Long-Lasting Spinal Oxytocin Analgesia Is Ensured by the Stimulation of Allopregnanolone Synthesis Which Potentiates GABAA Receptor-Mediated Synaptic Inhibition
Long-Lasting Spinal Oxytocin Analgesia Is Ensured by the Stimulation of Allopregnanolone Synthesis Which Potentiates GABAA Receptor-Mediated Synaptic Inhibition
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DOI：
10.1523/jneurosci.3084-12.2013
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发表时间：
2013-10-16
影响因子：
5.3
通讯作者：
Poisbeau, Pierrick
中科院分区：
文献类型：
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作者：
Juif, Pierre-Eric;Breton, Jean-Didier;Poisbeau, Pierrick
近年来，由于催产素（OT）在炎症和神经性疾病中具有减轻疼痛症状的功效，下丘脑对脊髓疼痛加工的控制受到了广泛关注。然而，OT脊髓抗痛觉的细胞和分子机制仍然知之甚少。在这项研究中，我们使用生化、电生理和行为学方法来证明，在足底注射lambda-卡拉胶诱导炎症24小时后，出现疼痛症状的大鼠脊髓中的OT水平升高。使用选择性OT受体拮抗剂，我们证明这种升高的OT含量是在机械和热模式下施加强直性镇痛的原因。这种现象似乎是由OT受体介导的神经甾体生成刺激介导的，这导致GABA(A)受体介导的突触抑制在II层脊髓神经元中增加。我们还提供证据表明，这种由OT受体激活后的细胞外信号相关蛋白激酶ERK1/2可能控制了这种由OT介导的脊髓抗痛觉的新机制。脊髓疼痛加工的催产素抑制控制正在成为未来治疗的一个有趣的目标，因为它招募了几种分子机制，这些机制可能通过非基因组和可能的基因组效应发挥持久的镇痛作用。
Hypothalamospinal control of spinal pain processing by oxytocin (OT) has received a lot of attention in recent years because of its potency to reduce pain symptoms in inflammatory and neuropathic conditions. However, cellular and molecular mechanisms underlying OT spinal antinociception are still poorly understood. In this study, we used biochemical, electrophysiological, and behavioral approaches to demonstrate that OT levels are elevated in the spinal cord of rats exhibiting pain symptoms, 24 h after the induction of inflammation with an intraplantar injection of lambda-carrageenan. Using a selective OT receptor antagonist, we demonstrate that this elevated OT content is responsible for a tonic analgesia exerted on both mechanical and thermal modalities. This phenomenon appeared to be mediated by an OT receptor-mediated stimulation of neurosteroidogenesis, which leads to an increase in GABA(A) receptor-mediated synaptic inhibition in lamina II spinal cord neurons. We also provide evidence that this novel mechanism of OT-mediated spinal antinociception may be controlled by extracellular signal-related protein kinases, ERK1/2, after OT receptor activation. The oxytocinergic inhibitory control of spinal pain processing is emerging as an interesting target for future therapies since it recruits several molecular mechanisms, which are likely to exert a long-lasting analgesia through nongenomic and possibly genomic effects.