Wnt/β-catenin通路介导NMDA与GABA能系统改变在瑞芬太尼诱导痛觉超敏中的机制研究

Remifentanil is widely used in clinics. However, the remifentanil induced hyperalgesia is concerned nowadays. Previous studies demonstrated that remifentanil induced hyperalgesia was attributed to the imbalance of NMDA receptor and GABA receptor. However, the downstream molecular mechanism is still poorly understood. In our previous study, we found that NMDA antagonists could dose-dependently inhibit the phosphorylation of NR2B subunit, and hence reverse hyperalgesia. remifentanil could also activate wnt3α/β-catenin signaling pathway and enhance the expression of wnt3α and wnt5 in spinal cord, which indicated that wnt/β-catenin signaling pathway was involved in the activation of NMDA receptor and hyperalgesia. Until now, rare literature related on the wnt pathway, imbalance of activated NMDA and GABA receptors and remifentanil induced hyperalgesia was found. We postulate that LRP receptor antagonist (Dkk-1) could change the ratio of NMDA/ GABA receptors through wnt/β-catenin signaling pathway. Based on the molecular, cellular, genetic research, we want to explore the modulation effect of LRP receptors and wnt/β-catenin signaling pathway, imbalance ration of NMDA/GABA receptor, in order to provide theoretical basis on remifentanil induced hyperalgesia.

瑞芬太尼的应用日益广泛，其引起的痛觉超敏也日益受到人们关注。既往研究发现痛觉超敏与NMDA受体和GABA受体的活化及两者比值有关，但是其下游机制尚未明确。我们前期研究发现，NMDA受体拮抗剂可以剂量依赖性地抑制NMDA受体NR2B亚基磷酸化进而改善痛觉超敏。瑞芬太尼也可以在脊髓水平激活wnt/β-catenin通路，使wnt3α和wnt5水平均增高，结果提示NMDA受体活化通过wnt/β-catenin通路起重要作用。目前未见活化的NMDA/GABA受体比值和wnt/β-catenin通路两者在瑞芬太尼痛觉超敏中的报道，我们提出假设：LRP受体拮抗剂Dkk-1可以通过wnt/β-catenin通路影响NMDA/GABA受体的表达。本课题拟从细胞，分子，组织，基因水平明确LRP受体的调控作用；探讨不同区域内的NMDA/GABA受体比值如何影响痛觉超敏；旨在为减少瑞芬太尼痛觉超敏提供理论依据。

瑞芬太尼引起的痛觉超敏（RIH）现象的报道日渐增多，目前尚无有效办法逆转。课题前期已经正式RIH产生了NMDA受体NR2B亚基的活化，抑制该亚基可以有效逆转RIH的发生。最近文献证明，GABA亚基的抑制，也是引起病理性疼痛的原因，除此之外，经典wnt3a通路也在神经病理性疼痛中起着重要作用。本研究在前期基础的RIH模型基础上，利用疼痛行为学，WB，免疫荧光，微透析等方法，进行利用经典wnt3a通路调节NMDA和GABA的受体活性来调控RIH的研究机制。还探索了KCC2联合GABA激动剂改善RIH的可行性，并通过大脑脊髓的微透析，研究RIH是否通过NMDA和GABA失衡来实现痛觉超敏。本研究将为瑞芬太尼痛觉超敏的临床控制提供新的干预途径。