Group I metabotropic glutamate receptor NMDA receptor coupling and signaling cascade mediate spinal dorsal horn NMDA receptor 2B tyrosine phosphorylation associated with inflammatory hyperalgesia
Group I metabotropic glutamate receptor NMDA receptor coupling and signaling cascade mediate spinal dorsal horn NMDA receptor 2B tyrosine phosphorylation associated with inflammatory hyperalgesia
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DOI：
10.1523/jneurosci.3422-04.2004
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发表时间：
2004-10-13
影响因子：
5.3
通讯作者：
Ren, K
中科院分区：
文献类型：
--
作者：
Guo, W;Wei, F;Ren, K
后爪炎症诱导大鼠脊髓背角中NMDA受体（NMDAR）2B（NR 2B）亚基的酪氨酸磷酸化（tyr-P），其与痛觉过敏的起始和发展密切相关。在这里，我们表明，在弗氏佐剂诱导的炎症大鼠中，增加的背角NR 2B tyr-P被I组代谢型谷氨酸受体（mGluR）拮抗剂阻断[7- 10]。（羟基亚氨基）环丙烯并[B]色烯-1a-羧酸乙酯（CPCCOEt）和2-甲基-6-（苯乙炔基）-吡啶（MPEP），通过Src抑制剂CGP 77675，但不通过MAP激酶抑制剂2 '-氨基-3'-甲氧基黄酮。钙通道的分析表明，在体内NR 2B酪氨酸-P被阻断的IP 3受体拮抗剂2-氨基乙氧基二苯基硼酸盐（2APB），但不是由离子型谷氨酸受体和电压依赖性钙通道的拮抗剂，这表明NR 2B酪氨酸-P是依赖于细胞内钙释放。在背角切片制备中，I组（二羟基苯基甘氨酸）而非II组[（2 R，4 R）-4-氨基吡咯烷-2，3-二羧酸酯]和III组[L-AP 4（L-（+）-2-氨基-4-膦酰基丁酸）]、mGluR激动剂、IP 3受体（D-IP 3）激动剂和PKC（PMA）激活剂诱导与体内炎症后观察到的类似的NR 2B tyr-P。免疫共沉淀表明，Shank，突触后密度蛋白与mGluRs，形成了一个复杂的涉及PSD-95（突触后密度-95），NR 2B，和Src在脊髓背角。双重免疫荧光研究表明，NR 1与mGluR 5共定位于背角神经元。mGluR 5也与NR 2B共免疫沉淀。最后，鞘内预处理CPCCOEt、MPEP和2APB减轻炎性痛觉过敏。因此，炎症和mGluR诱导的NR 2B tyr-P具有相似的机制。I组mGluR-NMDAR偶联级联导致NMDAR的磷酸化，并且对于炎症后脊髓背角敏化和行为痛觉过敏的起始似乎是必需的。
Hindpaw inflammation induces tyrosine phosphorylation (tyr-P) of the NMDA receptor ( NMDAR) 2B (NR2B) subunit in the rat spinal dorsal horn that is closely related to the initiation and development of hyperalgesia. Here, we show that in rats with Freund's adjuvant-induced inflammation, the increased dorsal horn NR2B tyr-P is blocked by group I metabotropic glutamate receptor (mGluR) antagonists [7-(hydroxyimino) cyclopropa[b] chromen-1a-carboxylate ethyl ester ( CPCCOEt) and 2-methyl-6-(phenylethynyl)- pyridine ( MPEP), by the Src inhibitor CGP 77675, but not by the MAP kinase inhibitor 2'-amino-3'-methoxyflavone. Analysis of the calcium pathways shows that the in vivo NR2B tyr-P is blocked by an IP3 receptor antagonist 2-aminoethoxydiphenylborate (2APB) but not by antagonists of ionotropic glutamate receptors and voltage-dependent calcium channels, suggesting that the NR2B tyr-P is dependent on intracellular calcium release. In a dorsal horn slice preparation, the group I ( dihydroxyphenylglycine), but not group II [(2R, 4R)-4-aminopyrrolidine-2,3-dicarboxylate] and III [ L-AP4 (L-(+)- 2-amino-4-phosphonobutyric acid)], mGluR agonists, an IP3 receptor (D-IP3) agonist, and a PKC (PMA) activator, induces NR2B tyr-P similar to that seen in vivo after inflammation. Coimmunoprecipitation indicates that Shank, a postsynaptic density protein associated with mGluRs, formed a complex involving PSD-95 ( postsynaptic density-95), NR2B, and Src in the spinal dorsal horn. Double immunofluorescence studies indicated that NR1 is colocalized with mGluR5 in dorsal horn neurons. mGluR5 also coimmunoprecipitates with NR2B. Finally, intrathecal pretreatment of CPCCOEt, MPEP, and 2APB attenuates inflammatory hyperalgesia. Thus, inflammation and mGluR-induced NR2B tyr-P share similar mechanisms. The group I mGluR-NMDAR coupling cascade leads to phosphorylation of the NMDAR and appears necessary for the initiation of spinal dorsal horn sensitization and behavioral hyperalgesia after inflammation.