加巴喷丁治疗神经病理性疼痛的作用及可能机制

目的观察TRPA1在加巴喷丁（gabapentin，GBP）治疗神经病理性疼痛（neuropathicpain，NPP）大鼠模型背根神经节（DRG）中的表达变化，探讨GBP治疗神经病理性疼痛的作用及可能机制。方法健康雄性SD大鼠48只，采用随机数字表法分为假手术对照组（Sham组）、慢性坐骨神经压榨性损伤（CCI）组、CCI＋生理盐水组（CCI＋NS组）、CCI＋小剂量GBP组（CCI＋GBP1组）、CCI＋中剂量GBP组（CCI＋GBP2组）、CCI＋大剂量GBP组（CCI＋GBP3组），每组8只。术后14天，CCI＋GBP1组、CCI＋GBP2组、CCI＋GBP，组分别鞘内注射GBP1g／L、3g／L和10g／L，CCI＋Ns组给予等渗生理盐水。术前1天、给药前1h及给药后2、4、6、8h分别测定各组机械缩足阈值（MWT）和热缩足潜伏期（TWL）。给药后9h取大鼠腰段脊髓，ELISA法检测肿瘤坏死因子α（TNF—α）、白细胞介素（IL）-6、IL-10表达和核因子KB（NF—KB）的活性。同时，选Sham组、CCI组、CCI＋NS组及CCI＋GBP，组给药后9h取大鼠背根神经节，应用RT—PCR技术检测TRPA1离子通道mRNA的表达。结果①与Sham组比较，CCI、CCI＋NS、CCI＋GBP1、CCI＋GBP2、CCI＋GBP，组术后MWT和TWL均下降（P〈0．叭）。与CCI组比较，GBP治疗后，CCI＋GBP1、CCI＋GBP2、CCI＋GBP，组MWT和TWL上升（P〈0．05）。②与Sham组比较，CCI、CCI＋NS、CCI＋GBP1、CCI＋GBP2、CCI＋GBP3组腰段脊髓NF—κB、TNF-α、IL-6及IL-10表达上升（P〈0．05）。GBP治疗后，CCI＋GBP2、CCI＋GBP3组NF—κB、TNF-α、IL-6表达下降，IL-10表达上升（P〈0．05）。③与Sham组比较，CCI、CCI＋NS及CCI＋GBP，组TRPA1表达上升（P〈0．05）。与CCI组及CCI＋NS组相比，CCI＋GBP，组TRPA1表达下降（P〈0．05）。结论GBP可有效治疗大鼠CCI后NPP，其镇痛机制可能与减低脊髓NF—κB活性，抑制TNF—α及IL-6表达，增强IL-10表达有关，同时可降低TRPA1的表达。

Efficacy and possible mechanism of gabapentin in treating the neuropathic pain in rats

Objective To observe the expressions of TRPA1 in dorsal root ganglion （DRG） during treatment of neuropathic pain （NPP） by gabapentin （GBP） so as to investigate the efficacy and possible mechanism. Methods 56 male SD rats were divided into 6 groups using a random number table ： sham operation control group （Sham） , chronic constriction injury （CCI） control group （CCI） , CCI ＋ normal saline control group （CCI ＋ NS） , CCI ＋ small dose of GBP group （ CCI ＋ GBP1 ） , CCI ＋ median dose of GBP group （ CCI ＋ GBP2 ） , and CCI ＋ large dose of GBP group （ CCI ＋ GBP3 ）. There were 8 rats in each group. The rats in the CCI ＋ NS group received normal saline and the rats in 3 GBP groups received 10 μg/10μl, 30 μg/10μl and 100μg/10 μl dose of GBP via intrathecal injection on 14 d after CCI, respectively . Mechanical withdrawal threshold （MWT） and thermal withdrawal latency （TWL） of the left paws were measured 1 d before operation, 1 h before intrathecal injection, and 2, 4, 6, 8 h after intrathecal injection. Lumbar spinal cord were obtained 9 h after intrathecal injection to determine the expressions of TNF - α, IL -6, IL - 10 and NF - κB. Sham group, CCI group, CCI ＋ NS group, CCI ＋ GBP3 group were selected to determine the expressions of TR- PAl mRNA ,when dorsal root ganglia were obtained 9 h after intrathecal injection. Results ① Compared with Sham group, MWT and TWL decreased in CCI group, CCI ＋ NS group, CCI ＋ GBP1 group, CCI ＋ GBP2 group, and CCI ＋ GBP3 group （P 〈0.01 ）. Compared with CCI group, when GBP were given, the MWT and TWL of CCI ＋ GBP1 group, CCI ＋ GBP2 group, and CCI ＋ GBP3 group increased （P 〈 0. 05 ）.② Compared with Sham group, NF - κB, TNF - α, IL - 6, and IL - 10 increased in CCI group, CCI ＋ NS group, CCI ＋ GBP1 group, CCI ＋ GBP2 group, and CCI ＋ GBP3 group （P 〈0.05）. When GBP were given , NF - κB, TNF -α and IL - 6 decreased, and IL - 10 increased in lumbar spinal cord in CCI ＋ GBP2 group and CCI ＋ GBP3 group （P 〈 0.05 ）. ① Compared with Sham group, TRPA1 increased in CCI group, CCI ＋ NS group, and CCI ＋ GBP3 group （P 〈 0.05）. Compared with CCI group, TRPA1 decreased in CCI ＋ GBP3 group （P 〈 0.05）. Conclusion GBP may effectively relieve the NPP induced by CCI possibly via reducing the NF -κB activity in lumbar spinal cord, and inhibiting the expressions of TNF - α and IL - 6 and increasing the expression of IL - 10 in lumbar spinal cord , and can reduce the expressions of TRPA1.