Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior.
Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior.
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DOI：
10.1016/j.pain.2010.02.008
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发表时间：
2010-05
期刊：
影响因子：
7.4
通讯作者：
Sorkin LS
中科院分区：
文献类型：
--
作者：
Choi JI;Svensson CI;Koehrn FJ;Bhuskute A;Sorkin LS
在本研究中，足底角叉菜胶诱导增加机械异常性疼痛，磷酸化的PKB/Akt和GluR 1丝氨酸845（PKA网站）以及GluR 1，但不是GluR 2运动到神经元膜。膜GluR 1/GluR 2比率的这种变化指示Ca++渗透性AMPA受体插入。脊髓治疗前（而非治疗后）使用肿瘤坏死因子（TNF）拮抗剂依那西普（100µg）可减轻疼痛行为，阻断生化变化。通过脊髓抑制磷脂酰肌醇3-激酶（PI-3 K）（渥曼青霉素; 1和5μg）和LY 294002; 50和100μg）以及Akt（Akt抑制剂IV; 3μg）也可减轻疼痛行为。磷酸化Akt仅见于灰质中的神经元和白色物质中的少突胶质细胞。有趣的是，这种增加首先出现在浅层背角和α运动神经元中（峰值45分钟），随后出现在深层背角神经元中（峰值2小时）。Akt和GluR 1磷酸化，AMPA受体运输和机械性异常性疼痛都是TNF依赖性的。Akt和GluR 1的磷酸化是否在疼痛行为的串联或平行或上游仍有待确定。当然，TNF介导的GluR 1运输似乎在炎性疼痛中起主要作用，并且TNF介导的效应例如这些可能代表神经胶质促进神经元敏化（脊髓LTP）和病理性疼痛的途径。
In the present study, intraplantar carageenan induced increased mechanical allodynia, phosphorylation of PKB/Akt and GluR1 ser 845 (PKA site) as well as GluR1, but not GluR2 movement into neuronal membranes. This change in membrane GluR1/GluR2 ratio is indicative of Ca++ permeable AMPA receptor insertion. Pain behavior was reduced and biochemical changes blocked by spinal pretreatment, but not post-treatment, with a tumor necrosis factor (TNF) antagonist, Etanercept (100µg). Pain behavior was also reduced by spinal inhibition of phosphatidylinositol 3-kinase (PI-3K) (wortmannin; 1 and 5µg) and LY294002; 50 and 100µg) and Akt (Akt inhibitor IV; 3µg). Phosphorylated Akt was found exclusively in neurons in grey matter and in oligodendrocytes in white matter. Interestingly, this increase was seen first in superficial dorsal horn and α-motor neurons (peak 45 min) and later (peak 2 h post-injection) in deep dorsal horn neurons. Akt and GluR1 phosphorylation, AMPA receptor trafficking and mechanical allodynia were all TNF dependent. Whether phosphorylation of Akt and GluR1 are in series or in parallel or upstream of pain behavior remains to be determined. Certainly, TNF mediated GluR1 trafficking appears to play a major role in inflammatory pain and TNF mediated effects such as these could represent a path by which glia contribute to neuronal sensitization (spinal LTP) and pathological pain.
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