Modulation of SUR1 KATP Channel Subunit Activity in the Peripheral Nervous System Reduces Mechanical Hyperalgesia after Nerve Injury in Mice
Modulation of SUR1 KATP Channel Subunit Activity in the Peripheral Nervous System Reduces Mechanical Hyperalgesia after Nerve Injury in Mice
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DOI：
10.3390/ijms20092251
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发表时间：
2019-05-01
影响因子：
5.6
通讯作者：
Klein, Amanda H.
中科院分区：
文献类型：
--
作者：
Luu, Wing;Bjork, James;Klein, Amanda H.
ATP 敏感 K+ 通道 (K-ATP) 与慢性疼痛期间的超敏反应有关，并且被认为是 mu 阿片受体的下游靶标。 K-ATP 通道的多种亚型存在于外周和中枢神经系统中，它们的活性可能与啮齿类动物的慢性疼痛表型呈负相关。在这项研究中，我们研究了可能与小鼠神经性疼痛有关的不同 K-ATP 通道亚基。在利用脊神经结扎的慢性疼痛模型中，发现背根神经节和脊髓中的 SUR1 和 Kir6.2 亚基显着下调。局部或鞘内给予 SUR1-K-ATP 通道亚型激动剂可在脊神经结扎后产生镇痛作用，但 SUR2 激动剂则无镇痛作用。在离体神经记录中，对周围神经末梢施用 SUR1 激动剂二氮嗪可降低机械诱发电位。与对照小鼠相比，通过相关腺病毒策略对 SUR1 进行基因敲除会导致机械痛觉过敏，但不会导致热痛觉过敏。来自神经性小鼠的行为数据表明，SUR1 亚型 K-ATP 通道活性的局部减少会加剧神经性疼痛症状。由于神经性疼痛具有重要的临床意义，因此钾通道成为镇痛治疗的靶点，特别是因为它们在伤害感受器中表达，并且在调节参与疼痛传递的神经元的兴奋性方面可能发挥重要作用。
The ATP-sensitive K+ channel (K-ATP) is involved in hypersensitivity during chronic pain and is presumed to be a downstream target of mu opioid receptors. Multiple subtypes of K-ATP channels exist in the peripheral and central nervous system and their activity may be inversely correlated to chronic pain phenotypes in rodents. In this study, we investigated the different K-ATP channel subunits that could be involved in neuropathic pain in mice. In chronic pain models utilizing spinal nerve ligation, SUR1 and Kir6.2 subunits were found to be significantly downregulated in dorsal root ganglia and the spinal cord. Local or intrathecal administration of SUR1-K-ATP channel subtype agonists resulted in analgesia after spinal nerve ligation but not SUR2 agonists. In ex-vivo nerve recordings, administration of the SUR1 agonist diazoxide to peripheral nerve terminals decreased mechanically evoked potentials. Genetic knockdown of SUR1 through an associated adenoviral strategy resulted in mechanical hyperalgesia but not thermal hyperalgesia compared to control mice. Behavioral data from neuropathic mice indicate that local reductions in SUR1-subtype K-ATP channel activity can exacerbate neuropathic pain symptoms. Since neuropathic pain is of major clinical relevance, potassium channels present a target for analgesic therapies, especially since they are expressed in nociceptors and could play an essential role in regulating the excitability of neurons involved in pain-transmission.