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

Adriana Della Pietra,Rashid Giniatullin,Juha R Savinainen

doi:10.3390/ijms22031204

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.

Highlights

Migraine is a widespread neurovascular disabling disorder affecting up to 15% of the worldwide population and is typically characterized by one-sided throbbing longlasting moderate or severe pain [1,2]
An alternative approach for migraine pain therapy might be based on the selective enhancement of endogenous cannabinoids, which are naturally generated in the nociceptive system in the body [22]
In contrast to monoacylglycerol lipase (MAGL), the basal fatty acid amide hydrolase (FAAH) activity in rat trigeminal ganglia (TG) and dorsal root ganglion (DRG) was relatively low at these peripheral parts of the nociceptive system (Figure 1A)

Summary

Introduction

Migraine is a widespread neurovascular disabling disorder affecting up to 15% of the worldwide population and is typically characterized by one-sided throbbing longlasting moderate or severe pain [1,2]. Migraine is associated with multiple psychiatric comorbidities such as anxiety, depression and panic disorders [3,4,5,6]. Migraine has a clear trend to chronicization, namely, a progression from episodic to chronic migraine [7] This trend might be due to excessive use of analgesic including opioids drugs leading to condition known as a ’medication overuse headache’ [8]. The enhancement of endoCBs-activities is primarily important for conditions such as Clinical Endocannabinoid Deficiency (CECD), which was already proposed as a complication for several treatment-resistant types of pain, including migraine [16,24]

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Discussion

Conclusion