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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.
“Is it possible to develop an effective analgesic medication that does not have abuse potential?”
Alternative TitleAlternative TitleAlternative TitleAlternative Title
Reward PathwayReward PathwayReward PathwayReward Pathway
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?
• Noxious Stimulus-Induced Antinociception • Induced by
» Capsaicin (spicy component of chili peppers)» Thermal stimulation
Pain-Induced AnalgesiaPain-Induced AnalgesiaPain-Induced AnalgesiaPain-Induced Analgesia
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
-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
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)
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.
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
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
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
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
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
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
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
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
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
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?
Jon Levine
Brian Schmidt
Claudia Tambeli
Lei Luo
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