TNF-α contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2.
TNF-α contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2.
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DOI：
10.1016/j.pain.2010.11.014
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发表时间：
2011-02
期刊：
影响因子：
7.4
通讯作者：
Ji RR
中科院分区：
文献类型：
--
作者：
Zhang L;Berta T;Xu ZZ;Liu T;Park JY;Ji RR
肿瘤坏死因子-α（TNF-α）是一种关键的促炎细胞因子。一般认为，TNF-α主要通过TNF受体亚型-1（TNFR 1）发挥作用。我们研究了TNFR 1和TNFR 2在脊髓突触传递和炎性疼痛中的不同作用。与野生型（WT）小鼠相比，TNFR 1和TNFR 2敲除（KO）小鼠表现出正常的热敏感性和未改变的兴奋性突触传递在脊髓中，所揭示的自发兴奋性突触后电流（sEPSC）在脊髓切片的层II神经元。然而，在TNFR 1-和TNFR 2-KO小鼠中，鞘内注射TNF-α后的热痛觉过敏和福尔马林试验中的第二阶段自发性疼痛均减少。特别地，足底注射完全弗氏佐剂（CFA）后的热痛觉过敏在TNFR 2-KO小鼠的早期阶段减少，但在TNFR 1-KO小鼠的早期和后期阶段都减少。因此，CFA在第1天引起脊髓中TNFR 2 mRNA水平的短暂增加。值得注意的是，TNF-α诱发了板层II神经元中sEPSC频率的急剧增加，这在TNFR 1-KO小鼠中被消除，在TNFR 2-KO小鼠中减少。TNF-α还增加了板层II神经元的NMDA电流，这种增加在TNFR 1-KO小鼠中被消除，但在TNFR 2-KO小鼠中保留。最后，鞘内注射NMDA受体拮抗剂MK-801可预防鞘内注射TNF-α引起的热痛敏。我们的研究结果支持TNF-α通过TNFR 1和TNFR 2在调节突触可塑性（中枢致敏）和炎性疼痛中的核心作用。我们的数据还揭示了TNFR 2在介导早期炎症性疼痛中的独特作用。
Tumor necrosis factor-alpha (TNF-α) is a key proinflammatory cytokine. It is generally believed that TNF-α exerts its effects primarily via TNF receptor subtype-1 (TNFR1). We investigated distinct role of TNFR1 and TNFR2 in spinal cord synaptic transmission and inflammatory pain. Compared to wild-type (WT) mice, TNFR1 and TNFR2 knockout (KO) mice exhibited normal heat sensitivity and unaltered excitatory synaptic transmission in the spinal cord, as revealed by spontaneous excitatory postsynaptic currents (sEPSCs) in lamina II neurons of spinal cord slices. However, heat hyperalgesia after intrathecal TNF-α and the second-phase spontaneous pain in the formalin test were reduced in both TNFR1- and TNFR2-KO mice. In particular, heat hyperalgesia after intraplantar injection of complete Freund's adjuvant (CFA) was decreased in the early phase in TNFR2-KO mice but reduced in both early and later phase in TNFR1-KO mice. Consistently, CFA elicited a transient increase of TNFR2 mRNA levels in the spinal cord on day 1. Notably, TNF-α evoked a drastic increase in sEPSC frequency in lamina II neurons, which was abolished in TNFR1-KO mice and reduced in TNFR2-KO mice. TNF-α also increased NMDA currents in lamina II neurons, and this increase was abolished in TNFR1-KO mice but retained in TNFR2-KO mice. Finally, intrathecal injection of the NMDA receptor antagonist MK-801 prevented heat hyperalgesia elicited by intrathecal TNF-α. Our findings support a central role of TNF-α in regulating synaptic plasticity (central sensitization) and inflammatory pain via both TNFR1 and TNFR2. Our data also uncover a unique role of TNFR2 in mediating early-phase inflammatory pain.
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