EEndondocanabinoidcanabinoid systsystemem
Cannabis sativa L.Cannabis sativa L.Cannabis sativa L.Cannabis sativa L.Cannabis sativa L.Cannabis sativa L.Cannabis sativa L.Cannabis sativa L.
(marijuana(marijuana(marijuana(marijuana(marijuana(marijuana(marijuana(marijuana,,,,,,,, hahahahahahahahaššššššššisisisisisisisis))))))))
E F F E C T SE F F E C T SE F F E C T SE F F E C T S
42O cannabinoids
bronchodilatatoryantiemetic
snížení nitroočního tlaku
antispastic
analgesic
antiinflamatory
neuroprotective
imunomodulant
hypno/sedative
PSYCHOTROPICPSYCHOTROPIC →→→→→→→→ THCTHC
((GaoniGaoni && Mechoulam, 1964)Mechoulam, 1964)
CANNABIS SATIVACANNABIS SATIVA
marijuanamarijuana
increasing appetite
Endocannabinoid system (ECS)
Piomelli et al., 2000; Wilson R, 2002; Di Marzo V, 2005
CBCB1,21,2 receptorreceptorss (W.(W. DevaneDevane etet alal.,.,
1988)1988)
eendondoccanannnabinoidabinoidss (W.(W. DewaneDewane,,
L. Hanus , 1992, 1995, 2000)L. Hanus , 1992, 1995, 2000)
N
H
O
O
P
O
O-
O
O-R2
R1O
O
O
CH
O-R3
OH
N
H
OH
O
O
O
CH
OH
OH
NAPE-PLD DAG Lipase
precursors
from phospholipid
endocanabinoids
2-ArachidonoylglycerolAnandamide
fromfrom arachidonicarachidonic acidacid
• no storage
• active localy
• fast biodegradation
(metabolization + uptake)
O
OH
H2N
OH HO CH
OH
OH
Fatty Acid Amide Hydrolase MAG Lipase
EndoEndocannabinoidscannabinoids synthetizedsynthetized onon demanddemand
fromfrom
cellcell membranemembrane
Di Marzo, Nature 2001; Nature reviews 2004
Endocannabinoid system (ECS)
eendondoccanabinoidanabinoidss
= retrograderetrograde
synapticsynaptic
messengersmessengers
Piomelli et al., 2000; Wilson R, 2002; Di Marzo V, 2005
= modulatory system
of the CNS
CBR
R
E
T
E
FunctionFunction ofof thethe endoendoccanannnabinoidabinoid systsysteemm onon synapsesynapse
biodegradationbiodegradation
CB1 Receptor
Extracellular
N-terminal
Intracellular
C-terminal
Y
Extracellular
N-terminal
Intracellular
C-terminal
CB2 Receptor
Expresion of cannabinoid receptors
• cortex, hipocampus
• basal ganglia
• hypothalamus
• cerebellum
• spinal cord
• enteric nervous system
• adipocytes
• endothelial cells
• hepatocytes
• muscles
• GIT
CBCB11
• immun cells:
T cells, B cells, line, tonsiles
and
activovates glial cells, ↑↑ in neuropathies
CBCB22
Matsuda 1997; Cota et al 2003; Galiègue et al 1995;
Pertwee et al 1997; Liu et al 2005; Osei-Hyiaman et al 2005
antagonistantagonist
rimonabantrimonabant
THCTHCTHCTHCTHCTHCTHCTHC
causescauses dependencedependence tolerancetolerance andand
withdrawalwithdrawal syndromsyndrom
EFFECTSEFFECTS -- psychicpsychic ++ somaticsomatic
• euforia, sedation ( Howlet, 1995; Ameri, 1999; Chaperon a Thiebot, 1999 )
• analgesia (Johnson at al., 1981; Comton et al., 1992 )
•antiemetetic (Sallan et al., 1975;, Levitt, 1986; Darmani, 2000 )
• anticonvulsive ( Consroe et al., 1975; Grinspoon a Bakalar, 1993 )
• antispasmoid (“ movement disorders“) (Clifford, 1983; Meinck., 1993)
• antiasthmatic (Tashkin et al., 1975; Tashkin et al., 1993 )
• antiglaucomatic ( Adler a Geller, 1986; Porcella et al. 2000 )
(Costa a kol., 2000; Tanda a kol., 2000;
Justinová akol., 2003, 2005)
CBCB11 receptorreceptorss importantimportant inin ::
–– regultionregultion ofof foodfood intakeintake
–– lipid alipid a glucoseglucose metabolismmetabolism
Kirkham et al., 2002; DiMarzo et al., 2001; Jarmshidiet et al., Brit J Pharm., 2001;
Ravinet Trillou et al. 2003; Bensaid et al., 2003; Caballero, 2003; Van Gaal et al.
2005; Carr a Brunzell 2004; Pagotto a Pasquali, 2005; Eckel et al., 2005
inin developmentdevelopment ofof cardiometaboliccardiometabolic riskrisk factorsfactors
v
PROSPECTIVE USEPROSPECTIVE USE
of CBof CB11 cannabinoidcannabinoid receptorreceptor blockersblockers
decreasedecrease ofof cardiometaboliccardiometabolic riskrisk factorsfactors
inin smokingsmoking secessecessionsion
? ?? ? treatmenttreatment ofof drugdrug addictionaddiction? ?? ?