Antinociceptive effects of tetrazole inhibitors of endocannabinoid inactivation: cannabinoid and non-cannabinoid receptor-mediated mechanisms.
OBJECTIVE
Tetrazoles were recently developed as inhibitors of the cellular uptake of the endocannabinoid anandamide or of its hydrolysis by fatty acid amide hydrolase (FAAH), but were proposed to act also on non-endocannabinoid-related serine hydrolases.


METHODS
We tested, in a model of inflammatory pain induced in mice by formalin, five chemically similar inhibitors: (i) OMDM119 and OMDM122, two potent carbamoyl tetrazole FAAH inhibitors with no effect on anandamide uptake; (ii) LY2183240, a carbamoyl tetrazole with activity as both FAAH and uptake inhibitor; (iii) OMDM132, a non-carbamoyl tetrazole with activity only as uptake inhibitor and iv) OMDM133, a non-carbamoyl tetrazole with no activity at either FAAH or uptake.


RESULTS
All compounds (2.5-10 mg kg(-1), i.p.) inhibited the second phase of the nocifensive response induced by intraplantar injection of formalin. The effects of OMDM119, OMDM122 and OMDM133 were not antagonized by pretreatment with cannabinoid CB(1) receptor antagonists, such as rimonabant or AM251 (1-3 mg kg(-1), i.p.). The effects of LY2183240 and OMDM132 were fully or partially antagonized by rimonabant, respectively, and the latter compound was also partly antagonized by the CB(2) receptor antagonist, AM630.


CONCLUSIONS
(i) non-FAAH hydrolases might be entirely responsible for the antinociceptive activity of some, but not all, tetrazole FAAH inhibitors, (ii) the presence of a carbamoylating group is neither necessary nor sufficient for such compounds to act through targets other than FAAH and (iii) inhibition of anandamide uptake is responsible for part of this antinociceptive activity, independently of effects on FAAH.
Maione
S
S
Endocannabinoid Research Group, Section of Pharmacology 'L Donatelli', Department of Experimental Medicine, Second University of Naples, Naples, Italy.
Morera
E
E
Marabese
I
I
Ligresti
A
A
Luongo
L
L
Ortar
G
G
Di Marzo
V
V
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010146:Pain / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D010147:Pain Measurement; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D013777:Tetrazoles; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide