脂氧素，炎症"刹车"信号，在椎间盘突出所致根性神经痛中的作用及机制研究

Radicular pain, or radiculitis,is pain that experienced along the dermatome (or sensory distribution) of a nerve due to pressure on the nerve root and is hardly to be cured. The most common cause of radicular pain is intervertebral disc herniation and its mechanism is still not well understood. Reports have demonstrated that inflammatory response induced by protrused nucleus pulposus plays a key role in the process of radicular pain. But anti-inflammatory therapy for the radicular pain did not produce good results. In recent years, it has been proved that the resolution of inflammation is an active programmed process. The inhibition of the inflammatory reaction might present an obstacle in the inflammation resolution. So inflammatory resolution, as a hopeful strategy in the therapy of inflammation, is becoming a new research hotspot. Lipoxins represent a unique class of lipid mediators serving as endogenous "braking signals" in inflammation that possesses a wide spectrum of anti-in?ammatory and proresolution bioactions. In our previous study, we have found that intrathecal delivery of lipoxinA4 could alleviate the mechanical allodynia and thermal hyperalgesia and inhibit the upregulation of proinflammatory cytokines in the radicular pain model of rats in a dose-dependent manner. Here we will establish a rat model of non compressive lumbar herniated intervertebral disc and examine the analgesic effect and the safety of lipoxins on the radicular pain. Using siRNA, western blot, real-time qPCR, ELISA, patch clamp and immunofluorescence method etc, we will detect the alterations of lipoxinA4 and its receptor in the spinal cord, nucleus pulposus and DRG in the animal model and further explore the influence of lipoxinA4 on the function of immune cells, neurons and glia cells and related receptors and signal transduction pathways (MAPKs,NF-κB etc).Thus we try to find a novel preventative and therapeutic approach for the radicular pain caused by intervertebral disc herniation.

根性神经痛是椎间盘突出症患者最难以忍受的症状，机制不清，迁延难愈。研究证实突出髓核组织诱发的炎症反应是根性神经痛形成和维持的重要因素。然而传统的抗炎治疗临床疗效欠佳。新近发现炎症是一个从启动到消退的程序化过程，抑制炎症发生的抗炎策略同时蕴藏着阻碍炎症消退之隐患，故促进炎症消退的治疗策略成为目前研究热点。脂氧素是重要的促炎症消退介质，被称为炎症的"刹车信号"。我们前期工作证实鞘内注射脂氧素可以有效缓解根性神经痛模型大鼠的痛敏状态。本研究拟在此基础上，建立非压迫性椎间盘突出症大鼠模型，评价脂氧素的镇痛效果和安全性。并应用siRNA、Western Blot、qPCR、ELISA、膜片钳、荧光免疫等技术，围绕脂氧素对髓核、DRG及脊髓背角等部位相关受体与信号转导通路(MAPKs、NF-κB)的影响，通过在体和离体实验，深入探讨脂氧素促进神经炎症消退的作用机制，为根性神经痛的治疗提供新的思路。

根性神经痛是椎间盘突出症患者最难以忍受的症状，疼痛剧烈，迁延难愈。研究证实除机械压迫因素以外，突出髓核组织诱发的炎症反应是根性神经痛形成和维持的重要因素。新近研究发现炎症是一个从启动到消退的程序化过程，然而传统抗炎治疗从抑制炎症发生角度出发，临床消退欠佳，同时该策略蕴藏着阻碍炎症消退的隐患。因此，本课题提出了“促炎症消退策略”治疗根性神经痛。内源性促炎症消退介质，如脂氧素、消退素，被称为炎症的“刹车信号”，在炎症发生早期即发挥重要的促炎症消退的重要作用。本研究通过建立非压迫性椎间盘突出症大鼠模型，成功复制出根性神经痛的临床症状，并应用实时荧光定量PCR、ELISA、Western Blot、免疫组化等技术，证实了突出髓核造成相应节段背根神经节及脊髓背角的炎症反应及疼痛信号通路（MAPKs、NF-κB）的活化。应用鞘内置管给予外源性的脂氧素或消退素的给药方式，证实了脂氧素或消退素具有减轻模型大鼠机械触痛，炎性介质的释放，促进抗炎介质表达及抑制疼痛相关通路活化的作用。结果表明，促炎症消退介质对于神经炎症及根性神经痛具有显著的改善作用。这对进一步揭示腰椎间盘突出症的发病机制、探讨脂氧素和消退素促进神经炎症消退的作用机制、研制更加有效的治疗炎症及根性神经痛的药物提供了新的思路。