A powerful dual MAGL/FAAH inhibitor AKU-005 against migraine pain of peripheral meningeal origin

Abstract text (incl. figure legends and references)

Question. Migraine is a neurological multifactorial disease whose worst symptom is pain. To deal with disturbing migraine pain, we propose the engaging of endocannabinoid system (ECS) via inhibition of enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), which are degrading 2-arachidonoylglicerol (2-AG) and anandamide (AEA), respectively. To this end, we explored the analgesic effect of enhanced endocannabinoids (endoCBs) in peripheral meningeal tissues where pain signaling is of often originating in migraine, leading later to central sensitization.

Methods. To develop the functional platform for such purpose, we measured by activity-based protein profiling (ABPP) the activity of the main endoCBs-hydrolases, MAGL and FAAH and by LC-MS/MS the levels of 2-AG and AEA in rat meninges. We explored the analgesic effect of enhanced endoCBs with electrophysiological recordings from rat peripheral meningeal afferents.

Results. We found that in the meninges, 2-AG is the main endoCB, much exceeding the level of AEA. However, local depolarization increased the AEA ~2 folds without affecting 2-AG levels. The dual MAGL/FAAH inhibitor AKU-005 slightly increased basal nociceptive activity of trigeminal nerves. Instead, it significantly decreased, through CB1 receptors, meningeal nociceptive activity induced by depolarizing action of KCl, indicating analgesic effect.

Conclusions. These results suggest that 2-AG and AEA can differently contribute to counteract migraine pain by tonic or transient activity dependent release from meninges. These findings support the therapeutic perspective for engagement of both endoCBs analgesic molecules at early stages of attack. Thus, our novel dual ultrapotent MAGL/FAAH inhibitor AKU-005 appeared to be a promising tool in reducing migraine nociception originating in the meninges.