【作者】 陈绍辉；

【导师】 罗爱伦； 赵晶；

【作者基本信息】 中国协和医科大学 ， 麻醉学， 2006， 博士

【摘要】 目的：抗癫痫药加巴喷丁对神经病理性疼痛有良好的疗效，但其作用机制仍未明了。本研究采用小鼠坐骨神经部分结扎模型，观察加巴喷丁(GBP)对大脑皮层基因差异表达的影响。方法：120只BALB／c雄性小鼠，体重20～22克，随机分为6组(每组n=20)：(1)CON：对照，腹腔注射生理盐水；(2)CON+GBP组：对照，腹腔注射加巴喷丁100mg／kg；(3)SHAM：假手术，腹腔注射生理盐水；(4) SHAM+GBP：假手术，腹腔注射加巴喷丁100mg／kg；(5) MOD：手术结扎部分坐骨神经，腹腔注射生理盐水；(6)MOD+GBP：手术结扎部分坐骨神经，腹腔注射加巴喷丁100mg／kg。手术前后用Von Frey纤维细丝测量机械痛阈。从手术侧足的行为学变化和机械痛阈确认神经病理性疼痛模型成功。术后第15天开始按方案腹腔注射给药四周。给药结束后将小鼠断头处死，留取大脑皮层。选择SHAM、MOD和MOD+GBP组做基因表达差异检测(01igo神经科学离子通道与载体基因芯片及0ligo神经营养素与受体基因芯片)，并根据检测结果挑选部分变化显著的基因进行实时PCR验证。同时测定SHAM、SHAM+GBP、MOD和MOD+GBP组皮层的脑啡肽含量。结果：和CON、CON+GBP、SHAM、SHAM+GBP组小鼠相比较，MOD和MOD+GBP组小鼠手术侧足的机械性痛阂在坐骨神经部分结扎术后极显著下降(P＜0.01)。和MOD组小鼠相比较，MOD+GBP组小鼠手术侧足的机械性痛阈在加巴喷丁给药后极显著增高(P＜0.01)。MOD和SHAM相比较，脑源性神经生长因子(BDNF)、神经肽Y(NPY)、Pleiotrophin(PTN)等基因显著下调。MOD+GBP和MOD相比较，BDNF、NPY、PTN等基因显著上调。大脑皮层脑啡肽含量在SHAM、SHAM+GBP、MOD、MOD+GBP四组间差异无显著性。结论：加巴喷丁对神经病理性疼痛的镇痛机制可能与大脑皮层BDNF、NPY、PTN等基因的上调有关；其镇痛机制可能不涉及脑啡肽。更多还原

【Abstract】 Gabapentin is an anticonvulsant that has successfully been used to treat many neuropathic pain syndromes, although the mechanism of its antihyperalgesic action remains elusive. The aim of this study was to investigate the differences of gene expression in the cerebral cortex in mice after partial sciatic nerve ligation(PSNL) with or without gabapentin administration.120 male BALB/c mice weighing 20～22g were randomly divided into 6 groups(n=20 for each group): (1) CON: control, with intraperitoneal injection(i. p.) of saline. (2) CON+GBP: control, with gabapentin 100mg/kg i. p. (3) SHAM: sham operation, with saline i. p. (4) SHAM+GBP: sham operation, with gabapentin 100mg/kg i. p. (5) MOD: PSNL, with saline i. p. (6) MOD+GBP: PSNL, with gabapentin 100mg/kg i. p. Mechanical sensitivity was assessed with von Frey filaments before and after PSNL. Intraperitoneal injection of gabapentin or saline started from day 15 after the successful development of neuropathic pain models confirmed by behavioral changes and mechanical allodynia of the ipsilateral hind paw. After four-week administration of gabapentin, mice were sacrificed and cerebral cortex was harvested. Cerebral cortex of group SHAM, MOO, and MOD+GBP were used for gene detection(Oligo neuroscience ion channel and transporter gene array, and Oligo neurotrophin and receptors gene array), and enkephalin concentration was measured in group SHAM, SHAM+GBP, MOD, and MOD+GBP. Several genes markedly changed were selected for Real time-PCR analyses.Compared with group CON, CON+GBP, SHAM and SHAM+GBP, mechanical sensitivity of group MOD and MOD+GBP of the ipsilateral hind paw significantly decreased after PSNL(P＜0.01). Compared with group MOD, mechanical sensitivity of group MOD+GBP of the ipsilateral hind paw significantly increased after gabapentin administration(P＞0.01).Compared with group SHAM, several genes including brain-derived neurotrophic factor(BDNF), neuropeptide Y(NPY), and pleiotrophin markedly down-regulated in group MOD. Compared with group MOD, BDNF, NPY, and pleiotrophin markedly up-regulated in group MOD+GBP. There were no differences between group SHAM, SHAM+GBP, MOD and MOD+GBP in cortex enkephalin concentration.BDNF, NPY, and pleiotrophin, but not enkephalin may be involved in the antihyperalgesie action of gabapentin.更多还原