Veratramine Alleviates Neuropathic Pain in Male Rats With Chronic Constriction Injury and Inhibits the PI3K/Akt Pathway.

BACKGROUND

Neuropathic pain (NP), a debilitating complication of chronic diseases such as diabetes and cancer, remains inadequately managed by current therapies; approximately 30% of patients are unresponsive to monotherapy. This study investigates the effects and potential mechanisms of veratramine, a natural compound, in a rodent model of chronic constriction injury (CCI)-induced neuropathic pain.

METHODS

NP was induced via CCI in rodents. Veratramine's effects were assessed through behavioural tests (mechanical withdrawal threshold [MWT] and thermal withdrawal latency [TWL]). Apoptosis and inflammation in the sciatic nerve were analysed. Western blotting and immunofluorescence evaluated phosphorylation of NF-κB, IκB, p38 MAPK, and spinal glial activation. Transcriptome profiling identified key pathways, validated using the PI3K/Akt agonist 740 Y-P.

RESULTS

Veratramine significantly increased MWT and TWL, alleviating mechanical and thermal hypersensitivity. It reduced neuronal apoptosis and inflammatory cytokine release at injury sites. Protein analysis showed suppressed phosphorylation of NF-κB, IκB, and p38 MAPK, alongside reduced numbers of Iba-1-positive and GFAP-positive cells in the spinal dorsal horn. Transcriptome data implicated PI3K/Akt signalling pathway inhibition, confirmed by 740 Y-P co-treatment reversing veratramine's anti-inflammatory and analgesic effects.

CONCLUSION

These findings indicate that veratramine attenuates neuropathic pain in CCI rats, and its effects may involve inhibition of the PI3K/Akt signalling pathway, leading to reduced neuroinflammation and apoptosis. This study supports a role for veratramine in the modulation of neuropathic pain and highlights the PI3K/Akt pathway as a potential target for further investigation.

SIGNIFICANCE STATEMENT: The results of this study suggest that veratramine alleviates neuropathic pain in a rat model of CCI, and this effect is associated with suppression of the PI3K/Akt signalling pathway. These findings support a role for veratramine in modulating neuroinflammation and apoptosis, and may contribute to a better understanding of the molecular mechanisms involved in neuropathic pain.