鞘内注射水溶性脂聚体运载NR2B siRNA减轻坐骨神经缩窄性损伤大鼠神经病理性疼痛

脊髓背角N-甲基-D-天冬氨酸受体2B亚基（NR2B）的过度表达在神经病理性疼痛的产生和维持方面起关键作用，利用siRNA抑制NR2B的表达有望成为神经病理性疼痛甚至神经损伤治疗的新途径，然而，目前仍然缺乏NR2B siRNA安全且高效的载体。本实验探讨了低分子量聚乙烯亚胺和胆固醇组成的水溶性脂聚体（WSLP）运载NR2B siRNA治疗大鼠神经病理性疼痛的可行性，以寻找神经病理性疼痛基因治疗的安全且高效的载体。结果发现：WSLP与NR2B siRNA复合物（WSLP/siRNA）鞘内注射后3d，坐骨神经缩窄性损伤导致的神经病理性疼痛大鼠脊髓背角NR2B的基因表达显著下降，转录水平及蛋白水平的表达分别下降59%及54%（P < 0.01），WSLP/乱序siRNA(scRNA) 及低分子量聚乙烯亚胺/siRNA鞘内注射后NR2B的基因表达无明显变化。WSLP/siRNA鞘内注射后3，7，14及21d神经病理性痛大鼠患足的疼痛程度明显减轻，而注射低分子量聚乙烯亚胺/ siRNA及WSLP/scRNA却无此作用。由此表明，WSLP可有效运载siRNA抑制神经病理痛大鼠NR2B基因的过度表达，从而对神经病理性疼痛大鼠具有治疗作用。

Water-soluble lipopolymer delivery of N-methyl-D-aspartic acid receptor 2B siRNA relieves chronic neuropathic pain in rats

Spinal dorsal horn N-Methyl-D-aspartic acid receptor 2B (NR2B) overexpression plays an important role in the production and maintenance of neuropathic pain. Because small interfering RNA (siRNA) can inhibit NR2B expression, siRNA may provide a novel approach to treat neuropathic pain and possibly nerve injury. However, an efficient and safe vector for NR2B siRNA has not been discovered. This study shows that a water soluble lipopolymer (WSLP) comprised of low molecular weight polyethyleneimine (PEI) and cholesterol can deliver siRNA targeting NR2B for the treatment of neuropathic pain. Results show that intrathecal injection of WSLP/siRNA complexes for 3 days inhibit NR2B gene expression with reductions in mRNA and protein levels by 59% and 54%, respectively, compared with control rats (P < 0.01). Injection of WSLP complexed with scrambled siRNA, or PEI with siRNA did not show this inhibitory effect. Moreover, injection of WSLP/siRNA complexes significantly relieved neuropathic pain at 3, 7, 12, and 21 days, while injection of WSLP with scrambled siRNA or PEI with siRNA did not. These results demonstrate that WSLP can efficiently deliver siRNA targeting NR2B in vivo and relieve neuropathic pain.