Leptin Contributes to Neuropathic Pain via Extrasynaptic NMDAR-nNOS Activation

Yanling Liang,Wenyu Wu,Lei Nie,Lei Nie,Xingmei Zhang,Jieqin Wang,Jieqin Wang,Yinghong Tian,Xusheng Hou,Xusheng Hou,Yuxin Ma

doi:10.1007/s12035-020-02180-1

Abstract

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.

Highlights

Neuropathic pain resulting from injury of the peripheral or central nervous system has several clinical features, including hyperalgesia, allodynia, and spontaneous pain
The present study further examined whether leptin contributed to the pathogenesis of neuropathic pain by acting on synaptic or extrasynaptic N-methyl-D-aspartate receptors (NMDARs)
The present study demonstrated the following results: (1) the intrathecal administration of the NR2A-selective antagonist NVP-AAM077 and the NR2B-selective antagonist Ro256981 prevented and reversed spared nerve injury (SNI)-induced allodynia; (2) administration of exogenous leptin mimicked SNI-induced allodynia, which was prevented by NR2A and NR2B antagonists; (3) leptin enhanced spinal NR2B- but not NR2A-mediated currents in naïve lamina II neurons; and (4) leptin upregulated the expression of NR2B, but not NR2A, and neuronal nitric oxide synthase (nNOS) in cultured dorsal root ganglion (DRG) cells, which were blocked by the NR2B antagonist Ro25-6981

Summary

Introduction

Neuropathic pain resulting from injury of the peripheral or central nervous system has several clinical features, including hyperalgesia, allodynia, and spontaneous pain. Aspartate receptors (NMDARs) play a crucial role in the mechanisms of peripheral and central sensitization of neuropathic pain [1,2,3,4]. There are three main families of NMDAR subunits: NR1, a family of NR2 subunits (NR2A, NR2B, NR2C and NR2D); and two NR3 subunits Synaptic and extrasynaptic NMDARs comprise different subtypes. NR2A predominates at synaptic sites, and NR2B is mostly expressed at extrasynaptic sites in mature neurons in the hippocampus and cortex [5, 6], the spinal dorsal horn and dorsal root ganglion (DRG) [7,8,9,10]. NR2D is expressed to a lesser extent at extrasynaptic sites in the spinal dorsal horn [9]. NR2C is enriched in the cerebellum and rarely expressed in other brain regions [11, 12]

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