Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours.
Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours.
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DOI：
10.1038/s41598-017-04972-3
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发表时间：
2017-07-05
影响因子：
4.6
通讯作者：
Tsuda M
中科院分区：
文献类型：
--
作者：
Koga K;Kanehisa K;Kohro Y;Shiratori-Hayashi M;Tozaki-Saitoh H;Inoue K;Furue H;Tsuda M
脊髓背角（SDH）的抑制性中间神经元对于处理源自外周的体感觉信息至关重要。然而，gaba能SDH中间神经元的急性和选择性失活对疼痛加工的影响尚不完全清楚。在这项研究中，我们使用设计药物（DREADD）技术激活的设计受体和囊状GABA转运体- cre （Vgat-Cre）小鼠，在第四腰椎节段Vgat-Cre + GABAergic SDH中间神经元中选择性表达修饰的人毒碱性Gi蛋白偶联受体（hM4Di）。我们发现氯氮平- n -氧化物（CNO）处理迅速使这些神经元超极化，并在这些小鼠中诱导自发的有害行为。在vgate - cre负层II神经元中，CNO可促进A纤维介导的多突触兴奋反应，这一作用需要n -甲基- d -天冬氨酸（NMDA）受体激活。NMDA受体拮抗剂也能降低cno诱导的攻击性行为。此外，这些攻击性行为被普瑞巴林抑制，但对吗啡有抗性。我们的研究结果表明，Vgat-Cre + SDH中间神经元在吗啡抵抗性伤害行为中发挥重要作用，并表明这种方法可能为理解阿片类药物抵抗性疼痛信号传导机制和开发新型镇痛药提供有用的模型。
Inhibitory interneurons in the spinal dorsal horn (SDH) are crucial for processing somatosensory information originating in the periphery. However, the effects of the acute and selective inactivation of GABAergic SDH interneurons on pain processing are not fully understood. In this study, we used designer receptors exclusively activated by designer drugs (DREADD) technology and vesicular GABA transporter-Cre (Vgat-Cre) mice to selectively express a modified human muscarinic Gi protein-coupled receptor (hM4Di) in Vgat-Cre + GABAergic SDH interneurons in the fourth lumbar segment. We found that clozapine-N-oxide (CNO) treatment rapidly hyperpolarized these neurons and induced spontaneous nocifensive behaviours in these mice. In Vgat-Cre neg lamina II neurons, CNO produced facilitation of A fibre-mediated polysynaptic excitatory responses, an effect that required N-methyl-D-aspartate (NMDA) receptor activation. The CNO-induced nocifensive behaviours were also reduced by NMDA receptor antagonism. Moreover, these nocifensive behaviours were suppressed by pregabalin but resistant to morphine. Our findings indicate that Vgat-Cre + SDH interneurons play an important role in morphine-resistant nocifensive behaviours and suggest that this approach may provide a useful model for understanding the mechanisms of opioid-resistant pain signalling and for developing novel analgesics.