From the Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
Anesth Analg. 2013 May;116(5):1162-1169. doi: 10.1213/ANE.0b013e318282dda7. Epub 2013 Mar 1.
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the mammalian central nervous system. GABAergic transmission has an important role in regulating nociception at the spinal dorsal horn. It is terminated by rapid uptake of the neurotransmitter from the synaptic cleft into neurons and glial cells, via specific GABA transporters (GATs). Among the 4 GATs, GAT-3 has the greatest expression in central nervous system regions closely associated with nociceptive transmission, including the spinal cord. In this study, we examined the antinociceptive effect of intrathecal administration of a selective GAT-3 inhibitor, SNAP5114, on acute, inflammatory, and neuropathic pain in experimental models.
Male Sprague-Dawley rats were used to assess thermal, mechanical, and chemical nociception in the tail flick and hotplate tests, the paw pressure test, and the formalin test. A rotarod test was performed to assess motor function. Chronic constriction injury to the sciatic nerve was induced in the rats. The electronic von Frey test and the plantar test were then performed to assess mechanical allodynia and thermal hyperalgesia. SNAP5114 (10, 50, 100, or 200 μg) was administered intrathecally to examine antinociceptive activity. To confirm whether the action of SNAP5114 was mediated by GABAergic transmission, the GABAA receptor antagonist bicuculline (0.3 μg) or the GABAB receptor antagonist CGP35348 (30 μg) was administered intrathecally before 200 μg of SNAP5114 in the tail flick test, the formalin test, and the electronic von Frey test.
Spinally applied SNAP5114 in normal rats dose-dependently prolonged withdrawal latencies in the tail flick test and suppressed the late-phase response in the formalin test. SNAP5114 did not affect motor performance. In the chronic constriction injury rats, SNAP5114 inhibited mechanical allodynia dose-dependently. The antinociceptive action of SNAP5114 was partially reversed by bicuculline or CGP35348 at doses at which the antagonist alone did not affect baseline behavioral responses.
These results suggest that SNAP5114 exerts antinociceptive effects by activating GABAA and GABAB receptors in the spinal cord. The GAT-3 inhibitor may prove useful in treatment of various painful conditions.
γ-氨基丁酸（GABA）是哺乳动物中枢神经系统中的主要抑制性神经递质。GABA 能传递在脊髓背角中对伤害感受的调节中起重要作用。它通过特定的 GABA 转运体（GATs）将神经递质从突触间隙快速摄取到神经元和神经胶质细胞中而终止。在 4 种 GAT 中，GAT-3 在与伤害感受传递密切相关的中枢神经系统区域中表达最高，包括脊髓。在这项研究中，我们研究了鞘内给予选择性 GAT-3 抑制剂 SNAP5114 对急性、炎症和神经性疼痛模型的抗伤害作用。
雄性 Sprague-Dawley 大鼠用于评估尾巴闪烁和热板测试、足底压力测试和福尔马林测试中的热、机械和化学伤害感受。旋转棒测试用于评估运动功能。大鼠坐骨神经慢性缩窄性损伤。然后进行电子 von Frey 测试和足底测试，以评估机械性痛觉过敏和热痛觉过敏。鞘内给予 SNAP5114（10、50、100 或 200μg）以检查其镇痛活性。为了确认 SNAP5114 的作用是否通过 GABA 能传递介导，在尾巴闪烁测试、福尔马林测试和电子 von Frey 测试中，在给予 200μg SNAP5114 之前，鞘内给予 GABA A 受体拮抗剂荷包牡丹碱（0.3μg）或 GABA B 受体拮抗剂 CGP35348（30μg）。
在正常大鼠中，鞘内给予 SNAP5114 剂量依赖性地延长尾巴闪烁测试中的退缩潜伏期，并抑制福尔马林测试中的后期反应。SNAP5114 不影响运动性能。在慢性缩窄性损伤大鼠中，SNAP5114 剂量依赖性地抑制机械性痛觉过敏。在单独使用拮抗剂不影响基线行为反应的剂量下，SNAP5114 的镇痛作用部分被荷包牡丹碱或 CGP35348 逆转。
这些结果表明，SNAP5114 通过激活脊髓中的 GABA A 和 GABA B 受体发挥镇痛作用。GAT-3 抑制剂在治疗各种疼痛病症方面可能具有应用价值。
