Ouyang Junlin, Chen Xiaping, Su Shanchun, Li Xiaohui, Xu Xueqin, Yu Xinhua, Ke Changbin, Zhu Xiaohu
Department of Orthopedic Rehabilitation, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
Department of Scientific Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
Front Mol Neurosci. 2021 Feb 25;14:640533. doi: 10.3389/fnmol.2021.640533. eCollection 2021.
Neuropathic pain is a kind of chronic pain that remains difficult to treat due to its complicated underlying mechanisms. Accumulating evidence has indicated that enhanced synaptic plasticity of nociceptive interneurons in the superficial spinal dorsal horn contributes to the development of neuropathic pain. Neuroligin1 (NL1) is a type of excitatory postsynaptic adhesion molecule, which can mediate excitatory synaptic activity, hence promoting neuronal activation. Vglut2 is the most common marker of excitatory glutamatergic neurons. To explore the role of NL1 in excitatory neurons in nociceptive regulation, we used transgenic mice with cre recombinase expression driven by the Vglut2 promoter combined with viral vectors to knockdown the expression of NL1 in excitatory neurons in the spinal dorsal horn. We found that NL1 was upregulated in the L4-L6 spinal dorsal horn in Vglut2-cre mouse subjected to spared nerve injury (SNI). Meanwhile, the expression of phosphorylated cofilin (p-cofilin) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1 (GluR1) was also increased. Spinal microinjection of a cre-dependent NL1-targeting RNAi in Vglut2-cre mouse alleviated the neuropathic pain-induced mechanical hypersensitivity and reduced the increase in p-cofilin and GluR1 caused by SNI. Taken together, NL1 in excitatory neurons regulates neuropathic pain by promoting the SNI-dependent increase in p-cofilin and GluR1 in the spinal dorsal horn. Our study provides a better understanding of the role of NL1 in excitatory neurons, which might represent a possible therapeutic target for alleviating neuropathic pain.
神经性疼痛是一种慢性疼痛，由于其复杂的潜在机制，治疗起来仍然很困难。越来越多的证据表明，脊髓背角浅层伤害性中间神经元的突触可塑性增强有助于神经性疼痛的发展。神经连接蛋白1（NL1）是一种兴奋性突触后粘附分子，可介导兴奋性突触活动，从而促进神经元激活。Vglut2是兴奋性谷氨酸能神经元最常见的标志物。为了探究NL1在伤害性调节的兴奋性神经元中的作用，我们使用了由Vglut2启动子驱动cre重组酶表达的转基因小鼠，并结合病毒载体来敲低脊髓背角兴奋性神经元中NL1的表达。我们发现，在遭受 spared nerve injury（SNI）的Vglut2-cre小鼠的L4-L6脊髓背角中，NL1上调。同时，磷酸化丝切蛋白（p-丝切蛋白）和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体亚基1（GluR1）的表达也增加。在Vglut2-cre小鼠中脊髓微量注射cre依赖性靶向NL1的RNAi可减轻神经性疼痛诱导的机械性超敏反应，并减少SNI引起的p-丝切蛋白和GluR1的增加。综上所述，兴奋性神经元中的NL1通过促进脊髓背角中SNI依赖性的p-丝切蛋白和GluR1增加来调节神经性疼痛。我们的研究更好地理解了NL1在兴奋性神经元中的作用，这可能代表了一种减轻神经性疼痛的潜在治疗靶点。
