Journal Article

Hydrogen Sulfide (H2S) Generated in the Colon Induces Neuropathic Pain by Activating Spinal NMDA Receptors in a Rodent Model of Chronic Constriction Injury

Wang, Jin-Liang, Miao, Hui-Tao, Zhang, Li-Min, Zhang, Yong-Bo, Su, Dong-Dong, Li, Bao-Dong, Zhang, Nan, Miao, Jun, Wang, Jun, Liu, Hong-Zheng

2025

Overview

Neuropathic pain (NP) imposes a significant burden on individuals, manifesting as nociceptive anaphylaxis, hypersensitivity, and spontaneous pain. Previous studies have shown that traumatic stress in the nervous system can lead to excessive production of hydrogen sulfide (H 2 S) in the gut. As a toxic gas, it can damage the nervous system through the gut-brain axis. However, whether traumatic stress in the nervous system leading to excessive production of H 2 S in the gut can ultimately cause neuropathic pain through the gut-brain axis remains to be investigated. This study established a model of chronic constriction injury (CCI) in mice to determine its effects on gut H 2 S production, the associated damage via the gut-brain axis, the potential neuropathic pain, as well as the probable mechanism. A CCI mouse model was developed using a spinal nerve ligation approach. Subsequently, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were used to determine the mice’s pain thresholds. A variety of assays were performed, including immunofluorescence, western blotting, real-time quantitative Polymerase Chain Reaction (PCR), and membrane clamp whole-cell recordings. Mice subjected to CCI showed decreased MWT and TWL, decreased ZO-1 staining, decreased HuD staining, increased Glial fibrillary acidic protein (GFAP) staining, increased expression of tumor necrosis factor-alpha (TNF-α) protein and interleukin-6 (IL-6) protein, increased expression of NMDAR2B (NR2B) protein and NR2B mRNA, increased colocalization of vGlut2- and c-fos-positive cells, and a higher amplitude of evoked excitatory postsynaptic potential (EPSP) compared to Sham group. These changes were significantly reversed by H 2 S inhibitor treatment, and the specific NMDA receptor inhibitor MK-801 effectively restored the neurotoxicity of H 2 S. H 2 S is involved in CCI-induced neuropathic pain in mice, which might be mediated by the activation of the NMDA signaling pathway.

• Publisher: Springer US,Springer Nature B.V
• Subject: Anaphylaxis / Animals / Biochemistry / Biomedical and Life Sciences / Biomedicine / Brain damage / c-Fos protein / Cell Biology / Chronic pain / Colon - metabolism / Constriction / Constrictions / Disease Models, Animal / Dizocilpine / Excitatory postsynaptic potentials / Gene expression / Glial fibrillary acidic protein / Glutamate receptors / Glutamic acid receptors (ionotropic) / Gut-brain axis / Hydrogen production / Hydrogen sulfide / Hydrogen Sulfide - metabolism / Hypersensitivity / Immunofluorescence / Inhibitors / Interleukin 6 / Latency / Male / Mice / Mice, Inbred C57BL / mRNA / N-Methyl-D-aspartic acid receptors / Nervous system / Neuralgia / Neuralgia - etiology / Neuralgia - metabolism / Neurochemistry / Neurology / Neurosciences / Neurotoxicity / Pain / Pain perception / Polymerase chain reaction / Proteins / Real time / Receptors / Receptors, N-Methyl-D-Aspartate - metabolism / Signal transduction / Spinal Cord - metabolism / Spinal nerves / Staining / Traumatic brain injury / Tumor necrosis factor-TNF / Tumor necrosis factor-α / Western blotting