Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabinoid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain.
The antinociceptive effects of the endocannabinoids (ECs) are enhanced by inhibiting catabolic enzymes such as fatty acid amide hydrolase (FAAH). The physiological relevance of the metabolism of ECs by other pathways, such as cyclooxygenase-2 (COX2) is less clear. To address this question we compared the effects of local inhibition of FAAH versus COX2 (URB597 and nimesulide, respectively) on inflammatory hyperalgesia and levels of endocannabinoids and related molecules in the hindpaw. Inflammatory hyperalgesia was measured following intraplantar injection of carrageenan. Effects of intraplantar injection of URB597 (25 microg and 100 microg) or nimesulide (50 microg) on hyperalgesia and hindpaw levels of anandamide (AEA), 2-arachidonoylglycerol (2AG) and N-palmitoylethanolamine (PEA) were determined. Although both doses of URB597 increased levels of AEA and 2AG in the carrageenan inflamed hindpaw, only the lower dose of URB597 attenuated hyperalgesia (P<0.05). Nimesulide attenuated both hyperalgesia and hindpaw oedema (P<0.001, P<0.01, respectively) and increased levels of PEA (P<0.05) in the hindpaw. Since both AEA and PEA are ligands for peroxisome proliferator-activated receptor-alpha (PPARalpha), the effects of the PPARalpha antagonist GW6471 on nimesulide- and URB597-mediated effects were studied. GW6471, but not a PPARgamma antagonist, blocked the inhibitory effects of nimesulide and URB597 on hyperalgesia. Our data suggest that both COX2 and FAAH play a role in the metabolism of endocannabinoids and related molecules. The finding that PPARalpha antagonism blocked the inhibitory effects of nimesulide and URB597 suggests that PPARalpha contributes to their antinociceptive effects in the carrageenan model of inflammatory hyperalgesia.
School of Biomedical Sciences and Institute of Neuroscience, Medical School, Queens Medical Centre, University of Nottingham, Nottinghamshire NG7 2UH, UK. maulik.jhaveri@nottingham.ac.uk
Maulik D
MD
Jhaveri
Denise
D
Richardson
Ian
I
Robinson
Michael J
MJ
Garle
Annie
A
Patel
Yan
Y
Sun
Devi R
DR
Sagar
Andrew J
AJ
Bennett
Stephen P H
SP
Alexander
David A
DA
Kendall
David A
DA
Barrett
Victoria
V
Chapman
D000577:Amides; D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002219:Carbamates / Q000627:therapeutic use; D002351:Carrageenan; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004983:Ethanolamines; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D047493:PPAR alpha / Q000378:metabolism*; D010147:Pain Measurement; D010169:Palmitic Acids / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000627:therapeutic use; D013997:Time Factors; D016474:Weight-Bearing / Q000502:physiology; D000099252:Fatty Acid Amide Hydrolases
D000577:Amides; D000581:Amidohydrolases; D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D002351:Carrageenan; D051546:Cyclooxygenase 2; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D047493:PPAR alpha; D010169:Palmitic Acids; D013449:Sulfonamides; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C005958:palmidrol; C012655:nimesulide