Leptin Contributes to Neuropathic Pain via Extrasynaptic NMDAR-nNOS Activation
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Leptin Contributes to Neuropathic Pain via Extrasynaptic NMDAR-nNOS Activation Yanling Liang 1 & Yuxin Ma 2 & Jieqin Wang 3 & Lei Nie 4 & Xusheng Hou 5 & Wenyu Wu 6 & Xingmei Zhang 1 & Yinghong Tian 7 Received: 26 June 2020 / Accepted: 14 October 2020 # The Author(s) 2020
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. Keywords Neuropathic pain . Leptin . NMDAR . Synaptic . Extrasynaptic
Introduction Neuropathic pain resulting from injury of the peripheral or central nervous system has several clinical features, including hyperalgesia, allodynia, and spontaneous pain. N-Methyl-D-
aspartate receptors (NMDARs) play a crucial role in the mechanisms of peripheral and central sensitization of neuropathic pain [1–4]. There are three main families of NMDAR subunits: NR1, a family of NR2 subunits (NR2A, NR2B, NR2C and NR2D); and two NR3 subunits (NR3A and
Yanling Liang and Yuxin Ma contributed equally to this work. * Xingmei Zhang [email protected]
3
Department of Pancreatobiliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510515, China
4
Department of Anesthesiology, The Third Xiangya Hospital of Central South University, Changsha 410000, China
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,
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