Bird Gary C, Lash L Leanne, Han Jeong S, Zou Xiaoju, Willis William D, Neugebauer Volker
Department of Neuroscience and Cell Biology, Marine Biomedical Institute, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-1069, USA.
J Physiol. 2005 May 1;564(Pt 3):907-21. doi: 10.1113/jphysiol.2005.084780. Epub 2005 Mar 10.
Mechanisms of pain-related plasticity in the amygdala, a key player in emotionality, were studied at the cellular and molecular levels in a model of arthritic pain. The influence of the arthritis pain state induced in vivo on synaptic transmission and N-methyl-d-aspartate (NMDA) receptor function was examined in vitro using whole-cell voltage-clamp recordings of neurones in the latero-capsular part of the central nucleus of the amygdala (CeA), which is now defined as the 'nociceptive amygdala'. Synaptic transmission was evoked by electrical stimulation of afferents from the pontine parabrachial area (part of the spino-parabrachio-amygdaloid pain pathway) in brain slices from control rats and from arthritic rats. This study shows that pain-related synaptic plasticity is accompanied by protein kinase A (PKA)-mediated enhanced NMDA-receptor function and increased phosphorylation of NMDA-receptor 1 (NR1) subunits. Synaptic plasticity in the arthritis pain model, but not normal synaptic transmission in control neurones, was inhibited by a selective NMDA receptor antagonist. Accordingly, an NMDA receptor-mediated synaptic component was recorded in neurones from arthritic animals, but not in control neurones, and was blocked by inhibition of PKA but not protein kinase C (PKC). Exogenous NMDA evoked a larger inward current in neurones from arthritic animals than in control neurones, indicating a postsynaptic effect. Paired-pulse facilitation, a measure of presynaptic mechanisms, was not affected by an NMDA-receptor antagonist. Increased levels of phosphorylated NR1 protein, but not of total NR1, were measured in the CeA of arthritic rats compared to controls. Our results suggest that pain-related synaptic plasticity in the amygdala involves a critical switch of postsynaptic NMDA receptor function through PKA-dependent NR1 phosphorylation.
杏仁核是情绪的关键调节者，在关节炎疼痛模型中，研究人员在细胞和分子水平上对其疼痛相关可塑性机制进行了研究。利用全细胞膜片钳记录杏仁核中央核外侧囊部（CeA，现被定义为“伤害性杏仁核”）神经元的电活动，研究体内诱导的关节炎疼痛状态对体外突触传递和N-甲基-D-天冬氨酸（NMDA）受体功能的影响。在来自对照大鼠和关节炎大鼠的脑片中，通过电刺激脑桥臂旁核区域（脊髓-臂旁-杏仁核疼痛通路的一部分）的传入神经来诱发突触传递。本研究表明，疼痛相关的突触可塑性伴随着蛋白激酶A（PKA）介导的NMDA受体功能增强以及NMDA受体1（NR1）亚基磷酸化增加。在关节炎疼痛模型中的突触可塑性，而非对照神经元中的正常突触传递，被选择性NMDA受体拮抗剂所抑制。相应地，在关节炎动物的神经元中记录到了NMDA受体介导的突触成分，而在对照神经元中未记录到，并且该成分被PKA抑制所阻断，但未被蛋白激酶C（PKC）抑制所阻断。外源性NMDA在关节炎动物神经元中诱发的内向电流比在对照神经元中更大，表明存在突触后效应。双脉冲易化是一种突触前机制的测量指标，不受NMDA受体拮抗剂的影响。与对照组相比，在关节炎大鼠的CeA中检测到磷酸化NR1蛋白水平升高，但总NR1水平未升高。我们的结果表明，杏仁核中与疼痛相关的突触可塑性涉及通过PKA依赖的NR1磷酸化对突触后NMDA受体功能的关键转换。
