Levcromakalim provokes an acute rapid-onset migraine-like phenotype without inducing cortical spreading depolarization.

BACKGROUND: Migraine headache attacks and accompanying sensory augmentation can be induced by several agents including levcromakalim (LVC), that is also capable of provoking aura-like symptoms in migraineurs. We investigated whether single LVC injection causes acute migraine-like phenotype in rats and induces/modulates cortical spreading depolarization (CSD), a rodent model of migraine aura.

METHODS: Wistar rats were administered LVC (1 mg/kg, i.p.) and compared to control (CTRL, vehicle, i.p.) and nitroglycerin (NTG, 10 mg/kg, i.p.) groups. Von Frey filaments were used to examine the periorbital and hind paw mechanical allodynia. Dark-light box (DLB), elevated plus maze (EPM), and open field arena (OFA) were used to evaluate light sensitivity and anxiety-related behaviors. The effects of LVC on CSD parameters, somatosensory evoked potentials, and baseline dural EEG (electroencephalography) were investigated. Possible CSD-induced c-fos expression was studied with Western Blot. Blood-brain barrier integrity in cortex was examined with Evans blue assay.

RESULTS: LVC and NTG administration robustly reduced periorbital mechanical thresholds in rats and induced anxiety-like behaviors and photophobia within 30 and 120 min, respectively. LVC induced migraine-like phenotype recovered in 2 h while NTG group did not fully recover before 4 h. Both LVC and NTG did not provoke DC (direct current) shift, EEG alterations or cortical c-fos expression characteristic to CSD. LVC did not induce de novo CSD and affect KCl (potassium chloride)-induced CSD parameters except for an increase in propagation failure. However, NTG significantly increased both CSD susceptibility and propagation failure. Somatosensory evoked potential (SSEP) configurations were not altered in both LVC and NTG groups, but SSEP latencies were prolonged after CSD. Acute LVC or NTG injection did not increase cortical BBB permeability.

CONCLUSIONS: Single LVC administration induced the fastest manifestation and recovery of acute migraine-like phenotype which was not mediated by CSD waves in the cerebral cortex. We suppose LVC triggered rapid-onset migraine-like symptoms are probably related to functional alterations in the trigeminal nociceptive system and K+  channel opening properties of LVC. Understanding the neurobiological mechanisms of this nociceptive window, may provide a novel target in migraine treatment.