Endocannabinoids and the regulation of their levels in health and disease.
OBJECTIVE
Endocannabinoids are defined as endogenous agonists of cannabinoid receptors, that is, of the two G-protein-coupled receptors for the Cannabis psychoactive principle Delta-tetra-hydrocannabinol. Two such endogenous mediators have been most thoroughly studied so far: anandamide and 2-arachidonoylglycerol. Here we review the mechanisms for the regulation of their levels under physiological and pathological conditions, and recent findings on their role in disease.


RESULTS
It is becoming increasingly clear that, although both anandamide and 2-arachidonoyl-glycerol are produced and degraded 'on demand', the levels of these two compounds appear to be regulated in different, and sometimes even opposing, ways, often using redundant molecular mechanisms. Alterations of endocannabinoid levels have been found in both animal models of pain, neurological and neurodegenerative states, gastrointestinal disorders and inflammatory conditions, and in blood, cerebrospinal fluid and bioptic samples from patients with various diseases.


CONCLUSIONS
Endocannabinoid levels appear to be transiently elevated as an adaptive reaction to re-establish normal homeostasis when this is acutely and pathologically perturbed. In some chronic conditions, however, this system also contributes to the progress or symptoms of the disorder. As a consequence, new therapeutic drugs are being designed from both stimulants and blockers of endocannabinoid action.
Di Marzo
Vincenzo
V
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy. vdimarzo@icmib.na.cnr.it
Petrosino
Stefania
S
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000096:biosynthesis / Q000378:metabolism*; D063388:Endocannabinoids; D001068:Feeding and Eating Disorders / Q000378:metabolism; D005767:Gastrointestinal Diseases / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D012016:Reference Values
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; C109143:N-arachidonylphosphatidylethanolamine; D010714:Phosphatidylethanolamines