Neuropathic pain is a very complex chronic pain state, the detailed molecular mechanisms of which remain unclear. In the present study, Shank3 was found to play an important role in neuropathic pain in rats following spared nerve injury (SNI). Shank3 was upregulated in the spinal dorsal horn of rats subjected to SNI, and mechanical hypersensitivity to noxious stimuli in these rats could be alleviated by knock down of Shank3. Shank3 also interacted with hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) and promoted the expression of HCN2 in central neurons of the spinal dorsal. Together with the SNI-dependent increase of HCN2, we also found that the postsynaptic protein of excitatory synapse (PSD95) was increased in rats following SNI. Taken together, our results showed that Shank3 modulated neuropathic pain by facilitating the SNI-dependent increase of HCN2 and the expression of PSD95 in spinal dorsal horn neurons. Our findings revealed new synaptic remodeling mechanisms linking Shank3 with neuropathic pain.

中文翻译：

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Shank3 通过促进 HCN2 的 SNI 依赖性增加和 PSD95 的表达来促进神经性疼痛

神经性疼痛是一种非常复杂的慢性疼痛状态，其详细的分子机制仍不清楚。在本研究中，发现 Shank3 在幸免神经损伤 (SNI) 后大鼠的神经性疼痛中起重要作用。Shank3 在接受 SNI 的大鼠的脊髓背角中上调，并且这些大鼠对有害刺激的机械超敏反应可以通过敲低 Shank3 来缓解。Shank3 还与超极化激活的环核苷酸门控通道 2 (HCN2) 相互作用，并促进 HCN2 在脊髓背侧中枢神经元中的表达。连同 HCN2 的 SNI 依赖性增加，我们还发现 SNI 后大鼠兴奋性突触的突触后蛋白 (PSD95) 增加。综合起来，我们的研究结果表明，Shank3 通过促进 SNI 依赖性 HCN2 的增加和脊髓背角神经元中 PSD95 的表达来调节神经性疼痛。我们的研究结果揭示了将 Shank3 与神经性疼痛联系起来的新突触重塑机制。