Department of Neurology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China.
Neurosci Bull. 2019 Apr;35(2):301-314. doi: 10.1007/s12264-018-0285-8. Epub 2018 Sep 11.
Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brush-evoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1 (Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury (SNI). Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in naïve but also in ML133-pretreated mice. In contrast, bicuculline, a GABA receptor antagonist, induced only punctate, but not dynamic, allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents (gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration or acute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively. In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.
神经病理性疼痛是一种以自发性疼痛和机械性痛觉过敏为特征的慢性衰弱性症状。它以不同的形式出现，包括毛刷诱发的动态和纤维诱发的点状机械性痛觉过敏。钾通道 2.1（Kir2.1）表现出强烈的内向整流，调节 I 层投射神经元的活性。然而，Kir2.1 通道与机械性痛觉过敏之间的关系仍不清楚。在这项研究中，我们首先发现鞘内给予选择性 Kir2.1 抑制剂 ML133 预处理，可优先抑制 spared nerve injury（SNI）小鼠的动态性，但不影响点状机械性痛觉过敏。鞘内注射低剂量的 strychnine，一种甘氨酸受体抑制剂，选择性地诱导动态性，但不诱导点状机械性痛觉过敏，不仅在未处理的小鼠中，而且在 ML133 预处理的小鼠中也是如此。相比之下，bicuculline，一种 GABA 受体拮抗剂，只诱导点状机械性痛觉过敏，而不诱导动态性机械性痛觉过敏。这些结果表明甘氨酸能传递参与了动态性机械性痛觉过敏的发展。我们进一步发现，SNI 显著抑制了脊髓背角 II-III 层边界神经元的甘氨酸能自发性抑制性突触后电流（gly-sIPSCs）的频率，但不影响其幅度，而 ML133 预处理可防止 SNI 诱导的 gly-sIPSC 减少。此外，SNI 后 5 天，鞘内给予 ML133 或急性浴灌流以及 strychnine 均可分别敏感地逆转 SNI 诱导的动态性，但不引起点状机械性痛觉过敏，以及 lamina IIi 神经元中的 gly-sIPSC 减少。综上所述，我们的研究结果表明，脊髓背角 Kir2.1 通道的阻断通过增强甘氨酸能抑制性传递选择性地抑制动态性，但不抑制点状机械性痛觉过敏。
