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Addiction Medicine: State of the Art 2003 Is There a Common Neural Substrate for Analgesia and Reward?

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

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Addiction Medicine: State of the Art 2003 Is There a Common Neural Substrate for Analgesia and Reward?

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

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

  3. Reward Pathway

  4. 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?

  5. Pain-Induced Analgesia • Noxious Stimulus-Induced Antinociception • Induced by • Capsaicin (spicy component of chili peppers) • Thermal stimulation

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

  7. Pre-treatment 30 min post-treatment Subcutaneous morphine 10 mg/kg mV Intraplantar capsaicin 250 mg mV msec msec

  8. Analgesia: Noxious Stimulation vs Morphine

  9. Methods • 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.

  10. 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

  11. Intra-Accumbens Opioid / Dopamine Receptors

  12. Nicotinic Receptors

  13. Opioid Receptor Subtypes capsaicin alone + kappa + delta + mu

  14. 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 Recap

  15. Systemic Morphine - NAc Nic. Receptors

  16. NAc Dopamine / JOR

  17. Opioids Cocaine, amphetamine Nicotine Noxious stimulation Mu, delta, kappa receptors Dopamine receptors Acetylcholine nicotinic rec. Mu, delta, dopamine, nicotine receptors Summary: Intra-accumbens Receptors

  18. Summary: Intra-accumbens Dopamine Dopamine in nucleus accumbens increases in response to administration of • Opioids • Cocaine/amphetamine • Nicotine • Noxious stimulation

  19. Conclusion 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?

  20. Jon Levine Brian Schmidt Claudia Tambeli Lei Luo

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