Pharmacological Modulation of the Kynurenine Pathway Using PF-04859989 Modulates PACAP Signaling in Migraine-Relevant Trigeminal Sensitization

Background: Migraine is a disabling neurological disorder in which neuropeptides, particularly pituitary adenylate cyclase-activating polypeptide (PACAP), play pathogenic roles. The kynurenine pathway (KP) is increasingly implicated in migraine-related glutamatergic and neuroinflammatory mechanisms. Previously, we showed that the neuroprotective metabolite kynurenic acid attenuates PACAP overexpression following trigeminovascular activation. This study investigated the effects of kynurenine aminotransferase II (KAT-II) inhibition on PACAP expression and KP metabolites during trigeminal sensitization. Methods: Rats received Complete Freund’s Adjuvant (CFA) or saline injection into the right whisker pad. KAT-II inhibitor PF-04859989 (16 and 32 mg/kg) or saline was administered intraperitoneally 72 h later. Blood samples and nucleus trigeminus caudalis (TNC) were collected for PACAP and KP quantification. Results: CFA treatment induced significant PACAP overexpression in the TNC and altered peripheral KP metabolite levels. PF-04859989 further increased PACAP expression, reaching significance at the 16 mg/kg dose, whereas no significant additional effect was observed at 32 mg/kg. In parallel, treatment with PF-04859989 altered peripheral KP metabolite concentrations in the peripheral inflammatory model, predominantly at the lower dose. Conclusions: This study demonstrates that KAT-II inhibition by PF-04859989 modulates PACAP signaling and KP metabolism under trigeminal inflammatory conditions. These findings support KP–PACAP interactions and may identify novel migraine-related therapeutic targets.