SIGMAR1 Drives the Development of Neuropathic Pain by Promoting AMPA Receptor Membrane Trafficking Through...

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.