Interictal serum L‐kynurenine and PACAP‐38 levels in relation to allodynia and migraine subtypes

OBJECTIVE: This study aimed to evaluate the relationship between serum levels of L-kynurenine (L-KYN) and pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), two molecules implicated in migraine pathophysiology and migraine subtypes (episodic and chronic), as well as the presence of allodynia. We hypothesized that dysregulation of the kynurenine pathway and prepro-pituitary adenylate cyclase-activating polypeptide (PACAP) signaling would be reflected in altered serum L-KYN and PACAP-38 levels across migraine subtypes and in relation to allodynia. BACKGROUND: Migraine is a complex neurological disorder characterized by central sensitization and trigeminovascular activation. Although the kynurenine pathway and PACAP-38 have been implicated in migraine pathophysiology, their associations with migraine subtypes and allodynia remain insufficiently understood. METHODS: In this observational cross-sectional study, a total of 137 patients diagnosed with migraine who presented to the neurology outpatient clinic of a tertiary university hospital, and 40 age- and sex-matched healthy volunteers as a control group, were included. Interictal serum L-KYN and PACAP-38 levels were measured in all participants using the enzyme-linked immunosorbent assay. Clinical assessments comprised the Beck Depression Inventory, Beck Anxiety Inventory, MIDAS, Allodynia Symptom Checklist, and a visual analogue scale. Data analyses included nonparametric tests, correlation analyses, and multivariable logistic and robust regression models. RESULTS: Interictal serum L-KYN and PACAP-38 levels were significantly lower in patients with migraine compared with controls (PACAP-38: H(2) = 84.742, p < 0.001; L-KYN: H(2) = 68.991, p < 0.001), with numerically lower levels in chronic migraine than in episodic migraine. Both molecules showed strong discriminatory ability between patients with migraine and healthy controls (area under the curve = 0.977 for PACAP-38; area under the curve = 0.922 for L-KYN). A strong positive correlation was observed between serum L-KYN and PACAP-38 levels (ρ = 0.772, p < 0.001). Aura (odds ratio = 4.6, 95% confidence interval [1.3 to 16.2], p = 0.017) and secondary/high school educational level (odds ratio = 6.8, 95% interval [1.5 to 31.3], p = 0.015) emerged as independent predictors of allodynia. CONCLUSION: Interictal serum L-KYN and PACAP-38 levels are associated with migraine subtypes and allodynia, with potential utility as clinically relevant peripheral indicators associated with migraine-related neurobiological processes.