Etifoxine stimulates allopregnanolone synthesis in the spinal cord to produce analgesia in experimental mononeuropathy
Etifoxine stimulates allopregnanolone synthesis in the spinal cord to produce analgesia in experimental mononeuropathy
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DOI：
10.1002/j.1532-2149.2013.00367.x
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发表时间：
2014-02-01
影响因子：
3.6
通讯作者：
Poisbeau, P.
中科院分区：
文献类型：
--
作者：
Aouad, M.;Petit-Demouliere, N.;Poisbeau, P.
研究背景病理性疼痛常与脊髓神经元的过度兴奋有关。减少这种兴奋性理论上可以通过放大GABAA受体（GABAARs）介导的现有脊髓抑制控制来实现。在这项研究中，我们使用非苯二氮卓类抗焦虑药艾提伏辛（EFX）来表征其作为止痛药和脊髓作用机制的兴趣。EFX增强GABAAR功能，但也可以增加其功能，刺激当地的合成3-还原型神经甾体（3 NS），最有效的内源性调节剂，这种receptor.MethodsThe EFX镇痛的疗效和贡献的3 NS在大鼠模型的mononeuropathy进行了评估。EFX的脊髓贡献通过鞘内注射后疼痛症状的变化、EFX和3 NS的脊髓含量以及FosB相关基因的表达（长期可塑性的标志物）来表征。完全抑制神经性疼痛症状。这种作用是完全介导的3 NS和可能由allopregnanolone，这是发现在高浓度的脊髓。在很好的协议，鞘内注射后的EFX镇痛水平证实，脊髓是一个特权的目标，以及有限的表达FosB/FosB基因产物是高度表达在持续性pain states.ConclusionsThis临床前研究表明，刺激生产的内源性镇痛药，如3 NS是一个有趣的策略，以减少神经性疼痛症状。由于EFX已经在几个国家被规定为抗焦虑药，因此需要迅速评估其在人类临床中的应用。
BackgroundPathological pain states are often associated with neuronal hyperexcitability in the spinal cord. Reducing this excitability could theoretically be achieved by amplifying the existing spinal inhibitory control mediated by GABAA receptors (GABAARs). In this study, we used the non-benzodiazepine anxiolytic etifoxine (EFX) to characterize its interest as pain killer and spinal mechanisms of action. EFX potentiates GABAAR function but can also increase its function by stimulating the local synthesis of 3-reduced neurosteroids (3NS), the most potent endogenous modulators of this receptor.MethodsThe efficacy of EFX analgesia and the contribution of 3NS were evaluated in a rat model of mononeuropathy. Spinal contribution of EFX was characterized through changes in pain symptoms after intrathecal injections, spinal content of EFX and 3NS, and expression of FosB-related genes, a marker of long-term plasticity.ResultsWe found that a 2-week treatment with EFX (>5mg/kg, i.p.) fully suppressed neuropathic pain symptoms. This effect was fully mediated by 3NS and probably by allopregnanolone, which was found at a high concentration in the spinal cord. In good agreement, the level of EFX analgesia after intrathecal injections confirmed that the spinal cord is a privileged target as well as the limited expression of FosB/FosB gene products that are highly expressed in persistent pain states.ConclusionsThis preclinical study shows that stimulating the production of endogenous analgesics such as 3NS represents an interesting strategy to reduce neuropathic pain symptoms. Since EFX is already prescribed as an anxiolytic in several countries, a translation to the human clinic needs to be rapidly evaluated.