In vivo imaging of the endocannabinoid system: a novel window to a central modulatory mechanism in humans

Abstract

Marijuana (Cannabis sativa) has been used both recreationally and for medicinal purposes since ancient times, but it was not until the 1990s that the receptors responsible for many of the actions of Δ-tetrahydrocannabinol (Δ-THC), the main psychoactive ingredient of cannabis, were identified [1] and cloned [2]. Since then, the knowledge on the endogenous cannabinoid system, its physiology, pharmacology and therapeutic potential has expanded enormously. This so-called endocannabinoid system (ECS) consists of two currently known subtype receptors, CB1 and CB2, their endogenous ligands, synthesising and degrading enzymes such as fatty acid amide hydrolase (FAAH) and several transport proteins [3, 4]. Endocannabinoids are a new class of lipids, which include amides, esters and ethers of long chain polyunsaturated fatty acids. Unlike classical neurotransmitters, endocannabinoids are typically formed postsynaptically “on demand” by lipid synthesis and exert their effects predominantly on presynaptic located receptors [5]. Anandamide (N-arachidonoylethanolamine; AEA) and 2arachidonoylglycerol are the main endogenous agonists of cannabinoid receptors able to mimic several pharmacological effects of Δ-THC. Their activity at the receptors is limited by cellular uptake followed by intracellular hydrolysis [6]. The majority of the cannabinoid effects on the central nervous system (CNS) are mediated by the CB1 receptor (CB1-R), a G-protein-coupled seven-domain transmembrane receptor which appears to be one of the most abundant G-coupled receptors in the human brain [7]. Signal transduction through the CB1-R occurs through inhibition of cyclic adenosine monophosphate (cAMP) production through inhibition of adenylate cyclase, inhibition of calcium influx, activation of potassium channels and activation of the mitogen-activated protein kinase (MAPK) pathway. The CB2-R is also expressed in the brain but at much lower levels in the normal brain [8]. CB2-R are predominantly found on activated microglia in the CNS or outside the CNS in the immune system: B-lymphocytes in the spleen, lymph nodes, tonsils and the GI tract [9]. Signal transduction through the CB2-R also occurs via inhibition of adenylate cyclase and activation of MAPK [9].