Abstract
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.
Highlights
Migraine usurps the trigeminovascular pathway to cause severe headache, with widespread dysfunction extending to additional locations due to connections with the limbic system evidenced through human [1,2,3,4,5] and animal studies [6]
Initial measures in human migraineurs involved testing whether endogenous Na+, K+-ATPase inhibitors are detectable in cerebrospinal fluid (CSF), whether they change in the ictal compared to interictal states, and whether they differ from levels in CSF from controls
For the first time, that endogenous ouabain-like compounds (EOLC) is protective against migraine, as evidenced by increased CSF EOLC levels during the interictal state, and decreased levels during the ictal state
Summary
Migraine usurps the trigeminovascular pathway (meninges, trigeminal ganglion, trigeminocervical complex, thalamus, and somatosensory cortex) to cause severe headache, with widespread dysfunction extending to additional locations due to connections with the limbic system (hypothalamus, amygdala, and hippocampus) evidenced through human [1,2,3,4,5] and animal studies [6]. Migraine symptoms arise from altered neuronal excitability in these pathways, but the causative mechanism that triggers abnormal excitability and symptoms remains elusive [7,8,9]. Cortical spreading depression (CSD) [10] is strongly supported as the basis for aura in migraine [11, 12], and experimentally-triggered CSD may produce a migraine analogue [13]. CSD remains the best candidate to initiate migraine; what initiates CSD or other cortical triggers [17] in migraine is not understood
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