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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). Discovery of CB2. GPR55 a putative third cannabinoid receptor?.

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Discovery of CB2

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  1. In situ hybridization (Munro et al. 1993) Discovery of CB2

  2. Binding studies (Munro et al. 1993) Discovery of CB2

  3. In situ hybridization (Munro et al. 1993) Discovery of CB2

  4. GPR55 a putative third cannabinoid receptor? First described as a cannabinoid receptor in a patent by Astra-Zeneca in 2004

  5. GPR55 a putative third cannabinoid receptor? (Brown 2007)

  6. 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)

  7. Endogenous cannabinoids

  8. (Cadas et al 1996) Mechanisms of anandamide formation

  9. (Piomelli 2003) Mechanisms of 2-AG formation

  10. Accumulation of [3H] ethanolamide following incubation with [3H]AEA Accumulation of [3H] ethanolamide or [3H] arachidonate in phopholipids following incubation with [3H]AEA (Di Marzo et al 1994) Endocannabinoids’ inactivation system Degradation Fatty acid amido-hydrolase (FAAH)

  11. 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

  12. Inhibition of [3H]AEA accumulation by AM404 (Beltramo et al 1997) Endocannabinoids’ inactivation system Internalization

  13. (Piomelli 2003) AEA inactivation

  14. Fatty acid amide hydrolase (FAAH) Cycloxygenase-2 (COX-2), 12- and 15-lipoxygenases (LOXs) Cytochrome P450 (P450) (Giuffrida and McMahon 2009) AEA inactivation

  15. 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

  16. PLC NAT DAG NAPE MAGL FAAH PLD DGL PE-PC PIPX Endocannabinoids uptake uptake Endocannabinoids (AEA, 2-AG, noladin ehter, virodhamine, NADA) 2+ Ca K CB3 CB1 - CB2 + Gi/o Gi/o Gα12-13? ? - - SMase +/- AC ? - + ceramide ATP cAMP Raf-1 NFkappaB + JNK MAPK The endocannabinoid system

  17. Cannabinoid system physiological effects • Motor impairement • Memory impairement • Catalepsy • Temperature decrease • Analgesia • Pressure modification • Immune suppression/stimulation

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