N-methyl D-aspartate receptor subtype 2B antagonist, Ro 25-6981, attenuates neuropathic pain by inhibiting postsynaptic density 95 expression.
N-methyl D-aspartate receptor subtype 2B antagonist, Ro 25-6981, attenuates neuropathic pain by inhibiting postsynaptic density 95 expression.
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N-甲基 D-天冬氨酸受体亚型 2B 拮抗剂 Ro 25-6981 通过抑制突触后密度 95 表达来减轻神经性疼痛。
DOI：
10.1038/s41598-018-26209-7
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发表时间：
2018-05-18
影响因子：
4.6
通讯作者：
Yao YX
中科院分区：
文献类型：
--
作者：
Huang LE;Guo SH;Thitiseranee L;Yang Y;Zhou YF;Yao YX
突触后密度-95 （PSD-95）是一种突触支架蛋白，在神经性疼痛的发展中起着至关重要的作用。然而，其潜在机制尚不清楚。为了研究PSD-95在n -甲基- d -天冬氨酸受体亚型2B （NR2B）介导的慢性疼痛中的作用，我们利用大鼠坐骨神经慢性收缩损伤（CCI）模型研究了PSD-95的激活与NR2B功能之间的关系。我们发现，CCI动物脊髓背角中PSD-95总蛋白和cAMP反应元件结合蛋白（CREB）、磷酸化NR2B、PSD-95和CREB的表达水平以及NR2B与PSD-95的相互作用水平均有所增加。在热痛评估试验中，鞘内注射选择性NR2B拮抗剂Ro 25-6981增加了足爪戒断潜伏期。此外，Ro 25-6981反复处理可显著减轻热过敏，抑制cci诱导的脊髓背角PSD-95上调。此外，鞘内注射PSD-95抑制剂显著逆转了热痛和机械性痛觉过敏。我们的研究结果表明，阻断脊髓中NR2B信号可以作为治疗神经性疼痛的候选治疗方法。
Postsynaptic density-95 (PSD-95) is a synaptic scaffolding protein that plays a crucial role in the development of neuropathic pain. However, the underlying mechanism remains unclear. To address the role of PSD-95 in N-methyl-D-aspartate receptor subtype 2B (NR2B) -mediated chronic pain, we investigated the relationship between PSD-95 activation and NR2B function in the spinal cord, by using a rat model of sciatic nerve chronic constriction injury (CCI). We demonstrate that the expression levels of total PSD-95 and cAMP response element binding protein (CREB), as well as phosphorylated NR2B, PSD-95, and CREB, in the spinal dorsal horn, and the interaction of NR2B with PSD-95 were increased in the CCI animals. Intrathecal injection of the selective NR2B antagonist Ro 25-6981 increased paw withdrawal latency, in a thermal pain assessment test. Moreover, repeated treatment with Ro 25-6981 markedly attenuated the thermal hypersensitivity, and inhibited the CCI-induced upregulation of PSD-95 in the spinal dorsal horn. Furthermore, intrathecal injection of the PSD-95 inhibitor strikingly reversed the thermal and mechanical hyperalgesia. Our results suggest that blocking of NR2B signaling in the spinal cord could be used as a therapeutic candidate for treating neuropathic pain.
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