Effects of URB597, an inhibitor of fatty acid amide hydrolase (FAAH), on analgesic activity of paracetamol.
OBJECTIVE
Paracetamol is converted to an active metabolite AM404 via fatty acid amide hydrolase (FAAH). The aim of the present study was to ascertain whether a FAAH inhibitor URB597 antagonizes paracetamol analgesic activity (and to asses by this way the role of FAAH in analgesic activity of paracetamol).


METHODS
The interaction between a FAAH inhibitor URB597 and paracetamol was investigated in the writhing test in mice using an isobolographic analysis.


RESULTS
URB597 or paracetamol alone and in combinations produced dose-dependent antinociceptive effects. ED50 values were estimated for the individual drugs and an isobologram was constructed. The observed ED50 value for the URB57-paracetamol combination was 0.097 (0.062-0.247) mg/kg. This value did not differ significantly from the theoretical additive ED50 value for the URB597-paracetamol combination which was 0.108 (0.059-0.198) mg/kg. Thus, inhibition of FAAH by URB597 was not followed by the lack of analgesic activity in paracetamol.


CONCLUSIONS
The present results suggest that the analgesic activity of paracetamol is not dependent solely on FAAH metabolic conversion to AM404 and that paracetamol exerts analgesic activity also by additional mechanisms.
Soukupová
Marie
M
Department of Pharmacology, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic. Marie.Soukupova@lf3.cuni.cz
Palazzo
Enza
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De Chiaro
Maria
M
Gatta
Luisa
L
Migliozzi
Anna Lucia
AL
Guida
Francesca
F
Luongo
Livio
L
Giordano
Catia
C
Siniscalco
Dario
D
De Novellis
Vito
V
Marabese
Ida
I
Krsiak
Miloslav
M
Maione
Sabatino
S
D000082:Acetaminophen / Q000494:pharmacology*; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016014:Linear Models; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects*; D000099252:Fatty Acid Amide Hydrolases
D000082:Acetaminophen; D000581:Amidohydrolases; D018712:Analgesics, Non-Narcotic; D001549:Benzamides; D002219:Carbamates; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester