Ginger Root Extract Mitigates Neuropathic Pain via Suppressing Neuroinflammation: Gut-Brain Connection

OBJECTIVES: Emerging evidence suggests an important role of the gut-brain-axis in the development of neuropathic pain (NP). We investigated the effects of gingerol-enriched ginger (GEG) on pain sensitivity and mRNA expression of inflammation and tight junction protein in GI tissues (colon and ileum) and nervous tissues (amygdala and spinal cord) of animals with NP. METHODS: Twenty-eight male rats were randomly divided into 5 groups: Naïve control, sham control, spinal nerve ligation (SNL, pain model), SNL + 0.375% (w/w in diet) GEG, and SNL + 0.75% (w/w in diet) GEG for 4 weeks. Pain sensitivity was assessed by von Frey filament tests, evoked audible vocalizations, and grimace tests in subjects. Intestinal permeability was assessed by lactulose/mannitol ratio in urine. The levels of mRNA expression of neuroinflammation (NF-κB) and tight junction (Claudin-1, Zonulin) in colon, ileum, amygdala, and spinal cord were determined by qRT-PCR. Data was analyzed by one-way ANOVA or one-way repeated measures ANOVA followed by post-hoc analysis. RESULTS: Compared to the sham group, the SNL group had significantly greater hypersensitivity (von Frey test), emotional responses (vocalizations), and spontaneous pain (grimace test). GEG supplementation significantly reduced hypersensitivity, emotional responses, and spontaneous pain (nose bulge, whisker change, and ear position) in SNL rats. GEG supplementation tended to decrease intestinal permeability of SNL-operated rats. The SNL group showed a significant increase in mRNA expression of Zonulin in amygdala and Claudin-1 in colon compared to the sham control group. GEG supplementation significantly suppressed the gene expression levels of Zonulin and Claudin-1 in amygdala and colon of SNL animals. GEG addition into the diet suppressed NF-κB gene expression in the amygdala, colon, and ileum of SNL rats. CONCLUSIONS: This study suggests GEG supplementation mitigated pain behaviors in a preclinical NP animal model. GEG also decreased SNL-induced neuroinflammation, intestinal permeability, and possible blood-brain barrier breakdown, which may explain the behavioral effects of GEG. FUNDING SOURCES: USDA-NIFA 2021-67,017-34,026.