Box 1 | The endogenous cannabinoid system

From the following article:

Cannabinoids: potential anticancer agents

Manuel Guzmán

Nature Reviews Cancer 3, 745-755 (October 2003)

doi:10.1038/nrc1188

Plant-derived cannabinoids such as Delta9-tetrahydrocannabinol (THC), as well as their synthetic analogues, act in the organism by activating specific cell-surface receptors that are normally engaged by a family of endogenous ligands — the endocannabinoids (see figure). The first endocannabinoid discovered was named anandamide (AEA), from the sanscrit ananda, 'internal bliss', and with reference to its chemical structure — arachidonoylethanolamide, the amide of arachidonic acid (AA) and ethanolamine (Et)100. A second arachidonic-acid derivative (2-arachidonoylglycerol (2-AG)) that binds to cannabinoid receptors was subsequently described101, 102. These endocannabinoid ligands, together with their receptors103, 104 and specific processes of synthesis105, 106, uptake107 and degradation108, constitute the endogenous cannabinoid system.

Cannabinoids: potential anticancer agents 

A well-established function of the endogenous cannabinoid system is its role in brain neuromodulation. Postsynaptic neurons synthesize membrane-bound endocannabinoid precursors and cleave them to release active endocannabinoids following an increase of cytosolic free Ca2+ concentrations: for example, after binding of neurotransmitters (NTs) to their IONOTROPIC (iR) or METABOTROPIC (mR) receptors109. Endocannabinoids subsequently act as retrograde messengers by binding to presynaptic CB1 cannabinoid receptors, which are coupled to the inhibition of voltage-sensitive Ca2+ channels and the activation of K+ channels110. This blunts membrane depolarization and exocytosis, thereby inhibiting the release of NTs such as glutamate, dopamine and gamma-aminobutyric acid (GABA) and affecting, in turn, processes such as learning, movement and memory, respectively111. Endocannabinoid neuromodulatory signalling is terminated by an unidentified membrane-transport system107 (T) and a family of intracellular degradative enzymes, the best characterized of which is fatty acid amide hydrolase (FAAH), which degrades AEA to AA and Et108. The endogenous cannabinoid system might also exert modulatory functions outside the brain, both in the peripheral nervous system and in extraneural sites, controlling processes such as peripheral pain, vascular tone, INTRAOCULAR PRESSURE and immune function.