Endogenous Na(+), K(+)-ATPase inhibitors and CSF [Na(+)] contribute to migraine formation

There is strong evidence that neuronal hyper-excitability underlies migraine, and may or may not be preceded by cortical spreading depression. However, the mechanisms for cortical spreading depression and/or migraine are not established. Previous studies reported that cerebrospinal fluid (CSF) [Na(+)] is higher during migraine, and that higher extracellular [Na(+)] leads to hyper-excitability. We raise the hypothesis that altered choroid plexus Na(+), K(+)-ATPase activity can cause both migraine phenomena: inhibition raises CSF [K(+)] and initiates cortical spreading depression, while activation raises CSF [Na(+)] and causes migraine. In this study, we examined levels of specific Na(+), K(+)-ATPase inhibitors, endogenous ouabain-like compounds (EOLC), in CSF from migraineurs and controls. CSF EOLC levels were significantly lower during ictal migraine (0.4 nM +/- 0.09) than from either controls (1.8 nM +/- 0.4) or interictal migraineurs (3.1 nM +/- 1.9). Blood plasma EOLC levels were higher in migraineurs than controls, but did not differ between ictal and interictal states. In a Sprague-Dawley rat model of nitroglycerin-triggered central sensitization, we changed the concentrations of EOLC and CSF sodium, and measured aversive mechanical threshold (von Frey hairs), trigeminal nucleus caudalis activation (cFos), and CSF [Na(+)] (ultra-high field (23)Na MRI). Animals were sensitized by three independent treatments: intraperitoneal nitroglycerin, immunodepleting EOLC from cerebral ventricles, or cerebroventricular infusion of higher CSF [Na(+)]. Conversely, nitroglycerin-triggered sensitization was prevented by either vascular or cerebroventricular delivery of the specific Na(+), K(+)-ATPase inhibitor, ouabain. These results affirm our hypothesis that higher CSF [Na(+)] is linked to human migraine and to a rodent migraine model, and demonstrate that EOLC regulates them both. Our data suggest that altered choroid plexus Na(+), K(+)-ATPase activity is a common source of these changes, and may be the initiating mechanism in migraine.