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

by Noah B. Gross, Nastaren Abad, David Lichtstein, Shiri Taron, Lorena Aparicio, Alfred N. Fonteh, Xianghong Arakaki, Robert P. Cowan, Samuel C. Grant, Michael G. Harrington

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 ²³Na 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.