Addiction Medicine: State of the Art 2003 Is There a Common Neural Substrate for Analgesia and Reward? Robert W. Gear, D.D.S., Ph.D.

“Is it possible to develop an effective analgesic medication that does not have abuse potential?” Alternative Title

Reward 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 Analgesia

Trigeminal jaw-opening reflex (JOR) Electrically stimulate mandibular incisor Measure amplitude of digastric EMG “Analgesia” = decrease in JOR Measuring Analgesia in the Rat

Pre-treatment30 min post-treatment Subcutaneous morphine 10 mg/kg Intraplantar capsaicin 250 mg msec mV

Analgesia: Noxious Stimulation vs Morphine

MethodsMethods 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 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 Receptors

Nicotinic Receptors

Opioid Receptor Subtypes capsaicin alone + kappa + delta + mu

RecapRecap 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. Receptors

NAc Dopamine / JOR

Summary: 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 Dopamine Dopamine in nucleus accumbens increases in response to administration of Opioids Cocaine/amphetamine Nicotine Noxious stimulation

ConclusionConclusion 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