FAAH inhibition as a preventive treatment for migraine: A pre-clinical study

Rosaria Greco, Chiara Demartini, Anna Maria Zanaboni, Elena Tumelero, Angelo Reggiani, Alessandra Misto, Daniele Piomelli, Cristina Tassorelli

Research output: Contribution to journalArticle

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 treatment, of migraine attacks. Further studies are needed to elucidate the exact cellular and molecular mechanisms underlying the protective effects of FAAH inhibition.

Original languageEnglish
Pages (from-to)104624
JournalNeurobiology of Disease
DOIs
Publication statusE-pub ahead of print - Oct 17 2019

Fingerprint

Migraine Disorders
Nitroglycerin
Endocannabinoids
Amides
Trigeminal Nuclei
Hyperalgesia
Therapeutics
Animal Models
Proto-Oncogene Proteins c-fos
Trigeminal Ganglion
Nitric Oxide Synthase Type I
Locus Coeruleus
Calcitonin Gene-Related Peptide
Hydrolases
Pain Measurement
Serine
fatty-acid amide hydrolase
Inhibition (Psychology)
Clinical Studies
Fatty Acids

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FAAH inhibition as a preventive treatment for migraine : A pre-clinical study. / Greco, Rosaria; Demartini, Chiara; Zanaboni, Anna Maria; Tumelero, Elena; Reggiani, Angelo; Misto, Alessandra; Piomelli, Daniele; Tassorelli, Cristina.

In: Neurobiology of Disease, 17.10.2019, p. 104624.

Research output: Contribution to journalArticle

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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 treatment, of migraine attacks. Further studies are needed to elucidate the exact cellular and molecular mechanisms underlying the protective effects of FAAH inhibition.",
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AU - Tumelero, Elena

AU - Reggiani, Angelo

AU - Misto, Alessandra

AU - Piomelli, Daniele

AU - Tassorelli, Cristina

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N2 - 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 treatment, of migraine attacks. Further studies are needed to elucidate the exact cellular and molecular mechanisms underlying the protective effects of FAAH inhibition.

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