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1. Analgesic actions of N-arachidonoyl-serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors.

Author

Maione S, De Petrocellis L, de Novellis V, Moriello AS, Petrosino S, Palazzo E, Rossi FS, Woodward DF, and Di Marzo V

Subjects
Amides, Analgesics, Non-Narcotic administration & dosage, Animals, Arachidonic Acids administration & dosage, Cannabinoid Receptor Modulators metabolism, Cell Line, Endocannabinoids, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacology, Ethanolamines, Injections, Subcutaneous, Male, Mice, Pain Measurement, Palmitic Acids metabolism, Rats, Rats, Wistar, Receptor, Cannabinoid, CB1 agonists, Recombinant Proteins antagonists & inhibitors, Recombinant Proteins genetics, Serotonin administration & dosage, Serotonin pharmacology, TRPV Cation Channels genetics, Amidohydrolases antagonists & inhibitors, Analgesics, Non-Narcotic pharmacology, Arachidonic Acids pharmacology, Serotonin analogs & derivatives, TRPV Cation Channels antagonists & inhibitors
Abstract

Background and Purpose: N-arachidonoyl-serotonin (AA-5-HT) is an inhibitor of fatty acid amide hydrolase (FAAH)-catalysed hydrolysis of the endocannabinoid/ endovanilloid compound, anandamide (AEA). We investigated if AA-5-HT antagonizes the transient receptor potential vanilloid-1 (TRPV1) channel and, as FAAH and TRPV1 are targets for analgesic compounds, if it exerts analgesia in rodent models of hyperalgesia., Experimental Approach: AA-5-HT was tested in vitro, on HEK-293 cells overexpressing the human or the rat recombinant TRPV1 receptor, and in vivo, in rats and mice treated with formalin and in rats with chronic constriction injury of the sciatic nerve. The levels of the endocannabinoids, AEA and 2-arachidonoylglycerol, in supraspinal (periaqueductal grey, rostral ventromedial medulla), spinal or peripheral (skin) tissues were measured., Key Results: AA-5-HT behaved as an antagonist at both rat and human TRPV1 receptors (IC(50)=37-40 nM against 100 nM capsaicin). It exerted strong analgesic activity in all pain models used here. This activity was partly due to FAAH inhibition, elevation of AEA tissue levels and indirect activation of cannabinoid CB(1) receptors, as it was reversed by AM251, a CB(1) antagonist. AA-5-HT also appeared to act either via activation/desensitization of TRPV1, following elevation of AEA, or as a direct TRPV1 antagonist, as suggested by the fact that its effects were either reversed by capsazepine and 5'-iodo-resiniferatoxin, two TRPV1 antagonists, or mimicked by these compounds administered alone., Conclusions and Implications: Possibly due to its dual activity as a FAAH inhibitor and TRPV1 antagonist, AA-5-HT was highly effective against both acute and chronic peripheral pain.

Published
2007
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2. Analgesic actions of N-arachidonoyl-serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors

Author

MAIONE, Sabatino, DE PETROCELLIS L, DE NOVELLIS, Vito, MORIELLO AS, PETROSINO S, PALAZZO, E, ROSSI FS, WOODWARD DF, DI MARZO V., PALAZZO, Enza, Maione, Sabatino, DE PETROCELLIS, L, DE NOVELLIS, Vito, Moriello, A, Petrosino, S, Palazzo, E, Rossi, F, Woodward, Df, DI MARZO, V., and Palazzo, Enza

Subjects
Male, Serotonin, Injections, Subcutaneous, TRPV Cation Channels, Arachidonic Acids, Palmitic Acids, Amidohydrolases, Cell Line, Mice, Receptor, Cannabinoid, CB1, Cannabinoid Receptor Modulators, Animals, FAAH, pain, Enzyme Inhibitors, Rats, Wistar, Pain Measurement, endocannabinoid, Analgesics, Non-Narcotic, cannabinoid, Amides, Research Papers, Recombinant Proteins, Rats, nervous system, Ethanolamines, vanilloid, lipids (amino acids, peptides, and proteins), psychological phenomena and processes, Endocannabinoids
Abstract

BACKGROUND AND PURPOSE: N-arachidonoyl-serotonin (AA-5-HT) is an inhibitor of fatty acid amide hydrolase (FAAH)-catalysed hydrolysis of the endocannabinoid/ endovanilloid compound, anandamide (AEA). We investigated if AA-5-HT antagonizes the transient receptor potential vanilloid-1 (TRPV1) channel and, as FAAH and TRPV1 are targets for analgesic compounds, if it exerts analgesia in rodent models of hyperalgesia. EXPERIMENTAL APPROACH: AA-5-HT was tested in vitro, on HEK-293 cells overexpressing the human or the rat recombinant TRPV1 receptor, and in vivo, in rats and mice treated with formalin and in rats with chronic constriction injury of the sciatic nerve. The levels of the endocannabinoids, AEA and 2-arachidonoylglycerol, in supraspinal (periaqueductal grey, rostral ventromedial medulla), spinal or peripheral (skin) tissues were measured. KEY RESULTS: AA-5-HT behaved as an antagonist at both rat and human TRPV1 receptors (IC(50)=37-40 nM against 100 nM capsaicin). It exerted strong analgesic activity in all pain models used here. This activity was partly due to FAAH inhibition, elevation of AEA tissue levels and indirect activation of cannabinoid CB(1) receptors, as it was reversed by AM251, a CB(1) antagonist. AA-5-HT also appeared to act either via activation/desensitization of TRPV1, following elevation of AEA, or as a direct TRPV1 antagonist, as suggested by the fact that its effects were either reversed by capsazepine and 5'-iodo-resiniferatoxin, two TRPV1 antagonists, or mimicked by these compounds administered alone. CONCLUSIONS AND IMPLICATIONS: Possibly due to its dual activity as a FAAH inhibitor and TRPV1 antagonist, AA-5-HT was highly effective against both acute and chronic peripheral pain.

Published
2007

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