Phosphorylation of NR2B NMDA subunits by protein kinase C in arcuate nucleus contributes to inflammatory pain in rats.
Phosphorylation of NR2B NMDA subunits by protein kinase C in arcuate nucleus contributes to inflammatory pain in rats.
复制标题
弓状核中蛋白激酶 C 对 NR2B NMDA 亚基的磷酸化导致大鼠炎症性疼痛。
DOI：
10.1038/srep15945
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发表时间：
2015-10-30
影响因子：
4.6
通讯作者：
Jiang X
中科院分区：
文献类型：
--
作者：
Bu F;Tian H;Gong S;Zhu Q;Xu GY;Tao J;Jiang X
下丘脑弓状核（ARC）在疼痛处理中起着关键作用。虽然众所周知，抑制ARC中的NMDA受体（NMDAR）可减轻外周炎症诱导的痛觉过敏，但ARC中NMDAR激活的潜在机制仍不清楚。蛋白激酶C（PKC）参与在生理和病理条件下激活的几个信号级联。因此，我们假设PKC的上调激活ARC中的NMDAR，从而导致炎性痛觉过敏。ARC内注射PKC特异性抑制剂白屈菜红碱（CC）可剂量依赖性地减轻完全弗氏佐剂（CFA）诱导的热痛敏和机械痛敏。在体细胞外记录显示，CC或MK-801（NMDAR拮抗剂）的微电泳显着降低ARC神经元的自发放电和痛诱发放电的增强。此外，注射CFA后，ARC中总PKC γ和磷酸化PKCγ的表达明显增强。有趣的是，CFA注射也显著提高了磷酸化NR 2B（Tyr 1472）的水平，而不影响总NR 2B的表达。重要的是，ARC内注射CC逆转了ARC中磷酸化NR 2B亚基的上调。总之，外周炎症导致ARC中PKC激活介导的NMDAR激活，从而产生热和机械痛觉过敏。
The arcuate nucleus (ARC) of the hypothalamus plays a key role in pain processing. Although it is well known that inhibition of NMDA receptor (NMDAR) in ARC attenuates hyperalgesia induced by peripheral inflammation, the underlying mechanism of NMDAR activation in ARC remains unclear. Protein kinase C (PKC) is involved in several signalling cascades activated in physiological and pathological conditions. Therefore, we hypothesised that upregulation of PKC activates NMDARs in the ARC, thus contributing to inflammatory hyperalgesia. Intra-ARC injection of chelerythrine (CC), a specific PKC inhibitor, attenuated complete Freund’s adjuvant (CFA) induced thermal and mechanical hyperalgesia in a dose-dependent manner. In vivo extracellular recordings showed that microelectrophoresis of CC or MK-801 (a NMDAR antagonist) significantly reduced the enhancement of spontaneous discharges and pain-evoked discharges of ARC neurons. In addition, CFA injection greatly enhanced the expression of total and phosphorylated PKCγ in the ARC. Interestingly, CFA injection also remarkably elevated the level of phosphorylated NR2B (Tyr1472) without affecting the expression of total NR2B. Importantly, intra-ARC injection of CC reversed the upregulation of phosphorylated NR2B subunits in the ARC. Taken together, peripheral inflammation leads to an activation of NMDARs mediated by PKC activation in the ARC, thus producing thermal and mechanical hyperalgesia.