Pharmacological Activity of Fatty Acid Amides Is Regulated, but Not Mediated, by Fatty Acid Amide Hydrolase in Vivo
| Autor: | Graeme Griffin, E. Gregory Hawkins, Benjamin F. Cravatt, Aron H. Lichtman |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Cannabinoid receptor
Oleamide Receptors Drug medicine.medical_treatment Oleic Acids Arachidonic Acids Motor Activity Pharmacology Amidohydrolases Body Temperature Glycerides Mice Radioligand Assay chemistry.chemical_compound Fatty acid amide hydrolase Cannabinoid Receptor Modulators medicine Animals Blepharoptosis Enzyme Inhibitors Receptors Cannabinoid Pain Measurement Mice Knockout Behavior Animal Fatty Acids Biological activity Anandamide Amides Endocannabinoid system Mice Inbred C57BL Monoacylglycerol lipase Kinetics nervous system chemistry Biochemistry Molecular Medicine lipids (amino acids peptides and proteins) Cannabinoid psychological phenomena and processes Endocannabinoids |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 302:73-79 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.302.1.73 |
| Popis: | Fatty acid amides (FAAs) represent a class of neuromodulatory lipids that includes the endocannabinoid anandamide and the sleep-inducing substance oleamide. Both anandamide and oleamide produce behavioral effects indicative of cannabinoid activity, but only anandamide binds the cannabinoid (CB1) receptor in vitro. Accordingly, oleamide has been proposed to induce its behavioral effects by serving as a competitive substrate for the brain enzyme fatty acid amide hydrolase (FAAH) and inhibiting the degradation of endogenous anandamide. To test the role that FAAH plays as a mediator of oleamide activity in vivo, we have compared the behavioral effects of this FAA in FAAH(+/+) and (−/−) mice. In both genotypes, oleamide produced hypomotility, hypothermia, and ptosis, all of which were enhanced in FAAH(−/−) mice, were unaffected by the CB1 antagonist N -(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-di-chlorophenyl)-4-methyl-1 H -pyrazole-3-carboxamide hydrochloride (SR141716A) and occurred in CB1(−/−) mice. Additionally, oleamide displayed negligible binding to the CB1 receptor in brain extracts from either FAAH(+/+) or (−/−) mice. In contrast, anandamide exhibited a 15-fold increase in apparent affinity for the CB1 receptor in brains from FAAH(−/−) mice, consistent with its pronounced CB1-dependent behavioral effects in these animals. Contrary to both oleamide and anandamide, monoacylglycerol lipids exhibited equivalent hydrolytic stability and pharmacological activity in FAAH(+/+) and (−/−) mice. Collectively, these results indicate that FAAH is a key regulator, but not mediator of FAA activity in vivo. More generally, these findings suggest that FAAs represent a family of signaling lipids that, despite sharing similar chemical structures and a common pathway for catabolism, produce their behavioral effects through distinct receptor systems in vivo. |
| Databáze: | OpenAIRE |
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