Inflammation alters trafficking of extrasynaptic AMPA receptors in tonically firing lamina II neurons of the rat spinal dorsal horn.
Inflammation alters trafficking of extrasynaptic AMPA receptors in tonically firing lamina II neurons of the rat spinal dorsal horn.
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DOI：
10.1016/j.pain.2011.01.016
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发表时间：
2011-04
期刊：
影响因子：
7.4
通讯作者：
Voitenko N
中科院分区：
文献类型：
--
作者：
Kopach O;Kao SC;Petralia RS;Belan P;Tao YX;Voitenko N
外周炎症改变脊髓背角神经元突触上AMPAR亚单位的运输，增加AMPAR的钙通透性。然而，尚不清楚在持续性炎性疼痛条件下，这些神经元突触外部位的AMPAR运输是否也会发生变化。应用膜片钳记录结合钙显象和钴染色，我们发现在正常情况下，大鼠脊髓背角胶状质(SG)神经元的突触外AMPAR池主要由含GluR2的钙离子非通透性受体组成。维持完全弗氏佐剂(CFA)诱导的炎症反应与AMPA诱导的电流和SG神经元的[Ca~(2+)]i瞬变有关，而如我们先前所示，突触诱发的AMPAR介导的电流的幅度在CFA后24小时没有改变。这些结果表明，突触外AMPAR上调，其钙离子通透性显著增加。这种增加发生在具有内在紧张性放电特性的SG神经元，但不存在于那些表现出强烈适应的神经元。这种增加还伴随着AMPA诱导电流的内向整流，以及对高选择性钙离子通透性AMPAR阻滞剂IEM-1460的敏感性增强。此外，电子显微镜和生化分析还显示，CFA后24小时，背角神经元突触外膜上的GluR1含量增加。综上所述，我们的研究结果表明，CFA诱导的炎症增加了兴奋性背角神经元突触外GluR1-含钙渗透性AMPAR的功能表达和比例。我们认为突触外AMPAR转运的改变可能参与了持续性炎症性疼痛的维持。
Peripheral inflammation alters AMPA receptor (AMPAR) subunit trafficking and increases AMPAR Ca2+ permeability at synapses of spinal dorsal horn neurons. However, it is unclear whether AMPAR trafficking at extrasynaptic sites of these neurons also changes under persistent inflammatory pain conditions. Using patch-clamp recording combined with Ca2+ imaging and cobalt staining, we found that, under normal conditions, an extrasynaptic pool of AMPARs in rat substantia gelatinosa (SG) neurons of spinal dorsal horn predominantly consists of GluR2-containing Ca2+-impermeable receptors. Maintenance of complete Freund’s adjuvant (CFA)-induced inflammation was associated with a marked enhancement of AMPA-induced currents and [Ca2+]i transients in SG neurons, while, as we previously showed, the amplitude of synaptically evoked AMPAR-mediated currents was not changed 24 h after CFA. These findings indicate that extrasynaptic AMPARs are upregulated and their Ca2+ permeability increases dramatically. This increase occurred in SG neurons characterized by intrinsic tonic firing properties, but not in those exhibited strong adaptation. This increase was also accompanied by an inward rectification of AMPA-induced currents and enhancement of sensitivity to a highly selective Ca2+-permeable AMPAR blocker, IEM-1460. Electron microcopy and biochemical assays additionally showed an increase in the amount of GluR1 at extrasynaptic membranes in dorsal horn neurons 24 h post-CFA. Taken together, our findings suggest that CFA-induced inflammation increases functional expression and proportion of extrasynaptic GluR1-containing Ca2+-permeable AMPARs in tonically firing excitatory dorsal horn neurons. We suggest that the altered extrasynaptic AMPAR trafficking might participate in the maintenance of persistent inflammatory pain.
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