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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.
Neuropharmacology. 2008 Jul; 55(1):85-93.N

Abstract

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.

Authors+Show Affiliations

School of Biomedical Sciences and Institute of Neuroscience, Medical School, Queens Medical Centre, University of Nottingham, Nottinghamshire NG7 2UH, UK. maulik.jhaveri@nottingham.ac.ukNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18534634

Citation

Jhaveri, Maulik D., et al. "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." Neuropharmacology, vol. 55, no. 1, 2008, pp. 85-93.
Jhaveri MD, Richardson D, Robinson I, et al. 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. Neuropharmacology. 2008;55(1):85-93.
Jhaveri, M. D., Richardson, D., Robinson, I., Garle, M. J., Patel, A., Sun, Y., Sagar, D. R., Bennett, A. J., Alexander, S. P., Kendall, D. A., Barrett, D. A., & Chapman, V. (2008). 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. Neuropharmacology, 55(1), 85-93. https://doi.org/10.1016/j.neuropharm.2008.04.018
Jhaveri MD, et al. 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. Neuropharmacology. 2008;55(1):85-93. PubMed PMID: 18534634.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Jhaveri,Maulik D, AU - Richardson,Denise, AU - Robinson,Ian, AU - Garle,Michael J, AU - Patel,Annie, AU - Sun,Yan, AU - Sagar,Devi R, AU - Bennett,Andrew J, AU - Alexander,Stephen P H, AU - Kendall,David A, AU - Barrett,David A, AU - Chapman,Victoria, Y1 - 2008/04/29/ PY - 2008/02/04/received PY - 2008/04/18/revised PY - 2008/04/21/accepted PY - 2008/6/7/pubmed PY - 2008/11/6/medline PY - 2008/6/7/entrez SP - 85 EP - 93 JF - Neuropharmacology JO - Neuropharmacology VL - 55 IS - 1 N2 - 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. SN - 0028-3908 UR - https://www.unboundmedicine.com/medline/citation/18534634/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(08)00123-8 DB - PRIME DP - Unbound Medicine ER -