Hu Jia-Hua, Yang Na, Ma Ying-Hua, Zhou Xiao-Gang, Jiang Jie, Duan Shu-Hui, Mei Zhen-Tong, Fei Jian, Guo Li-He
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
J Neurosci Res. 2003 Aug 15;73(4):565-72. doi: 10.1002/jnr.10677.
The present study focused on the involvement of gamma-aminobutyric acid transporter I (GAT1) in pain. We found that GABA uptake was increased in mouse spinal cord at 20 min and 120 min after formalin injection and in mouse brain at 120 min, but not 20 min, after formalin injection. In addition, the antinociceptive effects of GAT1-selective inhibitors were examined using assays of thermal (tail-flick) and chemical (formalin and acetic acid) nociception in C57BL/6J mice. The GAT1-selective inhibitors, ethyl nipecotate and NO-711, exhibited significant antinociceptive effects in these nociceptive assays. To study further the effects of GAT1 on pain, we used two kinds of GAT1-overexpressing transgenic mice (under the control of a CMV promoter or a NSE promoter) to examine the nociceptive responses in these mice. In the thermal, formalin, and acetic acid assays, both kinds of transgenic mice displayed significant hyperalgesia after nociceptive stimuli. In addition, the micro opioid receptor antagonist naloxone had no influence on nociceptive responses in wild-type and transgenic mice. The results indicate that GAT1 is involved in the regulation of pain processes, and point to the possibility of developing analgesic drugs that target GAT1 other than opioid receptors.
本研究聚焦于γ-氨基丁酸转运体I（GAT1）在疼痛中的作用。我们发现，在福尔马林注射后20分钟和120分钟时，小鼠脊髓中的GABA摄取增加，在福尔马林注射后120分钟而非20分钟时，小鼠脑中的GABA摄取增加。此外，使用C57BL/6J小鼠的热（甩尾）和化学（福尔马林和醋酸）伤害感受测定法，检测了GAT1选择性抑制剂的抗伤害感受作用。GAT1选择性抑制剂尼可刹米乙酯和NO-711在这些伤害感受测定中表现出显著的抗伤害感受作用。为了进一步研究GAT1对疼痛的影响，我们使用了两种GAT1过表达转基因小鼠（在巨细胞病毒启动子或神经元特异性烯醇化酶启动子的控制下）来检测这些小鼠的伤害感受反应。在热、福尔马林和醋酸测定中，两种转基因小鼠在伤害性刺激后均表现出显著的痛觉过敏。此外，微阿片受体拮抗剂纳洛酮对野生型和转基因小鼠的伤害感受反应没有影响。结果表明，GAT1参与疼痛过程的调节，并指出开发除阿片受体之外以GAT1为靶点的镇痛药的可能性。
