上调的δ-catenin通过棕榈酰化介导病理性疼痛的作用及机制

Pathological pain presents as a challenge in clinic work. Illumination of underlying mechanism will be helpful for its diagnosis and therapy. Our prior experiment showed that intrathecal injection of δ-catenin siRNA significantly inhibited the mechanical allodynia induced by oxaliplatin and L5-ventral root transection (L5-VRT), and the promoter region of δ-catenin exists potential binding sites with the transcription factor Pax6. These data implied that the upregulation of δ-catenin might be mediated in the transcription level. However, the mechanism underlying δ-catenin mediated allodynia remains unclear. We also found that the inhibition of δ-catenin palmitoylation prevented the Nav1.6 increases in the cell membrane and allodynia induced by L5-VRT. All these data suggested that the transcript factor Pax6 upregulated the δ-catenin expression via epigenetics, and the enhanced δ-catenin increased the Nav1.6 expression of cell membrane through DHHC-mediated palmitoylation, thereby mediating pathological pain. The present project aims to investigate: I) the mechanisms of Pax6-mediated δ-catenin upregulation on the pathological pain; II) the mechanisms underlying δ-catenin-mediated Nav1.6 upregulation. Our study will provide novel molecular target for prevention and therapy of pathological pain.

病理性疼痛是困扰临床的重要问题，机制不清。我们预实验首次显示： 鞘内注射δ-catenin siRNA显著抑制奥沙利铂或腰5脊神经前根切除（L5-VRT）诱导的痛觉过敏，且转录因子Pax6与δ-catenin启动子有潜在结合位点，提示转录水平可能介导脊髓背角δ-catenin的上调，机制不清。我们还发现：奥沙利铂显著上调棕榈酰转移酶20（DHHC20）及δ-catenin棕榈酰化水平，而DHHC5 siRNA阻断L5-VRT诱导的细胞膜钠通道1.6亚型上调及痛觉过敏。我们推测：奥沙利铂或L5-VRT通过Pax6上调δ-catenin表达，上调的δ-catenin通过棕榈酰化促进钠通道1.6转位至细胞膜，介导痛觉过敏。本研究将：1）明确Pax6上调δ-catenin的机制及其在病理性疼痛中的作用；2）探讨δ-catenin介导细胞膜钠通道1.6上调的作用及机制，为防治病理性疼痛提供潜在靶点。

δ-catenin的棕榈酰化对于突触可塑性及记忆形成都十分重要。我们发现：δ-catenin的棕榈酰化同样也是神经病理性疼痛的发生基础。在神经病理性疼痛大鼠模型的背根神经节感觉神经元中，Pax6的表达显著升高，同时发生棕榈酰化的δ-catenin和相应的棕榈酰化转移酶DHHC20/DHHC3的含量也均明显升高。通过鞘内注射2-BP或shRNA来抑制棕榈酰酰基转移酶或降低δ-catenin的水平均能够有效缓解化疗药奥沙利铂或神经损伤诱导的大鼠神经病理性疼痛。此外由转录因子Pax6介导的组蛋白乙酰化水平升高，调控δ-catenin表达增加，进而促进大鼠的疼痛行为学表征。以上结果表明：由Pax6上调介导的δ-catenin表达增加及由棕榈酰酰基转移酶DHHC20/DHHC5介导的δ-catenin/Nav1.6复合体互作增强促进了奥沙利铂或L5-VRT诱导大鼠痛觉过敏；因此阻断棕榈酰化的相关通路和机制很可能对于神经病理性疼痛的治疗大有裨益。