Fast non-genomic effects of progesterone-derived neurosteroids on nociceptive thresholds and pain symptoms
Fast non-genomic effects of progesterone-derived neurosteroids on nociceptive thresholds and pain symptoms
复制标题
DOI：
10.1016/j.pain.2008.06.016
复制
发表时间：
2008-10-31
期刊：
影响因子：
7.4
通讯作者：
Poisbeau, Pierrick
中科院分区：
文献类型：
--
作者：
Charlet, Alexandre;Lasbennes, Francois;Poisbeau, Pierrick
甘氨酸 (GlyR) 和 GABAA 受体 (GABAAR) 介导的快速抑制控制在预防异常性疼痛和痛觉过敏等病理性疼痛症状的出现方面发挥着重要作用。使用这些受体（特别是在脊髓中表达）的正变构调节剂可能代表了限制或阻止疼痛表达的有趣策略。在本研究中，我们使用了仅通过非基因组效应起作用的黄体酮代谢物的立体异构体，以评估 GlyR 和 GABAAR 对减少机械和热热过度伤害感受的贡献。我们发现 3 α 神经类固醇对于提高幼稚动物的伤害感受阈值特别有效。它还减少了角叉菜胶炎性疼痛模型中的机械异常性疼痛和热痛觉过敏。这种效应可能是由 GABAA 受体介导的，因为 3β 异构体效率较低。更有趣的是，3α5β神经类固醇仅对油机械性异常性疼痛有效，而对油热痛觉过敏没有作用。我们使用士的宁和荷包牡丹碱异常性疼痛模型来表征 3α5β 神经类固醇的这些矛盾效应。我们清楚地表明，3α5β神经类固醇通过 GABAAR 的正向变构调节发挥抗伤害作用，但同时通过降低 GlyR 功能而产生伤害感受。这说明了抑制性氨基酸受体通道及其变构调节剂在脊髓疼痛处理中的重要性。此外，我们的结果表明，在脊髓背角合成且副作用有限的神经类固醇对于治疗病理性疼痛症状可能具有重要意义。 (C) 2008 年国际疼痛研究协会。由 Elsevier B.V. 出版。保留所有权利。
Fast Inhibitory controls mediated by glycine (GlyRs) and GABAA receptors (GABAARs) play an important role to prevent the apparition of pathological pain symptoms of allodynia and hyperalgesia. The use of positive allosteric modulators of these receptors, specifically expressed in the spinal cord, may represent an interesting strategy to limit or block pain expression. In this Study, we have used stereoisomers of progesterone metabolites, acting only via non-genomic effects, in order to evaluate the contribution of GlyRs and GABAARs for the reduction of mechanical and thermal heat hypernociception. We show that 3 alpha neurosteroids were particularly efficient to elevate nociceptive thresholds in naive animal. It also reduced mechanical allodynia and thermal heat hyperalgesia in the carrageenan model of inflammatory pain. This effect is likely to be mediated by GABAA receptors since 3 beta isomer was inefficient. More interestingly, 3 alpha 5 beta neurosteroid was only efficient oil mechanical allodynia while having no effect oil thermal heat hyperalgesia. We characterized these paradoxical effects of 3 alpha 5 beta neurosteroid using the strychnine and bicuculline models of allodynia. We clearly show that 3 alpha 5 beta neurosteroid exerts an antinociceptive effect via a positive allosteric modulation of GABAARs but, at the same time, is pronociceptive by reducing GlyR function. This illustrates the importance of the inhibitory amino acid receptor channels and their allosteric modulators in spinal pain processing. Moreover, our results indicate that neurosteroids, which are synthesized in the dorsal horn of the spinal cord and have limited side effects, may be of significant interest in order to treat pathological pain symptoms. (C) 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.