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.