Abstract | BACKGROUND: METHODS: Both MAGL and FAAH activity and local 2-AG and AEA levels were measured by activity-based protein profiling (ABPP) and LC-MS/MS, respectively, in rat meninges obtained from hemiskulls of P38-P40 Wistar rats and human meninges from elderly patients undergoing non- migraine related neurosurgery. The action on endoCBs upon administration of novel dual MAGL/FAAH inhibitor AKU-005 on meningeal afferents excitability was tested by investigating paired KCl-induced spiking and validation with local (co-)application of either AEA or 2-AG. Finally, the specific TRPV1 agonist capsaicin and blocker capsazepine were tested. RESULTS: The basal level of 2-AG exceeded that of AEA in rat and human meninges. KCl-induced depolarization doubled the level of AEA. AKU-005 slightly increased spontaneous spiking activity whereas the dual MAGL/FAAH inhibitor significantly decreased excitation of nerve fibres induced by KCl. Similar inhibitory effects on meningeal afferents were observed with local applications of 2-AG or AEA. The action of AKU-005 was reversed by CB1 antagonist AM-251, implying CB1 receptor involvement in the anti-nociceptive effect. The inhibitory action of AEA was also reversed by AM-251, but not with the TRPV1 antagonist capsazepine. Data cluster analysis revealed that both AKU-005 and AEA largely increased long-term depression-like meningeal spiking activity upon paired KCl-induced spiking. CONCLUSIONS: In the meninges, high anti-nociceptive 2-AG levels can tonically counteract meningeal signalling, whereas AEA can be engaged on demand by local depolarization. AEA-mediated anti-nociceptive effects through CB1 receptors have therapeutic potential. Together with previously detected MAGL activity in trigeminal ganglia, dual MAGL/FAAH inhibitor AKU-005 appears promising as migraine treatment.
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Authors | Adriana Della Pietra, Georgii Krivoshein, Konstantin Ivanov, Raisa Giniatullina, Henna-Kaisa Jyrkkänen, Ville Leinonen, Marko Lehtonen, Arn M J M van den Maagdenberg, Juha Savinainen, Rashid Giniatullin |
Journal | The journal of headache and pain
(J Headache Pain)
Vol. 24
Issue 1
Pg. 38
(Apr 11 2023)
ISSN: 1129-2377 [Electronic] England |
PMID | 37038131
(Publication Type: Journal Article)
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Copyright | © 2023. The Author(s). |
Chemical References |
- Endocannabinoids
- fatty-acid amide hydrolase
- Monoglycerides
- capsazepine
- Carbamates
- Amidohydrolases
- Monoacylglycerol Lipases
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Topics |
- Rats
- Humans
- Animals
- Aged
- Endocannabinoids
(pharmacology)
- Monoglycerides
(therapeutic use)
- Chromatography, Liquid
- Nociception
- Carbamates
(pharmacology, therapeutic use)
- Rats, Wistar
- Tandem Mass Spectrometry
- Pain
(drug therapy)
- Amidohydrolases
(metabolism, therapeutic use)
- Migraine Disorders
(drug therapy)
- Monoacylglycerol Lipases
(metabolism)
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