SCN9A基因多态性与术后疼痛敏感性预测及其机制的相关性研究

There are more than 200 million surgical patients around the world every year. Because of the lack of specific predictors of individual pain sensitivity, the personalized treatment is not implemented and the quality of postoperative pain management is insufficient. The mutations of SCN9A gene which encodes sodium channel Nav1.7 change the functional Nav1.7 channels and furthermore affected individual pain perception. We have screened a novel SCN9A gene heterozygous mutation (V1104L) from two children with congenital analgesia. This novel mutation is present in 6.5% of healthy Chinese and may cause partial deletion of pain perception in general population. Then a latest European study also reveals that patients with mutation (C1719R) of SCN9A gene develop partial deletion of pain perception. In addition, R1150W which is present in healthy European females may enhance pain sensitivity. So we postulated that SCN9A gene mutations can change the function of Nav1.7 channel in different direction in the general population, presenting a "skewed state of pain perception", i.e. reducing or enhancing the pain sensitivity. By means of gene screening, preoperative pain threshold testing and postoperative pain assessment, we investigate the correlation between the SNPs of SCN9A and the postoperative pain sensitivity in Chinese Han population and furthermore demonstrate its mechanism by means of genes cloning in vitro, whole-cell patch-clamp technique, molecular dynamics simulation. Through these studies, we expect that individual pain sensitivity can be predicted by gene screening and personalized pain treatment as well as targets for gene therapy of pain achieved.

全球年手术量超过2亿，因疼痛及镇痛存在巨大的个体差异，且疼痛敏感性预测指标的缺乏，导致个体化治疗无法实现，术后镇痛不良常有发生。编码Nav1.7α亚基的基因SCN9A的突变会影响个体的疼痛感知，甚至决定疼痛的有或无。我们在先天性无痛症患儿SCN9A新发现的突变位点V1104L在一般人群中突变率达6.5%；随后欧洲报道疼痛不敏感患儿的突变位点C1719R也存在于正常人，而R1150W突变导致健康女性疼痛敏感性增强。据此我们推测SCN9A的SNPs可使Nav1.7通道功能状态发生转化，导致个体呈现"疼痛感知偏移态"，即疼痛敏感性降低或增强。本研究拟通过基因筛查、术前痛阈测定及术后疼痛评估，确定SCN9A的SNPs与汉族患者术后疼痛敏感性的相关性，进而在体外通过基因克隆、全细胞膜片钳技术和分子动力学模拟方法证实其机制。有望实现疼痛敏感性的基因预测，优化个体化术后镇痛，并为疼痛基因治疗提供靶点。

急性术后疼痛是所有手术患者可能经历的过程，因疼痛及镇痛存在巨大的个体差异，目前缺乏理想的、精确的预测个体疼痛敏感性的指标，导致术后镇痛不良常有发生，许多患者甚至发展为慢性持续性疼痛。若能术前准确预测患者对疼痛的敏感程度，则可更好地指导术后疼痛治疗，实现术后疼痛的个体化治疗。通过研究疼痛相关基因，解读个体间疼痛敏感性的差异，极有可能是未来镇痛的方向和前提。编码电压门控钠通道Nav1.7的SCN9A突变会影响个体的疼痛感知，甚至决定疼痛的有无。我们在先天性无痛患儿发现的SCN9A V1104L在一般人群突变率为6.5%；欧洲报道疼痛不敏感患儿SCN9A C1719R突变位点也存在于正常人，而R1150W突变可导致女性疼痛敏感性增强。据此，我们推测SCN9A的SNPs可导致Nav1.7功能状态发生改变，导致“疼痛感知偏移态”，即疼痛敏感性降低或增强。本研究通过基因筛查、术前痛阈值测定及术后疼痛评估，制定了健康在校大学生压痛阈值和热痛阈值的正常参考值，并分析了其影响因素，成果分别发表在《实用疼痛学杂志》《中国疼痛医学杂志》；结合基因分型和术前痛阈值测量和术后疼痛评估，证实SCN9A基因多态性与一般人群基础疼痛敏感性存在显著关联；并且SCN9A基因多态性影响腹腔镜手术患者术后疼痛敏感性，结果分别发表在疼痛学专业杂志《J Pain》和《Pain Physician》上；采用体外实验，通过克隆技术构建含有突变位点的质粒，通过膜片钳确认了突变位点在疼痛敏感性中的作用及机制，成果发表在《Molecular Pain》上。同时，在病例收集过程中，我们还收集到了无痛症和无痛无汗症患者病例三十余例，总结了中国无痛无汗症患儿的临床症状，并检测了疼痛相关基因，成果发表在《Medicine》和《Pediatric Neurology》上。本课题的实施，为疼痛敏感性的基因预测奠定了基础，可能进一步优化个体化术后镇痛，为疼痛的基因治疗提供靶点。