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钩吻碱甲——一种来自常绿钩吻藤的主要生物碱——通过作用于脊髓α3甘氨酸受体而在慢性疼痛中表现出强力且特异的镇痛作用

Gelsemine, a principal alkaloid from Gelsemium sempervirens Ait., exhibits potent and specific antinociception in chronic pain by acting at spinal α3 glycine receptors

来源:Scopus 发布时间:2013-12-26
作者:Zhang, J.-Y., Gong, N., Huang, J.-L., Guo, L.-C., Wang, Y.-X.
机构: 上海交通大学药学院King's Lab
期刊: Pain2013年11月11期154卷

 

Abstract

The present study examined the antinociceptive effects of gelsemine, the principal alkaloid in Gelsemium sempervirens Ait. A single intrathecal injection of gelsemine produced potent and specific antinociception in formalin-induced tonic pain, bone cancer-induced mechanical allodynia, and spinal nerve ligation-induced painful neuropathy. The antinociception was dose-dependent, with maximal inhibition of 50% to 60% and ED50 values of 0.5 to 0.6 μg. Multiple daily intrathecal injections of gelsemine for 7 days induced no tolerance to antinociception in the rat model of bone cancer pain. Spinal gelsemine was not effective in altering contralateral paw withdrawal thresholds, and had only a slight inhibitory effect on formalin-induced acute nociception. The specific antinociception of gelsemine in chronic pain was blocked dose-dependently by the glycine receptor (GlyR) antagonist strychnine with an apparent ID50 value of 3.8 μg. Gelsemine concentration-dependently displaced H3-strychnine binding to the membrane fraction of rat spinal cord homogenates, with a 100% displacement and a Ki of 21.9 μM. Gene ablation of the GlyR α3 subunit (α3 GlyR) but not α1 GlyR, by a 7-day intrathecal injection of small interfering RNA (siRNA) targeting α3 GlyR or α1 GlyR, nearly completely prevented gelsemine-induced antinociception in neuropathic pain. Our results demonstrate that gelsemine produces potent and specific antinociception in chronic pain states without induction of apparent tolerance. The results also suggest that gelsemine produces antinociception by activation of spinal α3 glycine receptors, and support the notion that spinal α3 glycine receptors are a potential therapeutic target molecule for the management of chronic pain.

通讯作者:Wang, Y.-X.; King's Lab, Shanghai Jiao Tong University School of Pharmacy, No. 6 Biomedicine Building, 800 Dongchuan Road, Shanghai 200240, China; email:yxwang@sjtu.edu.cn
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