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Analgesic actions of N-arachidonoyl-serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2007 Mar; Vol. 150 (6), pp. 766-81. Date of Electronic Publication: 2007 Feb 05. - Publication Year :
- 2007
-
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.<br />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.<br />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.<br />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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1188
- Volume :
- 150
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 17279090
- Full Text :
- https://doi.org/10.1038/sj.bjp.0707145