The Antinociceptive Effect of Intrathecal Administration of Glycine Transporter-2 Inhibitor ALX1393 in a Rat Acute Pain Model
The Antinociceptive Effect of Intrathecal Administration of Glycine Transporter-2 Inhibitor ALX1393 in a Rat Acute Pain Model
复制标题
DOI：
10.1213/ane.0b013e3181c7ebbb
复制
发表时间：
2010-02-01
影响因子：
5.7
通讯作者：
Sata, Takeyoshi
中科院分区：
文献类型：
--
作者：
Haranishi, Yasunori;Hara, Koji;Sata, Takeyoshi
背景技术背景：脊髓背角中的甘氨酸能神经元已经涉及外周炎症和慢性疼痛状态中脊髓疼痛处理的抑制。神经元亚型甘氨酸转运蛋白-2（GlyT 2）重新吸收突触前释放的甘氨酸并调节甘氨酸能神经传递。在这项研究中，我们研究了是否选择性GlyT 2抑制剂，ALX 1393，elevolan在大鼠急性疼痛model.METHODS：雄性Sprague-Dawley大鼠鞘内植入导管的镇痛作用。通过甩尾、热板、爪压和福尔马林试验评价了鞘内给予ALX 1393（4、20或40 μ g）对热、机械和化学伤害感受的影响。结果：ALX 1393对热刺激和机械刺激均表现出一定的抗伤害性作用，且呈剂量依赖性。ALX 1393的最大作用在给药后15 min观察到，并且显著作用持续约60 min。这些抗伤害性作用被ALX 1393给药后立即注射士的宁完全逆转。在福尔马林试验中，ALX 1393在早期和晚期均以剂量依赖性方式抑制疼痛行为，尽管在晚期的影响更大。相反，抗伤害作用，ALX 1393没有影响运动功能高达40微克。结论：这项研究表明，ALX 1393对急性疼痛的抗伤害作用。这些发现表明抑制性神经递质转运蛋白是治疗急性疼痛的有希望的靶点，并且GlyT 2的选择性抑制剂可能是一种新型治疗药物。（Anesth Analg 2010;110：615-21）
BACKGROUND: Glycinergic neurons in the spinal dorsal horn have been implicated in the inhibition of spinal pain processing in peripheral inflammation and chronic pain states. Neuronal isoform glycine transporter-2 (GlyT2) reuptakes presynaptically released glycine and regulates the glycinergic neurotransmission. In this study, we examined whether a selective GlyT2 inhibitor, ALX1393, elicits an antinociceptive effect in a rat acute pain model.METHODS: Male Sprague-Dawley rats were implanted with a catheter intrathecally. The effects of intrathecal administration of ALX1393 (4, 20, or 40 mu g) on thermal, mechanical, and chemical nociception were evaluated by tail flick, hot plate, paw pressure, and formalin tests. Furthermore, to explore whether ALX1393 affects motor function, a rotarod test was performed.RESULTS: ALX1393 exhibited antinociceptive effects on the thermal and mechanical stimulations in a dose-dependent manner. The maximal effect of ALX1393 was observed at 15 min after administration, and a significant effect lasted for about 60 min. These antinociceptive effects were reversed completely by strychnine injected immediately after the administration of ALX1393. In the formalin test, ALX1393 inhibited pain behaviors in a dose-dependent manner, both in the early and late phases, although the influence was greater in the late phase. In contrast to antinociceptive action, ALX1393 did not affect motor function up to 40 mu g.CONCLUSIONS: This study demonstrates the antinociceptive action of ALX1393 on acute pain. These findings suggest that the inhibitory neurotransmitter transporters are promising targets for the treatment of acute pain and that the selective inhibitor of GlyT2 could be a novel therapeutic drug. (Anesth Analg 2010;110:615-21)