addiction medicine: state of the art 2003 is there a common neural substrate for analgesia and...
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Addiction Medicine: State of the Art 2003Addiction Medicine: State of the Art 2003
Is There a Common Neural Substrate for Is There a Common Neural Substrate for Analgesia and Reward?Analgesia and Reward?
Addiction Medicine: State of the Art 2003Addiction Medicine: State of the Art 2003
Is There a Common Neural Substrate for Is There a Common Neural Substrate for Analgesia and Reward?Analgesia and Reward?
Robert W. Gear, D.D.S., Ph.D.Robert W. Gear, D.D.S., Ph.D.
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“Is it possible to develop an effective analgesic medication that does not have abuse potential?”
Alternative TitleAlternative TitleAlternative TitleAlternative Title
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Reward PathwayReward PathwayReward PathwayReward Pathway
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Opioids
Amphetamine
Cocaine
Nicotine
All these substances• Release dopamine in nucleus accumbens • Have high abuse potential• Produce analgesia in humans or animals
Is nucleus accumbens important for analgesia?
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• Noxious Stimulus-Induced Antinociception • Induced by
» Capsaicin (spicy component of chili peppers)» Thermal stimulation
Pain-Induced AnalgesiaPain-Induced AnalgesiaPain-Induced AnalgesiaPain-Induced Analgesia
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Trigeminal jaw-opening reflex (JOR)
• Electrically stimulate mandibular incisor• Measure amplitude of digastric EMG• “Analgesia” = decrease in JOR
Measuring Analgesia in the RatMeasuring Analgesia in the RatMeasuring Analgesia in the RatMeasuring Analgesia in the Rat
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-2 0 2 4 6 8 10 12 14-4
-2
0
2
4
-2 0 2 4 6 8 10 12 14
-2 0 2 4 6 8 10 12 14-4
-2
0
2
4
-2 0 2 4 6 8 10 12 14
Pre-treatment 30 min post-treatment
Subcutaneousmorphine10 mg/kg
Intraplantar capsaicin
250 mg
msec msec
mV
mV
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Analgesia: Noxious Stimulation vs MorphineAnalgesia: Noxious Stimulation vs MorphineAnalgesia: Noxious Stimulation vs MorphineAnalgesia: Noxious Stimulation vs Morphine
Time post-treatment (min)
0 15 30 45 60
JOR
EM
G A
tten
uat
ion
(%
)
80
60
40
20
0
-20
Morphine (10 mg/kg)CapsaicinH2O (50ºC)
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MethodsMethodsMethodsMethods
• To identify receptor subtypes mediating an effect, selective antagonists are administered.
• To isolate an effect to a particular brain region, agents are microinjected (0.5 µl). The region of interest is targeted with a stereotaxic device.
• We targeted nucleus accumbens and microinjected selective antagonists for opioid, dopamine, and nicotinic receptors.
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Nucleus Accumbens ExperimentsNucleus Accumbens ExperimentsNucleus Accumbens ExperimentsNucleus Accumbens Experiments
• Antagonists for opioid receptors subtypes:» Non-selective: naloxone» Mu selective: CTOP» Delta selective: naltrindole» Kappa selective: nor-binaltorphimine
• Acetylcholine nicotinic receptors: mecamylamine• Dopamine receptors: flupenthixol
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Intra-Accumbens Opioid / Dopamine ReceptorsIntra-Accumbens Opioid / Dopamine ReceptorsIntra-Accumbens Opioid / Dopamine ReceptorsIntra-Accumbens Opioid / Dopamine Receptors
Time post-capsaicin (min)
0 15 30 45 60
JOR
EM
G a
tten
uat
ion
(%
) 80
60
40
20
0
-20
Capsaicin alone
+ Naloxone+ Flupenthixol
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Nicotinic ReceptorsNicotinic ReceptorsNicotinic ReceptorsNicotinic Receptors
Time post-treatment (min)
0 15 30 45 60
JOR
EM
G A
tten
ua
tio
n (
%)
80
60
40
20
0
-20
Capsaicin
+ Mecamylamine
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Post-capsaicin (min)
0 15 30 45 60
JOR
att
enua
tioin
(%
)80
60
40
20
0
-20
-40
capsaicin alone
nor-binaltorphimine
CTOP
naltrindole
Opioid Receptor SubtypesOpioid Receptor SubtypesOpioid Receptor SubtypesOpioid Receptor Subtypes
capsaicin alone
+ kappa
+ delta+ mu
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RecapRecapRecapRecap
• Noxious stimuli can produce analgesia equivalent to high dose morphine
• This analgesic effect is mediated in nucleus accumbens
• Opioid, dopamine and nicotinic receptors are all involved
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Systemic Morphine - NAc Nic. ReceptorsSystemic Morphine - NAc Nic. ReceptorsSystemic Morphine - NAc Nic. ReceptorsSystemic Morphine - NAc Nic. Receptors
Post-treatment (min)
0 15 30 45 60
JOR
EM
G A
tten
uat
ion
(%
) 80
60
40
20
0
-20
morphine (5 mg/kg)
+ mecamylamine
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0 10 20 30 40 50 60
-200
20406080
100120
JORDopamine
0 10 20 30 40 50 60
Ch
ang
e (%
)
-200
20406080
100120
Post-capsaicin (min)
0 10 20 30 40 50 60-40
-20
0
20
40
60
80
Post-morphine (min)
0 10 20 30 40 50 60-40
-20
0
20
40
60
80
Naive
MorphineTolerant
Systemic Morphine Capsaicin
NAc Dopamine / JORNAc Dopamine / JORNAc Dopamine / JORNAc Dopamine / JOR
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Summary: Intra-accumbens ReceptorsSummary: Intra-accumbens ReceptorsSummary: Intra-accumbens ReceptorsSummary: Intra-accumbens Receptors
• Opioids • Cocaine, amphetamine• Nicotine• Noxious stimulation
• Mu, delta, kappa receptors• Dopamine receptors• Acetylcholine nicotinic rec.• Mu, delta, dopamine,
nicotine receptors
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Summary: Intra-accumbens DopamineSummary: Intra-accumbens DopamineSummary: Intra-accumbens DopamineSummary: Intra-accumbens Dopamine
Dopamine in nucleus accumbens increases in response to administration of
• Opioids• Cocaine/amphetamine• Nicotine• Noxious stimulation
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ConclusionConclusionConclusionConclusion
Nucleus accumbens appears to be a neural substrate for both behavioral reinforcement and
analgesia.
so
It may not be possible to separate analgesic effects from abuse potential.
but an intriguing unanswered question remains:
Can noxious stimuli be rewarding?
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Jon Levine
Brian Schmidt
Claudia Tambeli
Lei Luo