S1P receptor 1 antagonist ponesimod alleviates postherpetic neuralgia in rats by normalizing spinal TRPV1 expression and inhibiting MAPK-mediated glial activation.

Postherpetic neuralgia (PHN) remains a clinically challenging neuropathic pain condition with limited treatment efficacy. This study investigated whether the S1PR1 modulator ponesimod alleviates PHN-like symptoms in a resiniferatoxin (RTX)-induced rat model and examined its mechanism of action. Rats with RTX-induced PHN received ponesimod (30 mg/kg) for 14 days, with subsets co-administered capsaicin (TRPV1 agonist) or AMG9810 (TRPV1 antagonist). Behavioral tests (mechanical allodynia, thermal hyperalgesia), spinal cord immunofluorescence (TRPV1, Iba-1, GFAP), cytokine ELISAs (TNF-α, IL-1β, IL-6), and Western blot (p38/JNK/ERK phosphorylation) were performed. Behavioral assessments revealed ponesimod significantly reversed both mechanical allodynia and thermal hyperalgesia compared to vehicle-treated controls, though not to baseline levels. Molecular analyses demonstrated ponesimod normalized spinal TRPV1 overexpression, suppressed glial activation, reduced proinflammatory cytokines (IL-1β, TNF-α, IL-6), and inhibited MAPK phosphorylation. Critically, TRPV1 agonist capsaicin co-administration abolished ponesimod's therapeutic effects by restoring pain behaviors, neuroinflammation, and p38 phosphorylation, while TRPV1 antagonist AMG9810 enhanced analgesic efficacy. These findings establish the efficacy of ponesimod against PHN-like pathology through S1PR1-mediated regulation of both neuroinflammation and TRPV1 expression, with TRPV1-p38 signaling serving as the key mechanistic axis for its therapeutic actions. Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-025-00806-7.