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. 2024 Feb 7;51(1):281.
doi: 10.1007/s11033-023-09183-w.

Neuropathic pain development following nerve injury is mediated by SOX11-ARID1A-SOCS3 transcriptional regulation in the spinal cord

Dongsheng Le #  1 , Chao Zhang #  1 , Li Liu  1 , Mailin Zhao  1 , Yingping Liang  1 , Pingsheng Liao  1 , Fan Yang  2
Affiliations

Neuropathic pain development following nerve injury is mediated by SOX11-ARID1A-SOCS3 transcriptional regulation in the spinal cord

Dongsheng Le et al. Mol Biol Rep. .

Abstract

Background: Neuropathic pain, a complex condition originating from nervous system damage, remains a significant clinical challenge due to limited understanding of its underlying mechanisms. Recent research highlights the SOX11 transcription factor, known for its role in nervous system development, as a crucial player in neuropathic pain development and maintenance. This study investigates the role of the SOX11-ARID1A-SOCS3 pathway in neuropathic pain modulation within the spinal cord.

Methods and results: Using a spinal nerve ligation (SNL) model in mice, we observed a significant upregulation of Sox11 in the spinal cord dorsal horn post-injury. Intrathecal administration of Sox11 shRNA mitigated SNL-induced neuropathic pain behaviors, including mechanical allodynia and heat hyperalgesia. Further, we demonstrated that Sox11 regulates neuropathic pain via transcriptional control of ARID1A, with subsequent modulation of SOCS3 expression. Knockdown of ARID1A and SOCS3 via shRNA resulted in alleviation of Sox11-induced pain sensitization. Additionally, Sox11 overexpression led to an increase in ARID1A binding to the SOCS3 promoter, enhancing chromatin accessibility and indicating a direct regulatory relationship. These findings were further supported by in vitro luciferase reporter assays and chromatin accessibility analysis.

Conclusions: The SOX11-ARID1A-SOCS3 pathway plays a pivotal role in the development and maintenance of neuropathic pain. Sox11 acts as a master regulator, modulating ARID1A, which in turn influences SOCS3 expression, thereby contributing to the modulation of neuropathic pain. These findings provide a deeper understanding of the molecular mechanisms underlying neuropathic pain and highlight potential therapeutic targets for its treatment. The differential regulation of this pathway in the spinal cord and dorsal root ganglia (DRG) underscores its complexity and the need for targeted therapeutic strategies.

Keywords: ARID1A; Neuropathic pain; SOCS3; Sox11; Spinal dorsal horn.

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