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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Microglial Ca(2+)-activated K(+) channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain.
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Microglial Ca(2+)-activated K(+) channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain.

机译：小胶质细胞Ca（2+）激活的K（+）通道是S-氯胺酮对神经性疼痛的镇痛作用的可能分子靶标。

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Ketamine is an important analgesia clinically used for both acute and chronic pain. The acute analgesic effects of ketamine are generally believed to be mediated by the inhibition of NMDA receptors in nociceptive neurons. However, the inhibition of neuronal NMDA receptors cannot fully account for its potent analgesic effects on chronic pain because there is a significant discrepancy between their potencies. The possible effect of ketamine on spinal microglia was first examined because hyperactivation of spinal microglia after nerve injury contributes to neuropathic pain. Optically pure S-ketamine preferentially suppressed the nerve injury-induced development of tactile allodynia and hyperactivation of spinal microglia. S-Ketamine also preferentially inhibited hyperactivation of cultured microglia after treatment with lipopolysaccharide, ATP, or lysophosphatidic acid. We next focused our attention on the Ca(2+)-activated K(+) (K(Ca)) currents in microglia, which are known to induce their hyperactivation and migration. S-Ketamine suppressed both nerve injury-induced large-conductance K(Ca) (BK) currents and 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzim idazol-2-one (NS1619)-induced BK currents in spinal microglia. Furthermore, the intrathecal administration of charybdotoxin, a K(Ca) channel blocker, significantly inhibited the nerve injury-induced tactile allodynia, the expression of P2X(4) receptors, and the synthesis of brain-derived neurotrophic factor in spinal microglia. In contrast, NS1619-induced tactile allodynia was completely inhibited by S-ketamine. These observations strongly suggest that S-ketamine preferentially suppresses the nerve injury-induced hyperactivation and migration of spinal microglia through the blockade of BK channels. Therefore, the preferential inhibition of microglial BK channels in addition to neuronal NMDA receptors may account for the preferential and potent analgesic effects of S-ketamine on neuropathic pain.
机译：氯胺酮是临床上用于急性和慢性疼痛的重要镇痛药。一般认为，氯胺酮的急性镇痛作用是通过抑制伤害性神经元中的NMDA受体介导的。但是，神经元NMDA受体的抑制不能完全说明其对慢性疼痛的有效止痛作用，因为它们的效力之间存在显着差异。首先检查了氯胺酮对脊髓小胶质细胞的可能作用，因为神经损伤后脊髓小胶质细胞的过度活化会导致神经性疼痛。光学纯的S-氯胺酮可优先抑制神经损伤引起的触觉异常性疼痛的发展和脊髓小胶质细胞的过度活化。在用脂多糖，ATP或溶血磷脂酸处理后，S-氯胺酮还优先抑制培养的小胶质细胞的过度活化。接下来，我们将注意力集中在小胶质细胞中的Ca（2+）活化K（+）（K（Ca））电流上，已知该电流会诱导它们的过度活化和迁移。 S-氯胺酮抑制神经损伤引起的大电势K（Ca）（BK）电流和1,3-二氢-1- [2-羟基-5-（三氟甲基）苯基] -5-（三氟甲基）-2H-苯并咪唑-2-酮（NS1619）诱导的脊髓小胶质细胞BK电流。此外，鞘内注射Charybdotoxin（一种K（Ca）通道阻滞剂）可显着抑制神经损伤引起的触觉异常性疼痛，P2X（4）受体的表达以及脊髓小胶质细胞中脑源性神经营养因子的合成。相反，S-氯胺酮可完全抑制NS1619引起的触觉异常性疼痛。这些观察结果强烈表明，S-氯胺酮通过抑制BK通道来优先抑制神经损伤引起的脊髓小胶质细胞过度活化和迁移。因此，除神经元NMDA受体外，对小胶质BK通道的优先抑制作用可解释S-氯胺酮对神经性疼痛的优先和有效镇痛作用。

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