NMDA Receptor Phosphorylation and Trafficking after Pain

疼痛后 NMDA 受体磷酸化和运输

• 批准号: 6508520
• 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
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6508520
• 关键词: C fiber; NMDA receptors; behavior test; behavioral /social science research tag; behavioral habituation /sensitization; biological signal transduction; capsaicin; confocal scanning microscopy; dorsal horn; electrophysiology; heat stimulus; immunocytochemistry; immunoprecipitation; intracellular transport; laboratory rat; membrane transport proteins; mitogen activated protein kinase; neurons; pain; phosphorylation; protein kinase C; protein localization; protein structure function; synapses; tissue /cell culture; western blottings

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）：中枢敏化是由 C 传入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) 受体活性增强与中枢敏化的发展有关。该提议的中心假设是，外周伤害性输入至少部分通过改变背角 NMDA 受体的磷酸化和细胞内运输而导致中枢敏化。 本提案的目的是检查中枢敏化产生过程中背角 NMDA 受体亚基磷酸化和亚细胞分布的变化。此外，还将研究参与这些有害刺激诱导的 NMDA 受体亚基变化的细胞内信号通路，并将其与疼痛行为相关联。 拟议的实验将测试几个具体的假设：1）足以产生中枢敏化的外周有害刺激会改变脊髓背角神经元中 NMDA 受体亚基的磷酸化。 2) 足以产生中枢敏化的外周有害刺激会改变脊髓背角神经元中 NMDA 受体亚基的运输。 3) 外周有害刺激引起的 NMDA 受体亚基磷酸化和运输的变化与中枢敏化的行为测量在时间上相关。 尽管 NMDA 受体的翻译后变化被认为对于中枢敏化的突触可塑性至关重要，但对该假设的直接体内研究却很少。将研究背角神经元中 NMDA 受体从细胞内储存到突触后位点的磷酸化和运输，因为它们与中枢疼痛超敏反应有关。