SIGMAR1 Drives the Development of Neuropathic Pain by Promoting AMPA Receptor Membrane Trafficking Through Interacting with NPTX1 in Male Mice
Jie Ren1 · Yasi Zheng2 · Wu Yang1 · Xueli Yin1 · Guanxi Liu1 · Ting Xu3,4 · Jianbo Zhang5 · Wenjun Xin3,4 · Xueqin Zhang1,6 · Suyan Lin7
1 The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510182, China
2 Department of Anesthesiology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
3 Neuroscience Program of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
4 Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-sen University, Guangzhou 510120, China
5 Department of Pain Medicine, The Peking University Shenzhen Hospital, Shenzhen 518036, China
6 School of Health Management, Guangzhou Medical University, Guangzhou 510182, China
7 Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
Abstract
Early intervention in neuropathic pain can effectively delay its chronicity. Sigma non-opioid intracellular receptor 1 (SIGMAR1) is upregulated in the spinal dorsal horn during the development of spared nerve injury (SNI)-induced neuropathic pain. Methylated RNA immunoprecipitation confirmed that the SIGMAR1 upregulation was driven by mRNA N6-methyladenosine (m6A) modification. Intrathecal injection of the SIGMAR1 antagonist or siRNA effectively alleviated mechanical allodynia during the development of neuropathic pain. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and co-immunoprecipitation experiments revealed that SIGMAR1 directly binds to neuronal pentraxin-1 (NPTX1), promoting its ubiquitin-proteasome degradation. Intraspinal injection of adeno-associated virus (AAV) to specifically overexpress NPTX1 in neurons alleviates SNI-induced neuropathic pain, whereas NPTX1 knockdown reduces the mechanical pain threshold in naive male mice. Furthermore, bioinformatics predicts that NPTX1 binds the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR). Downregulation of NPTX1 promoted AMPAR membrane trafficking and central sensitization. Collectively, SIGMAR1, a potential therapeutic target for early-stage neuropathic pain, promotes AMPAR-mediated hyperexcitability of nociceptive neurons through interacting with NPTX1 in male mice.
Keywords
Neuropathic pain; Spinal dorsal horn; SIGMAR1; GluA1; NPTX1
