The tools of the trade - An overview of the pharmacology of the endocannabinoid system

The endocannabinoid system can be manipulated pharmacologically in a variety of ways, including directly acting agonists and inverse agonists, and indirectly acting compounds which affect the synthesis, cellular accumulation and metabolism of the two main endocannabinoids, anandamide and 2-arachidonoylglycerol. In this overview, the most commonly used compounds are discussed, primarily with respect to their targets of action and to their selectivities vis a vis off targets. For direct acting compounds such as cannabinoid receptor agonists, it is suggested that the use of several compounds with different chemical structures at relevant doses or concentrations is likely to minimise the risk of misinterpreting an off target effect as being an action mediated by cannabinoid receptors. For indirectly acting compounds, the same reasoning applies, and in the case of compounds affecting the accumulation of anandamide, it is important to recognize that the molecular target of these compounds is far from clear. Nonetheless, judicious use of the array of pharmacological tools currently available, and combination of these tools with RNA interference techniques and the use of genetically modified animals, provides a powerful approach with which to characterize the endocannabinoid system in the body.