髓核细胞死亡与局部炎症相互作用是椎间盘源性腰痛的重要诱因，但缺乏有效治疗手段。申请者前期研究发现压力经RIPK1/RIPK3/MLKL途径诱导髓核细胞坏死性凋亡，提示调控坏死性凋亡有望成为防治椎间盘源性腰痛的新靶点。我们预实验显示，抑制RIPK1/RIPK3活性可下调压力诱导的椎间盘炎性因子IL-1β和背根神经节疼痛介质COX-2表达以及激活抗炎元件Nrf2/ARE核心成分Nrf2。褪黑素可显著抗炎及缓解腰痛，且我们预实验表明褪黑素下调压力诱导的髓核细胞RIPK1及RIPK3表达。综上，我们提出假设：褪黑素可调控RIPK1/RIPK3-Nrf2/ARE信号轴以抑制压力诱导的髓核细胞坏死性凋亡及椎间盘炎症反应。我们拟应用体内外可控压力模型，采用SiRNA干扰、基因过表达等手段，从分子、细胞、组织、器官等水平验证该假设。本研究将从新的角度揭示椎间盘源性腰痛的机制，并为其有效防治提供全新的策略。

Interaction between nucleus pulposus (NP) cells death and local inflammation is an important inducement of discogenic low back pain (LBP), however, there is lack of effective treatment for LBP. The applicant reported that compression-induced NP cells necroptosis via RIPK1/RIPK3/MLKL pathway, implying that the regulation of necroptosis might be a new target for the prevention and treatment of discogenic LBP. Our preliminary experiments indicated that inhibition of RIPK1/RIPK3 axis activity down-regulated the expression of inflammatory factor IL-1β in intervertebral disc and pain mediator COX-2 in dorsal root ganglion, and activated the core element Nrf2 of anti-inflammatory component Nrf2/ARE. Melatonin significantly resists inflammation and alleviates LBP, and our preliminary experiments showed that melatonin down-regulated the expression of RIPK1 and RIPK3 in NP cells under compression condition. Based on above, we hypothesized that: melatonin could regulate RIPK1/RIPK3-Nrf2/ARE signal axis to inhibit compression-induced NP cells necroptosis and inflammatory reaction in intervertebral disc. We plan to employ the controllable pressure model in vivo and in vitro, and adopt SiRNA interference technology and gene overexpression technology, to verify the above hypothesis from molecule, cell, tissue and organ levels. This project will reveal the mechanism of discogenic LBP from a new perspective and provide a new strategy for its effective prevention and treatment.