2. Academic Validation
  3. Microglial-derived nitric oxide regulates amygdala synaptic plasticity to drive chronic pain and depression induced by lumbar disc herniation

Microglial-derived nitric oxide regulates amygdala synaptic plasticity to drive chronic pain and depression induced by lumbar disc herniation

  • Neuropharmacology. 2025 Aug 29:280:110662. doi: 10.1016/j.neuropharm.2025.110662.
Zhenyu Huang 1,  Jiawen Sun 2,  Haokang Li 3,  Zhuang Hu 4,  Haibo Tan 5,  Yuanfei Fu 6,  Linchao Gao 7,  Xin Peng 8,  Hongkan Lou 9
Affiliations

Affiliations

  • 1 Ningbo Municipal Hospital of Traditional Chinese Medicine, Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, 315010, China. Electronic address: 2025N022@zcmu.edu.cn.
  • 2 Ningbo Municipal Hospital of Traditional Chinese Medicine, Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, 315010, China. Electronic address: sunjiawen2001@163.com.
  • 3 The fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China. Electronic address: kangkangsleep@outlook.com.
  • 4 Ningbo Municipal Hospital of Traditional Chinese Medicine, Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, 315010, China. Electronic address: zhuanghu@whu.edu.cn.
  • 5 The fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China. Electronic address: thb13265042784@163.com.
  • 6 Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China. Electronic address: yuanfay29@163.com.
  • 7 Ningbo Municipal Hospital of Traditional Chinese Medicine, Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, 315010, China. Electronic address: 28583800@qq.com.
  • 8 Ningbo Municipal Hospital of Traditional Chinese Medicine, Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, 315010, China. Electronic address: pengx@nit.zju.edu.cn.
  • 9 Ningbo Municipal Hospital of Traditional Chinese Medicine, Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, 315010, China. Electronic address: 2024N305@zcmu.edu.cn.
PMID: 40887007 DOI: 10.1016/j.neuropharm.2025.110662
Abstract

Lumbar disc herniation (LDH) is a major driver of chronic low back pain often accompanied by depression-like behaviors, yet the supraspinal mechanisms that link nociception to affective disturbance remain unclear. Here, we investigated the potential mechanisms by which microglia-derived nitric oxide (NO) modulates synaptic plasticity in the amygdala of a rat model of LDH. Behavioral assessments confirmed the presence of mechanical hyperalgesia and depression-like behaviors in LDH rats. Multi-omics profiling revealed increased L-arginine in CSF and enrichment of cGMP-PKG and glutamatergic, long-term potentiation pathways in the amygdala. Protein-level validation confirmed upregulation of iNOS, NO, cGMP, and PRKG2 in the amygdala. Concurrently, increased levels of IL-1β and TNF-α in both the amygdala and CSF, along with Iba1 and iNOS co-localization in microglia, confirmed a neuroinflammatory microenvironment. Enhanced expression of GRIA1, p-GRIA1, GRIN2B, and p-CaMKII indicated potentiation of excitatory synaptic transmission in the amygdala. In a microglia-neuron co-culture system, conditioned medium from CSF-activated BV2 cells upregulated PRKG2, cGMP, and synaptic plasticity markers in PC12 cells. These effects were abolished by the iNOS Inhibitor 1400W and mimicked by the NO donor DETA-NONOate, confirming a mechanistic link between microglial NO and neuronal plasticity. These findings suggested that LDH-induced neuroinflammation activates microglial iNOS in the amygdala, leading to NO elevations that engage the cGMP/PRKG2 pathway and drive pathological excitatory synaptic plasticity. Targeting this neuroimmune pathway may offer novel therapeutic strategies for chronic pain and related depression induced by LDH.

Keywords

Amygdala; Chronic pain; Depression; Lumbar disc herniation; Microglia; Synaptic plasticity.

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