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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >α2δ-1 gene deletion affects somatosensory neuron function and delays mechanical hypersensitivity in response to peripheral nerve damage
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α2δ-1 gene deletion affects somatosensory neuron function and delays mechanical hypersensitivity in response to peripheral nerve damage

机译：α2δ-1基因缺失影响躯体感觉神经元功能并延迟对周围神经损伤的反应引起的机械性超敏反应

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摘要

The α2δ-1 subunit of voltage-gated calcium channels is upregulated after sensory nerve injury and is also the therapeutic target of gabapentinoid drugs. It is therefore likely to play a key role in the development of neuropathic pain. In this study, we have examined mice in which α2δ-1 gene expression is disrupted, to determine whether α2δ-1 is involved in various modalities of nociception, and for the development of behavioral hypersensitivity after partial sciatic nerve ligation (PSNL). We find that naive α2δ-1-/- mice show a marked behavioral deficit in mechanical and cold sensitivity, but no change in thermal nociception threshold. The lower mechanical sensitivity is mirrored by a reduced in vivo electrophysiological response of dorsal horn wide dynamic range neurons. The CaV2.2 level is reduced in brain and spinal cord synaptosomes from α2δ-1-/- mice, and α2δ-1-/- DRG neurons exhibit lower calcium channel current density. Furthermore, a significantly smaller number of DRG neurons respond to the TRPM8 agonist menthol. After PSNL, α2δ-1-/- mice show delayed mechanical hypersensitivity, which only develops at 11 d after surgery, whereas in wild-type littermates it is maximal at the earliest time point measured (3 d). There is no compensatory upregulation of α2δ-2 or α2δ-3 after PSNL in α2δ-1-/- mice, and other transcripts, including neuropeptide Y and activating transcription factor-3, are upregulated normally. Furthermore, the ability of pregabalin to alleviate mechanical hypersensitivity is lost in PSNL α2δ-1-/- mice. Thus, α2δ-1 is essential for rapid development of mechanical hypersensitivity in a nerve injury model of neuropathic pain.
机译：电压门控性钙通道的α2δ-1亚基在感觉神经损伤后被上调，也是加巴喷丁类药物的治疗靶点。因此，它可能在神经性疼痛的发展中起关键作用。在这项研究中，我们检查了其中α2δ-1基因表达被破坏的小鼠，以确定α2δ-1是否参与了各种伤害性感受方式以及部分坐骨神经结扎（PSNL）后行为超敏反应的发展。我们发现，幼稚的α2δ-1-/-小鼠在机械和冷敏性方面表现出明显的行为缺陷，但在热伤害感受阈值方面没有变化。较低的机械敏感性反映在背角宽动态范围神经元的体内电生理反应降低。在来自α2δ-1-/-小鼠的脑和脊髓突触小体中，CaV2.2水平降低，并且α2δ-1-/-DRG神经元显示出较低的钙通道电流密度。此外，显着较少的DRG神经元对TRPM8激动剂薄荷醇有反应。 PSNL后，α2δ-1-/-小鼠表现出延迟的机械性超敏反应，仅在手术后11 d出现，而在野生型同窝小鼠中，其最早出现的时间点是最大的（3 d）。在α2δ-1-/-小鼠中PSNL后，α2δ-2或α2δ-3没有补偿性上调，并且其他转录物，包括神经肽Y和活化转录因子-3，也正常上调。此外，在PSNLα2δ-1-/-小鼠中普瑞巴林减轻机械超敏反应的能力丧失。因此，α2δ-1对于神经性疼痛的神经损伤模型中机械性超敏反应的快速发展必不可少。

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