Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo.

Abstract

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-1H-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.

• Authors: Aron H Lichtman, E Gregory Hawkins, Graeme Griffin, Benjamin F Cravatt
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 302 Issue 1 Pg. 73-9 (Jul 2002) ISSN: 0022-3565 [Print] United States
• PMID: 12065702 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amides
• Arachidonic Acids
• Cannabinoid Receptor Modulators
• Endocannabinoids
• Enzyme Inhibitors
• Fatty Acids
• Glycerides
• Oleic Acids
• Receptors, Cannabinoid
• Receptors, Drug
• oleylamide
• glyceryl 2-arachidonate
• Amidohydrolases
• fatty-acid amide hydrolase

Topics

• Amides (pharmacology)
• Amidohydrolases (antagonists & inhibitors, genetics, physiology)
• Animals
• Arachidonic Acids
• Behavior, Animal (drug effects)
• Blepharoptosis (chemically induced)
• Body Temperature (drug effects)
• Cannabinoid Receptor Modulators
• Endocannabinoids
• Enzyme Inhibitors (pharmacology)
• Fatty Acids (pharmacology)
• Glycerides (pharmacology)
• Kinetics
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Motor Activity (drug effects)
• Oleic Acids (pharmacology)
• Pain Measurement (drug effects)
• Radioligand Assay
• Receptors, Cannabinoid
• Receptors, Drug (drug effects)