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OPIOIDES Y
CANNABINOIDES
Rafael MALDONADO
Lab of Neuropharmacology Pompeu Fabra University
Barcelona
Cannabis sativa
Δ9-THC (Gaoni & Mechoulam, 1964) +
More than 60 Actif Compounds
CannabinoidReceptors
E
LL
M
472
1
1
360
CB1 , CB2 • Cells of the immune system
• Hippocampus • Basal Ganglia • Cerebellum • Other brain areas • Peripheral tissues
1990 1992
Δ9-Tetrahydrocannabinol O
OH1964
Cannabinoid receptor
Agonist
Β/γα* GTP
G Protein
Protein kinase A MAP kinases
Ca++ K+
The cannabinoid receptor
Endocannabinoidsareproducedondemandfromthecellmembrane
N H
O O
P O O -
O O - R 2
R 1 O
O O
C H O - R 3 O H
N H
O H O
O O
C H O H
O H
N A P E - P L D D A G L i p a s e
Phospholipid-derived precursors
Endocannabinoids
Degradation products
2-Arachidonoylglycerol Anandamide
Phospholipid remodeling
O O H
H 2 N O H H O C H O H O H
F a t t y A c i d A m i d e H y d r o l a s e M A G L i p a s e
Endocannabinoidssystemandpain
o Endocannabinoidsarereleaseinthecentralnervoussystemduringpainstates
o Endocannabinoids inhibit the transmission andpercep9onofnocicep9ves9muli
o CB1 and CB2 cannabinoid agonists have analgesiceffectsinmul9pleanimalmodelsandinhumans
BRAIN
BRAIN STEM
LOCUS COERULEUS
BRAIN STEM
SPINAL CORD
CORTEX
THALAMUS
HIPOTHALAMUS LIMBIC SYSTEM
SPIN
OT
HA
LA
MIC
PAT
HW
AY
PAG
N. RAPHE MAGNUS
OPIOIDS
LOCUS COERULEUS
CORTEX
THALAMUS
PAG
N. RAPHE MAGNUS
1.2 1.1
2.2
2.1
1.3
2.3
3.1
3.2
BRAIN
BRAIN STEM
BRAIN STEM
SPINAL CORD
1. Inhibition of pain transmission
3. Change in pain perception and significance
2. Activation of the inhibitory descending pathway
HIPOTHALAMUS LIMBIC SYSTEM
SPIN
OT
HA
LA
MIC
PAT
HW
AY
CANNABINOIDS
1. Inhibition of pain transmission
3. Change in pain perception and significance
2. Activation of the inhibitory descending pathway
LOCUS COERULEUS
CORTEX
TÁLAMO
PAG
N. RAPHE MAGNUS
1.2 1.1
2.1
2.2
3.1 BRAIN
BRAIN STEM
BRAIN STEM
SPINAL CORD
HIPOTHALAMUS LIMBIC SYSTEM
SPIN
OT
HA
LA
MIC
PAT
HW
AY
3.2
Opioids Cannabinoids
Disorientation/dizzines + +
Emesis + (antiemetic)
Constipation + -
Respiratory depression + -
Cardiovascular side effects + +
Urinary retention + -
Tolerance + (+)
Physical dependence + -
Memory impairment - +
THERAPEUTIC POTENTIAL USE
Neuropathic pain
Inflammatory pain
Opioid receptors
mu, delta & kappa
CB1
Cannabinoid receptors
CB2
THERAPEUTIC POTENTIAL USE
Neuropathic pain
Inflammatory pain
• Mostcommonformofarthri9s
• Degenera9ve,slowlyprogressingjointdisease
• Limitedefficacyofthesymptoma9ctreatment
Osteoarthri9s
Modelofosteoarthri9cpaininducedbymonosodiumiodoacetate(MIA)
• Wild-type• CB1KO• CB2KO• CB2xP(CB2over-expressioninCNS)
MIA:condrocyteglycolysisinhibitor
Mechanicalallodynia
Intra-ar9cularinjec9onofMIA
CrucialroleofCB2Rinosteoartri9spainCB1KO
CB2KO
CB2xP
Gene9callymodifiedmiceforCB1RandCB2RdevelopedsimilarhistologicalchangesaTerMIAinjec9on
Osteoarthri9cpain,emo9onalstateandcogni9vefunc9ons
Chronicosteoarthri9cpainAltera9onsoftheemo9onalstate(anxiety,depression)
(Goldenberg,2010)
Cogni9vedeficits(memory,decisionmaking)
(Hartetal,2000;DickandRashiq,2007)
RoleofCB1RandCB2Rintheemo9onalaltera9onsinducedbyMIA
1weekpostMIAinjec9on
SAL
MIACB1knockoutmice
CB2knockoutmice
%entriesinopen Totalentries%tinopenarms
%9me(s)
%entrie
s(coun
ts)
entrie
s(coun
ts)
0
10
20
30
40
50
0
5
10
15
20
25
30
0
10
20
30
40
50
0
10
20
30
40
50
%tinopenarms totalentries
WT CB1KO
%entrie
s(coun
ts)
entrie
s(coun
ts)
0
5
10
15
20
25
30
0 5
10 15 20 25 30 35
%entriesinopenarms
WT CB1KO WT CB1KO
%9me(s)
WT CB2KO WT CB2KO WT CB2KO
RoleofCB1RandCB2RinthememorydeficitinducedbyMIA
HABITUATION TRAINING TEST
Discrim
ina9
oninde
x
Discrim
ina9
oninde
x
WT CB1KO WT CB1KO-0,20
-0,10
0,00
0,10
0,20
0,30
0,40
0,50
0,60
-0,20
-0,10
0,00
0,10
0,20
0,30
0,40
0,50
0,60
CB1knockoutmice CB2knockoutmice
SAL
MIADiscrim
ina9
oninde
x
WT CB2KO-0,20
-0,10
0,00
0,10
0,20
0,30
0,40
0,50
0,60
Mechanicalallodynia
Anxiety Cogni9vedeficits
CB1KO
CB2KO
CB1KO
CB2KOCB2KO
CB1KO
Osteoartri9sMIAmodel
Evalua9onoftheendocannabinoidlevelsinthemouseosteoartrithispainmodel
Amygdala Hippocampus Prefrontalcortex
Plasma
0
4
8
12
16
20
0
4
8
12
16
20
0
4
8
12
16
20
24
0
4
8
12
16
20
24
0 4 8
12 16 20 24
0
2
4
6
8
10
nmol
/g
nmol
/g
nmol
/g
pmol
/g
pmol
/g
pmol
/g
2-AG 2-AG 2-AGAEA AEA AEA
0
10
20
30
40
50
60
0,0
0,2
0,4
0,6
0,8
ng/m
l
ng/m
l
SAL
MIA
2-AG AEA
LC/MS-MS
Roleoftheendocannabinoidsysteminosteoarthri9s:extrapola9ontohumans
Ø PainØ Anxietyanddepressivestate
Ø Cogni9on(visualmemory)
Ø Plasma9clevelsofendocannabinoids
Ø CB1RandCB2Rgeneexpressioninperipheralbloodlymphocytes
Subjects:Ø 16osteoarthri9spa9ents
Ø 14healthyvolunteers
Pain,affec9veandcogni9veparameters
inosteoarthri9spa9ents
Plasma9clevelsofendocannabinoidsinosteoarthri9spa9ents
Plasma
0
10
20
30
40
50
60
0,0
0,2
0,4
0,6
0,8
ng/m
l
ng/m
l SAL
MIA
2-AG AEA
InaccordancewithmouseMIAmodel
LC/MS-MS
CB1RandCB2Rgeneexpressioninperipherallymphocytes
VacutainerCPTtube(NC:1ml,Ficoll:2ml)
Bloodsample+HumanTotalLymphocyte
EnrichmentCocktail
Healthyvolunteers Osteoarthri9spa9ents
Correla9onsbetweenplasma9clevelsof2-AGandosteoarthri9sparameters
Conclusions
ü Theendocannabinoidsystem is involved in thephysiopathological processes leading to pain andemo9ona l a l t e r a9ons a s soc i a t ed w i thosteoarthri9s
ü The endocannabinoid system represents ap o t e n 9 a l b i om a r k e r a n d i n t e r e s 9 n gpharmacological target for therapeu9c purposesinosteoarthri9spain
Acknowledgements
JorgeManzanares
FranciscoNavarrete
RafaelMaldonado
CarmenLaPorta
AndreeaBura
RafaelDeLaTorre
AntoniPastor
JordiMonfort
JoneLlorente