化和运输

基本信息

批准号：
7099536
负责人：
GARY JAY BRENNER
金额：
$ 17.07万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2008-07-31
项目状态：
已结题

项目摘要

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 .

描述（由申请人提供）：中央敏化，依赖于C型输入产生的背角神经元兴奋性的活动依赖性增加，被认为是导致病理疼痛状态产生的主要机制。脊髓背角N-甲基-D-天冬氨酸（NMDA）受体的活性增强与中央敏化的发展有关。该提议的中心假设是，外周伤害感受输入至少可以通过改变磷酸化和背角NMDA受体的细胞内运输至少导致中心敏化。该建议的目的是检查中央敏化生成过程中背角NMDA受体亚基磷酸化和亚细胞分布的变化。此外，将研究这些有害刺激诱导的NMDA受体亚基变化的细胞内信号传导途径，并与疼痛行为相关。提出的实验将检验几种特定的假设：1）足以产生中央敏化的外围有害刺激改变了脊髓背角神经元中NMDA受体亚基磷酸化的变化。 2）足以产生中央敏化的外围有害刺激改变了NMDA受体亚基在脊髓背角神经元中的运输。 3）外围有害刺激引起的NMDA受体亚基磷酸化和运输的变化在时间上与中央敏化的行为度量有关。尽管认为NMDA受体的翻译后变化对于基于中央敏化的突触可塑性至关重要，但对假设的体内研究几乎没有直接研究。从细胞内存储到突触后部位，在背角神经元中NMDA受体的磷酸化和运输都将与中枢性疼痛超敏反应有关。