Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue, Guangzhou, 510515, China.
Department of Anatomy, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
Mol Neurobiol. 2021 Mar;58(3):1185-1195. doi: 10.1007/s12035-020-02180-1. Epub 2020 Oct 25.
Leptin is an adipocytokine that is primarily secreted by white adipose tissue, and it contributes to the pathogenesis of neuropathic pain in collaboration with N-methyl-D-aspartate receptors (NMDARs). Functional NMDARs are a heteromeric complex that primarily comprise two NR1 subunits and two NR2 subunits. NR2A is preferentially located at synaptic sites, and NR2B is enriched at extrasynaptic sites. The roles of synaptic and extrasynaptic NMDARs in the contribution of leptin to neuropathic pain are not clear. The present study examined whether the important role of leptin in neuropathic pain was related to synaptic or extrasynaptic NMDARs. We used a rat model of spared nerve injury (SNI) and demonstrated that the intrathecal administration of the NR2A-selective antagonist NVP-AAM077 and the NR2B-selective antagonist Ro25-6981 prevented and reversed mechanical allodynia following SNI. Administration of exogenous leptin mimicked SNI-induced behavioral allodynia, which was also prevented by NVP-AAM077 and Ro25-6981. Mechanistic studies showed that leptin enhanced NR2B- but not NR2A-mediated currents in spinal lamina II neurons of naïve rats. Leptin also upregulated the expression of NR2B, which was blocked by the NR2B-selective antagonist Ro25-6981, in cultured dorsal root ganglion (DRG) neurons. Leptin enhanced neuronal nitric oxide synthase (nNOS) expression, which was also blocked by Ro25-6981, in cultured DRG cells. However, leptin did not change NR2A expression, and the NR2A-selective antagonist NVP-AAM077 had no effect on leptin-enhanced nNOS expression. Our data suggest an important cellular link between the spinal effects of leptin and the extrasynaptic NMDAR-nNOS-mediated cellular mechanism of neuropathic pain.
瘦素是一种主要由白色脂肪组织分泌的脂肪细胞因子，它与 N-甲基-D-天冬氨酸受体（NMDAR）协同作用，导致神经性疼痛的发病机制。功能性 NMDAR 是一种异源二聚体复合物，主要由两个 NR1 亚基和两个 NR2 亚基组成。NR2A 优先位于突触部位，NR2B 在突触外部位丰富。瘦素在神经性疼痛中的作用与突触和突触外 NMDAR 有关。本研究探讨了瘦素在神经性疼痛中的重要作用是否与突触或突触外 NMDAR 有关。我们使用 spared nerve injury（SNI）大鼠模型，证明鞘内给予 NR2A 选择性拮抗剂 NVP-AAM077 和 NR2B 选择性拮抗剂 Ro25-6981 可预防和逆转 SNI 后的机械性痛觉过敏。外源性瘦素模拟了 SNI 诱导的行为性痛觉过敏，这也被 NVP-AAM077 和 Ro25-6981 所阻止。机制研究表明，瘦素增强了 naïve 大鼠脊髓 lamina II 神经元中 NR2B 介导的电流，但不增强 NR2A 介导的电流。瘦素还上调了培养的背根神经节（DRG）神经元中 NR2B 的表达，这一过程被 NR2B 选择性拮抗剂 Ro25-6981 所阻断。瘦素增强了神经元型一氧化氮合酶（nNOS）的表达，这一过程也被 Ro25-6981 阻断，但瘦素不改变 NR2A 的表达，NR2A 选择性拮抗剂 NVP-AAM077 对瘦素增强 nNOS 表达没有影响。我们的数据表明，瘦素在脊髓中的作用与 NMDA 受体-nNOS 介导的神经性疼痛的细胞机制之间存在重要的细胞联系。
