NEUROBIOLOGICAL MECHANISMS INVOLVED IN OPIOID PHARMACOLOGICAL EFFECTS

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NEUROBIOLOGICAL MECHANISMS INVOLVED IN OPIOID
PHARMACOLOGICAL EFFECTS

• Rafael MALDONADO
• Laboratory of Neuropharmacology
• University Pompeu Fabra
• Barcelona, Spain

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Mu-opioid receptor1993. Chen et al., Thompson et
al.Seven transmembrane domains (398 AA) CNS
peripheral tissues Delta-opioid receptor1992.
Evans et al., Kieffer et al. Seven transmembrane
domains (372 AA) CNS peripheral
tissuesKappa-opioid receptor1993. Meng et al.,
Yasuda et al. Seven transmembrane domains (380
AA) CNS peripheral tissues
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Neuroanatomical distribution of the mu-opioid
receptors
from Mansour, TINS, 1995
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opioid
receptor

G Protein
K
Ca
B/g
a
GTP
Protein Kinase A
Protein Kinase C
MAP Kinases
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PRODYNORPHINDynorphin A (k) Dynorphin B (k)
a-neoendorphin (k) b-neoendorphin (k)
Leu-enkephalin (d) (ENDOMORPHINS)????
PROOPIO- MELANOCORTINb-endorphin (m ,
d) PROENKEPHALINLeu-enkephalin (d)
Met-enkephalin (d)
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MU-OPIOID
RELEASE
DELTA-OPIOID
SYNTHESIS
AXONIC TRANSPORT
KAPPA-OPIOID
ENZYMATIC DEGRADATION
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Mechanisms involved in opioid-induced analgesia
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Neural pathways involved in pain transmission and
integration
CORTEX
BRAIN
THALAMUS
BRAIN
HIPOTHALAMUS
LIMBIC SYSTEM
PAG
BRAIN STEM
BRAIN STEM
LOCUS COERULEUS
SPINOTHALAMIC PATHWAY
BRAIN STEM
N. RAPHE MAGNUS
SPINAL CORD
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Pharmacological activation of the endogenous
opioid system produces antinociception
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1
BRAIN
CORTEX
3
THALAMUS
BRAIN
HYPOTHALAMUS
LIMBIC SYSTEM
BRAIN STEM
2
PAG
BRAIN STEM
2
LOCUS COERULEUS
SPINOTHALAMIC PATHWAY
BRAIN STEM
2
N. RAPHE MAGNUS
SPINAL CORD
1
1
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ADDICTION Compulsive drug intake in order to
obtain rewarding effects and/or to avoid the
negative effects of drug withdrawal, which is
maintained despite adverse consequences for the
user
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Mechanisms involved in opioid-induced physical
dependence
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NALOXONE-PRECIPITATED SOMATIC SIGNS OF MORPHINE
WITHDRAWAL IN MOR KNOCKOUT MICE
40
8
10

30
8
6
6
20
SNIFFING
4
JUMPPIMNG
WET DOG SHAKES
4
10
2
2
0
0
0
SALINE MORPHINE
SALINE MORPHINE
SALINE MORPHINE
30
6
6
5
20
4
4
3
TREMOR
PAW TREMOR
TEETH CHATTERING
10
2
2
1
0
0
0
SALINE MORPHINE
SALINE MORPHINE
SALINE MORPHINE
MUTANT
WILD-TYPE
MORPHINE PHYSICAL DEPENDENCE IS PRESERVED IN DOR
KOR KNOCKOUT MICE
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opioid
receptor

G Protein
B/g
a
GTP
Adenylyl cyclase
LOCUS COERULEUS Other brain structures (Mesolimbic
system, Striatum, Cortex, PAG)
Protein Kinase A
Phosphoproteins
CREB
Nucleus
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ACUTE MORPHINE TREATMENT
LOCUS COERULEUS
CORTEX HIPOCAMPO
Noradrenergic neuron
Opioid neuron
?
NA release
?
Enkephalins
MORPHINE
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CHRONIC MORPHINE TREATMENT
CORTEX HIPOCAMPO
LOCUS COERULEUS
Noradrenergic neuron
Opioid neuron
?
Normal NA release
PKA
Up-regulation
?
Enkephalins
MORPHINE
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MORPHINE WITHDRAWAL
CORTEX HIPOCAMPO
LOCUS COERULEUS
Noradrenergic neuron
Opioid neuron
?
NA release
PKA
Up-regulation
Enkephalins
?
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Mechanisms involved in opioid-induced rewarding
effects
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MORPHINE-INDUCED PLACE CONDITIONING IN MOR
KNOCKOUT MICE
500
400
300
WILD-TYPE
Score (s)
200
MUTANT
100
0
-100
MORPHINE
SALINE
MORPHINE REWARDING EFFECTS ARE PRESERVED IN DOR
KOR KNOCKOUT MICE
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MORPHINE CONDITIONED PLACE PREFERENCE IN D2
DOPAMINERGIC RECEPTOR KNOCKOUT MICE
150
100
50
Score (Sec)
0
-50
-100
SALINE
MORPHINE 3 mg/kg
Wild
-type mice
D2 Knockout mice
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Common Neural Substrate for Drug Addiction
From Nestler, Nature Rev Neurosci, 2119, 2001
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Nucleus Accumbens
Psychostimulants
Dopamine
Ventral Tegmental Area
Opioids Cannabinoids Alcohol Nicotine