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

Abstract

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.

Effect of Fatty Acid Amide Hydrolase Inhibitor URB597 on Orofacial Pain Perception in Rats

“…Inhibition of FAAH activity by URB597 resulted in an increase in AEA and CB1 receptor levels, as well as a decrease in CB2 receptor expression. Interestingly, 2-AG was less effective in our experiments despite the fact that it is present in higher concentrations in the brain than AEA and can induce stimulation equally through CB1 and CB2 receptors [58]. It may be due to lower levels of 2-AG access to the presynaptic CB1 receptors, as well as to the fact that the 2-AG-degrading enzyme is closer to the target of the CB1R than AEA.…”

Clinical Evidence of Cannabinoids in Migraine: A Narrative Review

“…A certain limitation of our study is that it is a narrative review and not a systematic one, but considering the aforementioned limits of the studies found (the small sample sizes, the lack of placebo-controlled studies, the often-retrospective design, the different titrations of cannabinoid preparations and the different routes of administration), the results of a systematic review would not have been too dissimilar from a narrative one. The adverse events linked to the modulation of the ECS, increasing eCBs, are still uncertain and should be properly assessed, because, although some authors believe it may be a relatively safe option [ 59 ], a recent clinical trial with a FAAH inhibitor (in this case, not used for migraine) was interrupted as a result of serious adverse events [ 60 ]. In conclusion, promising data are emerging on the possible role of ECS in migraine.…”

Persistent inflammation promotes endocannabinoid release and presynaptic cannabinoid 1 receptor desensitization

“…Direct microinjections of cannabinoid agonists into the PAG induce antinociception (Lichtman et al 1996, Martin et al 1995, Wilson et al 2008, Wilson-Poe et al 2013) through activation of CB1Rs that inhibit GABA release in the PAG (Vaughan et al 2000). Recent work has highlighted MAGL inhibitors as analgesic therapeutic options (Anderson et al 2014, Curry et al 2018, Della Pietra et al 2021, Diester et al 2021, Ignatowska-Jankowska et al 2015) but the data presented here suggest that MAGL inhibition may not be a viable strategy if inflammation impairs MAGL function and desensitizes CB1Rs. However, systemic administration of MAGL inhibitors, as well as fatty acid hydrolase (FAAH) inhibitors and combinations of the two, increase levels of the eCBs 2-AG and anadamide and result in anti-hyperalgesia in both neuropathic and inflammatory pain models (Anderson et al 2014, Jayamanne et al 2006, Mitchell et al 2005).…”