Regulation of Na⁺, K⁺−ATPase by ouabain-like compounds, phytocannabinoids, and endocannabinoids: a potential mechanism of action in migraine

Migraine disability is one of the leading causes of disability-adjusted life-years. Pharmacotherapy is the mainstay of physician-based treatment, with either rescue or prophylaxis as the primary goals. Data reported to date suggests that there exists a common mechanism at the root of migraine that varied triggers may activate, and interruption of this activation is key to migraine treatment. One possibility is that altered brain sodium homeostasis is the gateway to migraine. It has been suggested that cerebrospinal fluid (CSF) sodium homeostasis is fundamentally more labile in migraine, and reducing its variability, especially [Na + ] surges, would offer a more universal treatment that is not currently available. This project aims to investigate whether endocannabinoids and phytocannabinoids can directly regulate the Na + , K + −ATPase enzyme, thereby maintaining sodium homeostasis and potentially reducing migraine days or pain intensity. The results of this study indicate that several cannabinoids can directly regulate Na + , K + −ATPase in vitro , but the binding observed is too poor to represent a mechanism that would be effective in vivo . A more sophisticated model system might provide a more precise understanding of the regulation of Na + , K + −ATPase by cannabinoids and whether it is a viable explanation for their effect on migraine.