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<p>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 N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) 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.</p>

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SIGMAR1 Drives the Development of Neuropathic Pain by Promoting AMPA Receptor Membrane Trafficking Through Interacting with NPTX1 in Male Mice

  • 期刊论文

  • 发表日期：

    2025年12月29日

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  • Jie Ren,
  • Yasi Zheng,
  • Wu Yang,
  • Xueli Yin,
  • Guanxi Liu,
  • Ting Xu,
  • Jianbo Zhang,
  • Wenjun Xin,
  • Xueqin Zhang,
  • Suyan Lin

摘要

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.