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In migraine pain, cannabis has a promising analgesic action, which, however, is associated with side psychotropic effects. To overcome these adverse effects of exogenous cannabinoids, we propose migraine pain relief via activation of the endogenous cannabinoid system (ECS) by inhibiting enzymes degrading endocannabinoids. To provide a functional platform for such purpose in the peripheral and central parts of the rat nociceptive system relevant to migraine, we measured by activity-based protein profiling (ABPP) the activity of the main endocannabinoid-hydrolases, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). We found that in trigeminal ganglia, the MAGL activity was nine-fold higher than that of FAAH. MAGL activity exceeded FAAH activity also in DRG, spinal cord and brainstem. However, activities of MAGL and FAAH were comparably high in the cerebellum and cerebral cortex implicated in migraine aura. MAGL and FAAH activities were identified and blocked by the selective and potent inhibitors JJKK-048/KML29 and JZP327A, respectively. The high MAGL activity in trigeminal ganglia implicated in the generation of nociceptive signals suggests this part of ECS as a priority target for blocking peripheral mechanisms of migraine pain. In the CNS, both MAGL and FAAH represent potential targets for attenuation of migraine-related enhanced cortical excitability and pain transmission.

Distinct Activity of Endocannabinoid-Hydrolyzing Enzymes MAGL and FAAH in Key Regions of Peripheral and Central Nervous System Implicated in Migraine