趋化因子CCL3通路介导慢性炎症痛的外周机制及电针的干预作用

Chronic inflammatory pain is a common form of chronic pain. It has long duration and severely affects the normal life of the patients. Acupuncture is an efficient therapy to alleviate chronic pain. However, the mechanisms of acupuncture analgesia are still not fully understood. Recent studies suggest that acupuncture analgesia may be due to the intervention of acupuncture in peripheral or central pain/inflammatory molecule or signaling pathway. Evidence has suggested that chemokine CCL3 signaling is involved in chronic pain. Therefore, this current project aims to establish a pivotal role of CCL3 signaling of primary sensory neurons in chronic inflammatory pain by investigating the regulatory effects of chronic inflammatory pain on CCL3 signaling and the molecular mechanisms underlying the involvement of CCL3 signaling in chronic inflammatory pain. Next, we aim to explore the intervention of electroacupuncture (EA) on CCL3 signaling in the context of chronic inflammatory pain and the involvement of CCL3 signaling in EA induced analgesia by means of immunoblotting, electrophysiology, calcium imaging and pharmacology. This project will further unravel the molecular mechanisms of chronic inflammatory pain and provide novel theory for the explanation of acupuncture analgesia, which may help to improve the clinical practice of acupuncture analgesia.

慢性炎症痛是常见慢性痛，其持续时间较长，严重影响患者生活质量，往往给患者带来沉重身心负担。针刺是一种可有效缓解慢性痛的治疗手段，然而其镇痛机制目前尚不完全清楚。近期研究发现针刺的镇痛机制可能与其干预和调节中枢或外周与痛觉或炎症相关的分子或信号通路有关。有证据表明趋化因子CCL3信号通路参与了慢性痛。本项目拟通过观察慢性炎症痛对外周感觉神经元CCL3通路表达的调控作用，探讨外周CCL3通路参与慢性炎症痛的分子机制，进而确立该通路在慢性炎症痛中的重要作用。在此基础上，利用免疫印记、神经电生理、细胞内钙成像、药理学等手段探讨慢性炎症痛情况下电针对CCL3通路表达和功能的干预作用以及该通路在电针镇痛效应中的参与机制。本项目的开展将有助于进一步揭示慢性炎症痛产生的分子机制，同时为针刺镇痛效应的机制研究提供崭新理论依据，从而更好地指导针刺镇痛的临床实践工作。

慢性痛持续时间长，严重影响患者生活质量，给患者带来沉重身心负担。针刺是一种有效缓解慢性痛的治疗手段，然而其镇痛机制尚不完全清楚。近期研究发现针刺镇痛可能与其干预和调节中枢或外周与痛觉或炎症相关分子或信号通路有关。因此本项目以化疗药物紫杉醇诱发外周神经病理痛（CIPN）和复杂性区域性疼痛综合征（CRPS）等慢性痛动物模型为切入点，利用免疫学、神经电生理、细胞内钙成像、药理学等手段探讨电针对炎症信号通路的干预，阐明电针镇痛效应机制。主要发现如下：① 低频电针可有效抑制大鼠CIPN模型疼痛过敏症状，电针可有效抑制背跟神经节（DRG）中TLR4、MyD88及TRPV1蛋白过表达以及TRPV1通道功能活性增高。电针还能进一步减少脊髓背角（SCDH）星形胶质和小胶质细胞过度活化。电针镇痛作用可被TRPV1通道阻断剂模拟，并被TRPV1通道激动剂逆转。这项研究揭示了电针治疗CIPN的TLR4-MyD88-TRPV1通路干预机制，并提示低频电针可作为临床治疗CIPN的有效疗法。②成功建立大鼠CRPS模型，利用RNA-Seq对该模型大鼠DRG进行基因表达测序，发现一系列与疼痛相关基因表达的变化；发现TRPV1通道介导该模型大鼠DRG神经元过度兴奋以及SCDH中星形胶质和小胶质细胞过度活化，从而参与疼痛的机制；成功筛选电针治疗大鼠CRPS模型疼痛的优势电针频率，发现电针可减少脊髓背角趋化因子CXCL12/CXCR4信号通路表达以及SCDH中神经元、星形胶质细胞、小胶质细胞过度激活和磷酸化ERK过表达。这项研究揭示电针可通过干预SCDH中趋化因子CXCL12/CXCR4信号通路发挥镇痛疗效，并提示电针可作为一种临床有效缓解CRPS疼痛症状的手段。