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