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


METHODS
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.


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
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.
Maione
S
S
Department of Experimental Medicine, Section of Pharmacology L Donatelli, Second University of Naples, Naples, Italy.
De Petrocellis
L
L
de Novellis
V
V
Moriello
A Schiano
AS
Petrosino
S
S
Palazzo
E
E
Rossi
F Sca
FS
Woodward
D F
DF
Di Marzo
V
V
D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002460:Cell Line; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004983:Ethanolamines; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D010147:Pain Measurement; D010169:Palmitic Acids / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D012701:Serotonin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D000099252:Fatty Acid Amide Hydrolases
D000577:Amides; D000581:Amidohydrolases; D018712:Analgesics, Non-Narcotic; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D010169:Palmitic Acids; D043884:Receptor, Cannabinoid, CB1; D011994:Recombinant Proteins; D012701:Serotonin; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; C494484:TRPV1 receptor; C493922:Trpv1 protein, rat; C114007:arachidonoylserotonin; C005958:palmidrol