脊髓背角肝X受体抑制致炎细胞因子表达促进神经病理性疼痛恢复的作用及其机制

Our previous work has shown that peripheral nerve injury upregulates TSPO in the spinal dorsal horn when it induces neuropathic pain, which promotes recovery from neuropathic pain. Our recent studies showed that spared nerve injury (SNI) induced the upregulation of LXRα/β, and that LXRs agonist decreased SNI-induced mechanical allodynia, suggesting that LXRs may promote recovery from neuropathic pain,but the exact mechanisms are still unclear.Previous studies have demonstrated that LXR agonist can promote the synthesis of neuroactive steroids, whereas neuroactive steroids can inhibit the release of inflammatory cytokines. Our previous work has shown that overexpression of TNF-α contributs to neuropathic pain by enhancement of synaptic transmission in spinal dorsal horn. In the present study, we will determine which subtype of LXRs play a role in neuropathic pain. Next, we will examine whether LXRs can inhibit the release of cytokines in the spinal dorsal horn and examine whether neuroactive steroids play roles in this process. Meanwhile we will investigate whether LXRs affect the morphosis and function of spinal dorsal horn neurons. Whether TLR2/4 lead to the upregulation of LXRs will also be investigated. Thus we will elucidate the mechanisms that LXRs promote recovery from neuropathic pain by modulating the morphosis and function of neurons, and serve to develop new analgesics.

我们以往的工作表明，外周神经损伤在引起神经病理性疼痛的同时也上调脊髓背角TSPO，促进疼痛恢复。本项目的预实验发现，部分坐骨神经损伤（SNI）上调脊髓背角肝X受体（LXR）α/β，LXRs激动剂可抑制SNI引起的触诱发痛,提示LXRs可能也有促进疼痛恢复的作用，但机制不清。研究表明，LXRs激动剂可促进神经甾体合成，而神经甾体可抑制致炎细胞因子表达。我们以往的工作表明，TNF-α通过提高脊髓背角突触传递效率，放大痛信号。本项目拟明确何种LXR亚型在神经病理性疼痛中起作用，观察LXRs是否通过促进脊髓背角神经甾体合成而抑制致炎细胞因子表达，探讨LXRs是否改变背角投射神经元的突触结构和功能，最后研究外周神经损伤后脊髓背角LXRs的上调是否由TLR2/4介导。由此探讨SNI后脊髓背角由"TLR2/4→LXRs→神经甾体→致炎细胞因子"所介导的调节神经元结构和功能以促进神经病理性疼痛恢复的机制。

周围神经损伤常常会导致神经病理性疼痛，如何减轻疼痛是疼痛研究的核心问题。现在治疗神经病理性疼痛的药物大多是通过阻断某种功能增强的离子通道，比如钙通道阻断剂加巴贲丁，钠通道阻断剂（三环类，抗癫痫，抗惊厥药物）等。但是，单纯阻断离子通道只能缓解疼痛于一时，治标不治本。此外，钠通道和钙通道广泛分布于全身的可兴奋细胞，阻断这些离子通道还会不可避免地带来诸多副作用。LXRs 是配体激活的核转录因子，在哺乳动物中存在LXRα 和LXRβ两种亚型。本项目发现，部分坐骨神经损伤（SNI）上调脊髓神经元及少突胶质细胞背角肝X受体（LXR）α/β，提前连续给予或疼痛产生后7天给予一次LXRs激动剂T0901317或GW3965可抑制SNI引起的触诱发痛。LXRs激动剂可抑制脊髓胶质细胞的激活，抑制致炎细胞因子的释放，增加抗炎细胞因子的合成。上述作用可被神经甾体合成阻断剂阻断。 LXRα基因敲除取消了T09/GW对触诱发痛的抑制作用，且LXRα基因敲除小鼠 SNI后脊髓背角胶质细胞激活更为显著，致炎细胞因子释放更多。LXRα基因敲除小鼠外周神经损伤后疼痛出现的更早，消失的更晚。该项目j进一步发现激动LXRs可通过促进神经甾体的生成，进而平衡细胞因子的表达，最终抑制炎症反应而抑制病理性疼痛。研究结果提示在外周神经损伤后，LXRα可以作为一个保护性的蛋白发挥有益的作用。