Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA.
Mol Pain. 2010 May 6;6:26. doi: 10.1186/1744-8069-6-26.
NMDA receptors expressed by spinal cord neurons in the superficial dorsal horn are involved in the development of chronic pain associated with inflammation and nerve injury. The superficial dorsal horn has a complex and still poorly understood circuitry that is mainly populated by inhibitory and excitatory interneurons. Little is known about how NMDA receptor subunit composition, and therefore pharmacology and voltage dependence, varies with neuronal cell type. NMDA receptors are typically composed of two NR1 subunits and two of four NR2 subunits, NR2A-2D. We took advantage of the differences in Mg2+ sensitivity of the NMDA receptor subtypes together with subtype preferring antagonists to identify the NR2 subunit composition of NMDA receptors expressed on lamina II inhibitory and excitatory interneurons. To distinguish between excitatory and inhibitory interneurons, we used transgenic mice expressing enhanced green fluorescent protein driven by the GAD67 promoter.
Analysis of conductance ratio and selective antagonists showed that lamina II GABAergic interneurons express both the NR2A/B containing Mg2+ sensitive receptors and the NR2C/D containing NMDA receptors with less Mg2+ sensitivity. In contrast, excitatory lamina II interneurons express primarily NR2A/B containing receptors. Despite this clear difference in NMDA receptor subunit expression in the two neuronal populations, focally stimulated synaptic input is mediated exclusively by NR2A and 2B containing receptors in both neuronal populations.
Stronger expression of NMDA receptors with NR2C/D subunits by inhibitory interneurons compared to excitatory interneurons may provide a mechanism to selectively increase activity of inhibitory neurons during intense excitatory drive that can provide inhibitory feedback.
脊髓背角浅层神经元表达的 NMDA 受体参与了与炎症和神经损伤相关的慢性疼痛的发展。浅层背角具有复杂且仍未被充分了解的回路，主要由抑制性和兴奋性中间神经元组成。关于 NMDA 受体亚基组成，以及因此药理学和电压依赖性如何随神经元细胞类型而变化，知之甚少。NMDA 受体通常由两个 NR1 亚基和四个 NR2 亚基（NR2A-2D）中的两个组成。我们利用 NMDA 受体亚型对镁离子敏感性的差异以及对亚型具有选择性的拮抗剂，来鉴定在 II 层抑制性和兴奋性中间神经元上表达的 NMDA 受体的 NR2 亚基组成。为了区分兴奋性和抑制性中间神经元，我们使用了由 GAD67 启动子驱动的增强型绿色荧光蛋白表达的转基因小鼠。
对电导比和选择性拮抗剂的分析表明，II 层 GABA 能中间神经元表达同时含有 NR2A/B 的对镁离子敏感的受体和含有 NR2C/D 的 NMDA 受体，后者对镁离子的敏感性较低。相比之下，兴奋性 II 层中间神经元主要表达含有 NR2A/B 的受体。尽管这两种神经元群体中 NMDA 受体亚基表达存在明显差异，但局灶性刺激的突触输入仅由两种神经元群体中的 NR2A 和 2B 受体介导。
与兴奋性中间神经元相比，抑制性中间神经元中含有 NR2C/D 亚基的 NMDA 受体表达更强，这可能为在强烈的兴奋性驱动下选择性增加抑制性神经元的活动提供了一种机制，从而提供抑制性反馈。
