Levcromakalim Provokes a Rapid-Onset Migraine-like Phenotype Without Inducing Cortical Spreading Depolarization

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Abstract Background Migraine headache attacks and accompanying sensory augmentation can be induced by several agents including levcromakalim (LEV), that is also capable of provoking aura-like symptoms in migraineurs. We investigated whether acute LEV injection causes migraine-like phenotype in rats and induces/modulates cortical spreading depolarization (CSD), a rodent model of migraine aura. Methods Wistar rats were administered LEV (1mg/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 hindpaw 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 LEV on CSD parameters, somatosensory evoked potentials, and baseline dural EEG were investigated Possible CSD-induced c-fos expression was studied with Western Blot. BBB integrity in cortex is examined with Evans Blue Assay. Results LEV and NTG administration robustly reduced periorbital mechanical thresholds in rats and induced anxiety-like behaviors and photophobia within 30 and 120 minutes, respectively. LEV induced migraine like phenotype recovered in 2 hours while NTG group were not fully recovered before 4 hours. Both LEV and NTG did not provoke DC shift, EEG alterations or cortical c-fos expression characteristic to CSD. LEV did not affect KCl-induced CSD parameters except for an increase in propagation failure. However, NTG significantly increased both CSD susceptibility and propagation failure. Somatosensory evoked potential configurations were not altered in both LEV and NTG groups, but SSEP latencies were prolonged after CSD. Acute LEV or NTG injection did not increase cortical BBB permeability. Conclusions Acute systemic LEV administration induced the fastest manifestation and recovery of migraine like phenotype which was not mediated by CSD waves in the cerebral cortex. CSD modulating effects of LEV were less prominent compared to NTG, an agent without aura provoking properties. We suppose LEV triggered rapid-onset migraine-like symptoms are probably related to functional alterations in the trigeminal nociceptive system and K + channel opening properties of LEV. Understanding the neurobiological mechanisms of this nociceptive window, may provide a novel targets in migraine treatment.

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