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Discovery of CB2 In situ hybridization (Munro et al. 1993) Discovery of CB2 Binding studies (Munro et al. 1993) Discovery of CB2 In situ hybridization (Munro et al. 1993) GPR55 a putative third cannabinoid receptor? First described as a cannabinoid receptor in a patent by Astra-Zeneca in 2004 (Brown 2007) GPR55 a putative third cannabinoid receptor? (Brown 2007) Discovery of endogenous cannabinoids (Devane et al. 1992) • Screening for endogenous cannabinoid ligands using porcine brain • Identification of an arachidonic acid derivative (arachidonylethanolamide) that binds to CB receptor • This arachidonic acid derivative inhibited in a concentration dependent manner the binding of radiolabelled cannabinoid to synaptosomal membrane. • The compound is named Anandamide from the Sanskrit ananda (bliss, delight) Endogenous cannabinoids Mechanisms of anandamide formation (Cadas et al 1996) Mechanisms of 2-AG formation (Piomelli 2003) Endocannabinoids’ inactivation system Degradation Accumulation of [3H] ethanolamide following incubation with [3H]AEA Fatty acid amido-hydrolase (FAAH) Accumulation of [3H] ethanolamide or [3H] arachidonate in phopholipids following incubation with [3H]AEA (Di Marzo et al 1994) Endocannabinoids’ inactivation system Internalization Time course of [3H]AEA accumulation in neurons (circle) or astrocytes (square) (Beltramo et al 1997) Linewaver-Burk analysis of [3H]AEA accumulation in neurons (B) and astrocytes (C) Endocannabinoids’ inactivation system Internalization Inhibition of [3H]AEA accumulation by AM404 (Beltramo et al 1997) AEA inactivation (Piomelli 2003) AEA inactivation Fatty acid amide hydrolase (FAAH) Cycloxygenase-2 (COX-2), 12- and 15-lipoxygenases (LOXs) Cytochrome P450 (P450) (Giuffrida and McMahon 2009) 2-AG inactivation AEA and 2-AG internalization occur through a substantially common mechanism Monoacylglycerol lipase (MAGL) is considered the major enzyme responsible for 2-AG metabolism The endocannabinoid system PLC NAT DAG NAPE PE-PC FAAH PLD PIPX MAGL DGL Endocannabinoids uptake uptake Endocannabinoids (AEA, 2-AG, noladin ehter, virodhamine, NADA) Ca 2+ CB2 Gi/o +/- - ? K + - - CB3 CB1 Gi/o Gα12-13? SMase AC - + ceramide ATP cAMP NFkappaB Raf-1 + MAPK JNK ? Cannabinoid system physiological effects • • • • • • • Motor impairement Memory impairement Catalepsy Temperature decrease Analgesia Pressure modification Immune suppression/stimulation
