Inhibition of FAAH reduces nitroglycerin-induced migraine-like pain and trigeminal neuronal hyperactivity in mice
Abstract
There is evidence to suggest that a dysregulation of endocannabinoid signaling may contribute to the etiology and pathophysiology of migraine. Thus, patients suffering from chronic migraine or medication overuse headache showed alterations in the activity of the arachidonoylethanolamide (AEA) degrading enzyme fatty acid amide hydrolase (FAAH) and a specific AEA membrane transporter, alongside with changes in AEA levels. The precise role of different endocannabinoid system components is, however, not clear. We have therefore investigated mice with a genetic deletion of the two main cannabinoid receptors CB1 and CB2, or the main endocannabinoid degrading enzymes, FAAH and monoacylglycerol lipase (MAGL), which degrades 2-arachidonoylglycerol (2-AG), in a nitroglycerine-induced animal model of migraine. We found that nitroglycerin-induced mechanical allodynia and neuronal activation of the trigeminal nucleus were completely abolished in FAAH-deficient mice. To validate these results, we used two structurally different FAAH inhibitors, URB597 and PF3945. Both inhibitors also dose-dependently blocked nitroglycerin-induced hyperalgesia and the activation of trigeminal neurons. The effects of the genetic deletion of pharmacological blockade of FAAH are mediated by CB1 receptors, because they were completely disrupted with the CB1 antagonist rimonabant. These results identify FAAH as a target for migraine pharmacotherapy.
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FAAH inhibitors (PF-3845 and URB597) reverse allodynia in a mouse model of nitroglycerin-induced migraine through a CB1 receptor-dependent mechanism.
“FAAH inhibitors (ie, PF-3845 and URB597) reverse allodynia in a mouse model of nitroglycerin-induced migraine through a CB 1 receptor-dependent mechanism (Nozaki et al, 2015).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Nozaki et al, 2015
A dysfunction of the endocannabinoid system may contribute to the development of migraine attacks, and modulation of this system can be useful for the treatment of pain associated with migraine.
“These studies suggest that a dysfunction of the endocannabinoid system may contribute to the development of migraine attacks and modulation of this system can be useful for the treatment of pain associated to migraine.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Nozaki et al, 2015
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- Authors
- Nozaki, C., Markert, A., & Zimmer, A.
- Affiliations
- University of Bonn (DE)
- Corresponding author
- Nozaki, Chihiro
- Venue
- European Neuropsychopharmacology
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 25
- Issue
- 8
- Pages
- 1388-1396
- ISSN
- 0924-977X (ISSN-L)
- OpenAlex
- W2016327412
- Cited by
- 45
- References
- 32
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 1 · 2023: 5 · 2022: 7 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 6 · 2016: 1 · 2015: 1
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-11-01)
- Open access
- closed
- Locations
- European Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Agence Nationale pour la Gestion des Déchets Radioactifs
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Migraine and Headache Studies
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- fatty acid amide hydrolase, FAAH inhibition, migraine, endocannabinoid system, arachidonoyl ethanolamide, CB1 receptor, CB2 receptor, monoacylglycerol lipase, trigeminal nucleus, neuronal hyperactivity, mechanical allodynia, hyperalgesia, rimonabant, URB597, chronic migraine, medication overuse headache
- MeSH terms
- Rimonabant, Fatty Acid Amide Hydrolases, Amidohydrolases, Analgesics, Animals, Arachidonic Acids, Benzamides, Carbamates, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors, Nitroglycerin, Hyperalgesia, Male, Mice, Inbred C57BL, Migraine Disorders, Monoacylglycerol Lipases, Pain Measurement, Piperidines, Pyrazoles, Touch, Trigeminal Nuclei, Mice, Knockout, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Polyunsaturated Alkamides, Cannabinoid Receptor Antagonists, Endocannabinoids
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