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

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 (HS) 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 HS 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 HS 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 HS inhibitor treatment, and the specific NMDA receptor inhibitor MK-801 effectively restored the neurotoxicity of HS. HS is involved in CCI-induced neuropathic pain in mice, which might be mediated by the activation of the NMDA signaling pathway.