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鞘内给予甘氨酸转运体-2 抑制剂 ALX1393 在大鼠急性疼痛模型中的抗伤害作用。

The antinociceptive effect of intrathecal administration of glycine transporter-2 inhibitor ALX1393 in a rat acute pain model.

机构信息

Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.

出版信息

Anesth Analg. 2010 Feb 1;110(2):615-21. doi: 10.1213/ANE.0b013e3181c7ebbb.

Abstract

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 microg) 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 microg.

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.

摘要

背景

脊髓背角的甘氨酸能神经元被认为参与了外周炎症和慢性疼痛状态下脊髓疼痛处理的抑制。神经元同工型甘氨酸转运体-2(GlyT2)再摄取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,我们研究了选择性 GlyT2 抑制剂 ALX1393 是否在外周急性疼痛模型中产生镇痛作用。

方法

雄性 Sprague-Dawley 大鼠鞘内置管。通过尾巴闪烁、热板、爪压和福尔马林试验评估鞘内给予 ALX1393(4、20 或 40μg)对热、机械和化学性疼痛的影响。此外,为了探讨 ALX1393 是否影响运动功能,进行了旋转棒试验。

结果

ALX1393 以剂量依赖性方式对热和机械刺激表现出镇痛作用。ALX1393 的最大作用在给药后 15 分钟观察到,显著作用持续约 60 分钟。ALX1393 给药后立即注射士的宁可完全逆转这些镇痛作用。在福尔马林试验中,ALX1393 以剂量依赖性方式抑制疼痛行为,无论是在早期还是晚期,尽管晚期的影响更大。与镇痛作用相反,ALX1393 至 40μg 不影响运动功能。

结论

本研究表明 ALX1393 对急性疼痛具有镇痛作用。这些发现表明抑制性神经递质转运体是治疗急性疼痛的有前途的靶点,而选择性 GlyT2 抑制剂可能成为一种新型治疗药物。

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