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FAAH inhibition as a preventive treatment for migraine: A pre-clinical study
- Source :
- Neurobiology of Disease, Vol 134, Iss, Pp-(2020)
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Background Fatty-acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of endogenous fatty-acid amides, including the endocannabinoid anandamide (AEA). We previously reported that the peripherally restricted FAAH inhibitor URB937, which selectively increases AEA levels outside the central nervous system, reduces hyperalgesia and c-Fos expression in the trigeminal nucleus caudalis (TNC) and the locus coeruleus in an animal model of migraine based on nitroglycerin (NTG) administration. Aim To further investigate the relevance of FAAH inhibition in the NTG animal model of migraine by testing the effects of the globally active FAAH inhibitor URB597. Methods Our experimental approach involved mapping neuronal c-Fos protein expression, measurement of AEA levels in brain areas and in trigeminal ganglia, evaluation of pain-related behavior and quantification of molecular mediators in rats that received URB597 (2 mg/kg i.p.) either before or after NTG administration (10 mg/kg, i.p.). Results Pre-treatment with URB597 significantly reduced c-Fos immunoreactivity in the TNC and inhibited NTG-induced hyperalgesia in the orofacial formalin test. This behavioral response was associated with a decrease in neuronal nitric oxide synthase, calcitonin gene-related peptide and cytokine gene expression levels in central and peripheral structures. Administration of URB597 after NTG had no such effect. Conclusions The findings suggest that global FAAH inhibition may offer a therapeutic approach to the prevention, but not the abortive treatment, of migraine attacks. Further studies are needed to elucidate the exact cellular and molecular mechanisms underlying the protective effects of FAAH inhibition.
- Subjects :
- Male
0301 basic medicine
Migraine Disorders
Vasodilator Agents
Central nervous system
Endogeny
Pharmacology
lcsh:RC321-571
Amidohydrolases
Rats, Sprague-Dawley
Nitroglycerin
03 medical and health sciences
chemistry.chemical_compound
Trigeminal Caudal Nucleus
0302 clinical medicine
Animals
Medicine
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Migraine
business.industry
Anandamide
URB597
Endocannabinoid system
Rats
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
nervous system
Neurology
chemistry
Benzamides
Hyperalgesia
Locus coeruleus
lipids (amino acids, peptides, and proteins)
Carbamates
medicine.symptom
business
030217 neurology & neurosurgery
Intracellular
Subjects
Details
- ISSN :
- 09699961
- Volume :
- 134
- Database :
- OpenAIRE
- Journal :
- Neurobiology of Disease
- Accession number :
- edsair.doi.dedup.....28b35488ed31f0ca17b0d6d7f4ecc582