CXCL12/CXCR4对CCD损伤后DRG神经元兴奋性的调节及其机制研究

Chronic Compression of Dorsal Root Ganglion (CCD) model which mimic the compression of Dorsal Root Ganglion (DRG) is an idea model to investigate the pathophysiology of this kind of disease.After CCD, DRG neurons show hyperexcitability which responsible for the neuropathic pain. But the mechanisms account for the hyperexcitability is still unkonwn. Our previous data showed that after CCD the percentage of DRG neuron which respond to local perfusion of CXCL12 increased. That is local perfusion of CXCL12 induced increase of intracellular calcium concentration in more DRG neurons which demonstrated the increased expression of CXCL12 receptor CXCR4 on DRG neurons after CCD.Different from the classical role as a inflammatory attactant, CXCL12 may work as a neuromodulator at DRG level and directly activate DRG neurons through the CXCR4 receptor which in turn induce hyperexcitability of the neuron. Through this mechanism CXCL12 participate the induction and maintanance of pain sensory.We will test this hypothesis and elucidate the mechanisms through which CXCL12/CXCR4 activation lead to DRG neuron hyperexcitability. We will test if block CXCR4 systemicly by its antagonist will attenuate the pain behaviour after CCD. This project is promising to propose a new strategy to treat neuropathic pain.

各种损伤因素导致背根神经节（DRG）持续受压可产生根性神经痛，慢性压迫背根神经节（CCD），是研究这一类疾病的理想动物模型。CCD损伤后DRG神经元兴奋性增高，是引起神经病理性疼痛的主要因素，但兴奋性增高的机制尚未阐明。有证据表明趋化因子CXCL12及其受体CXCR4参与神经病理性疼痛，但其机制尚不明确。我们的前期数据表明CCD损伤后，CXCL12引起DRG神经元细胞内钙增高的神经元百分比增加，提示CCD损伤后背根节CXCR4上调。不同于传统炎性趋化作用，CXCL12可能通过激动DRG神经元上的CXCR4 受体，发挥神经调质作用，上调神经元兴奋性而直接参与疼痛产生和维持。我们将检验这一假设并阐明CXCL12/CXCR4调节DRG神经元兴奋性的信号通路及离子通道机制，并检验CXCR4拮抗剂对CCD后DRG神经元兴奋性增高及疼痛行为的影响。该研究有望提出治疗神经病理性疼痛的新策略、新靶点。