Pharmacology of Palmitoylethanolamide and Related Compounds

Anandamide (AEA) is surely an endogenous fatty acid that triggers the same cannabinoid receptors as tetrahydrocannabinol, the psychoactive substance in marijuana. In vivo, anandamide exerts numerous actions including effects upon inflammation and pain. Nevertheless, AEA has a brief time period of action as it is quickly metabolised, mainly by the intracellular enzyme fatty acid amide hydrolase (FAAH).The purpose of this dissertation is to determine and characterize compounds effective at preventing the metabolism of anandamide. The chemical technique took it’s origin from the endogenous anti-inflammatory compound palmitoylethanolamide¬†(PEA), a compound associated with anandamide having the capacity to inhibit anandamide degradation by substrate competition, but minus the capacity to directly trigger cannabinoid receptors. Several compounds were recognized as inhibitors of rat brain FAAH in the initial in vitro studies, without having major interest in the cannabinoid receptors….

Contents: Pharmacology of Palmitoylethanolamide

INTRODUCTION
The endocannabinoid system
Cannabinoid receptor ligands
In vivo effects of cannabinoid receptor activation
Anandamide (AEA)
N-acylethanolamines (NAEs)
Synthesis and release of anandamide
Anandamide uptake
Anandamide degradation
FAAH inhibitors
Therapeutic potential of FAAH inhibitors
AIMS OF THE STUDY
METHODS AND METHODOLOGICAL CONSIDERATIONS
FAAH assay
Anandamide uptake in RBL-2H3 and C6 cells
Radioligand binding experiments
Cell cultures
Cell proliferation assay
Analysis of cell density
Analysis of caspase activity
Animals
Plasma extravasation in mouse ear pinna
Mice paw skin release
Immunohistochemistry and PCR
Data analyses and statistics
RESULTS AND DISCUSSION
Inhibition of FAAH catalysed anandamide hydrolysis
Interaction with CB1 and CB2 cannabinoid receptors
Inhibition of anandamide uptake
Inhibition of anandamide uptake and hydrolysis in intact C6 cells
Effects of PIA, AM404 and VDM11 upon cell proliferation
Effects of PIA and JWH133 upon inflammation in vivo and in vitro
GENERAL CONCLUSIONS AND FUTURE PERSPECTIVES…

Source: Umea University

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