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OPIATES

Psych 181: Dr. Anagnostaras Lecture 8. OPIATES. Opioids. Opiates alkaloids found in the opium poppy (Papaver somniferum) [Gk. opion = “poppy juice”] Opioids compounds with opiate-like actions, including, but not confined to opiates (e.g., synthetic, endogenous opioids). Types of opioids.

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OPIATES

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  1. Psych 181: Dr. Anagnostaras Lecture 8 OPIATES

  2. Opioids Opiates • alkaloids found in the opium poppy (Papaver somniferum) • [Gk. opion = “poppy juice”] Opioids • compounds with opiate-like actions, including, but not confined to opiates (e.g., synthetic, endogenous opioids)

  3. Types of opioids 1. Naturally-occurring • opium • sap fromopium poppy Two major activealkaloids • morphine • codeine

  4. Morphine • Morpheus (god of Dreams) -son of Hypnos • ~ 10% of opiumby weight

  5. Codeine • methylmorphine • ~ 0.5% ofopium

  6. 2. Semi-synthetics

  7. 2. Semi-synthetics Heroin • diacetylmorphine • addition of two acetyl groups to morphine • ~ 10x more potent than morphine • pharmacological effect usually thought to be identical to morphine • in brain: heroin > morphine(new data suggest morphine and heroinmay have different actions; 1999)

  8. Semi-synthetic analgesics • Hydromorphone (Dilaudid®) • Hydrocodone (Hycodan®, Vicodin®) • Oxycodone (Percodan®, Oxycontin®)

  9. 3. Synthetics Phenylpiperidines • Fentanyl “china white” • Carfentanil (Wildnil®) • Meperidine (Demerol®) (MPPP) Methadone & Congeners • Methadone (Dolophine®) • Propoxyphene (Darvon®) Benzomorphans • Pentazocine (Talwin®)

  10. Analgesic potency Analgesic potency Mild to moderate pain codeine, propoxyphene (Darvon®) Moderately severe pain meperdine (Demerol®) Severe pain heroin, hydromorphone (Dilaudid®)

  11. "Perc-a-pop"

  12. 4. Opioid antagonists • naloxone (Narcan®) • naltrexone • Suboxone® (buprenorphine + naloxone)

  13. 5. Endogenous opioids • Enkephalins, endorphins and dynorphins • Morphine & codeine?

  14. History of use - opium Since recorded history Ingredient in all sorts of medicinal preparations

  15. History of use - morphine “Soldiers disease”

  16. History of use Ads for heroin

  17. Major effects Analgesia • Relief of pain in absence of impairment in other sensory modalities Euphoria - Pleasure • Produce sense of well being, reduce anxiety, positive feelings

  18. Other effects • Nausea & vomiting • Respiratory depression • Miosis (opposite of mydriasis) • Gastrointestinal effects • Cough Suppression • Motor effects

  19. Effects of repeated administration Tolerance, withdrawal & sensitization

  20. Tolerance and withdrawal LC unit activity Behavioral withdrawal score Time (hr) 12.18

  21. Sensitization • Psychomotor stimulant effects • Rewarding effects (conditioned place preference)

  22. Mechanisms of action • Primary action on opioid receptors located in CNS +/or periphery Different effects due to action at • Different receptor subtypes • Receptors in different locations

  23. Endogenous opioids Translation Post-translational processing 11.4

  24. Opioid peptide gene families Three different gene families • Proopiomelanocortin (POMC) • Proenkephalin • Prodynorphin (‘proenkephalin B’) 12.5

  25. Precursor gene families Proopiomelanocortin (POMC) • ß-endorphin • ACTH, melanocortin SH Proenkephalin -> Enkephalins • met-enkephalin & 2 extended met-enk • leu-enkephalin • Prodynorphine - forms of leu-enkephalin • Dynorphins, A and B • Neoendorphins, µ and 

  26. Differential distribution Endorphins • discrete • hypothalamic - endocrine related Enkephalins and Dynorphins • wide distribution, local circuit and short axon projections

  27. Opioid receptors

  28. Opioid receptors SubtypePreferred Ligand Mu (µ) Morphine & endorphins Delta () Enkephalins Kappa () Ketocyclazocine & dynorphins • Each subtype has subtypes

  29. Opioid receptors   

  30. Cellular actions • G protein coupled receptors • inhibitory Negatively-coupled 12.4

  31. Role in drug action

  32. Analgesia • Spinal actions • Dorsal horn of spinal cord • primary pain afferents 4.2

  33. Analgesia Spinal actions • inhibit incoming pain signals Opioid receptor 12.8

  34. Analgesia Supraspinal actions 12.10

  35. Analgesia Supraspinal actions Stimulation > analgesia andinhibit cells in dorsal horn 12.10

  36. Analgesia Supraspinal actions Lesion > block analgesiato systemic or local morphine 12.10

  37. Analgesia Supraspinal actions • µ1 sites seem most important • Specific blockade of µ1 shifts dose-response curve for morphine analgesia up to 12 fold to right

  38. Analgesia Heroin vs. Morphine • difference pharmacokinetic? • recent evidence for different receptors - MOR-1 knockouts

  39. Analgesia - MOR1 knockouts Schuller et al., Nature Neurosci. (1999) Morphine, but not heroin, analgesiaabolished in Mor1 knockout mice Analgesia (%) heroin > 6-acetyl-morphine in vivo

  40. Reinforcing effects

  41. Reinforcing effects • All classical opioid drugs of abuse have a preference for µ sites (e.g., morphine, heroin, methadone, fentanyl etc.) •  may contribute, but little known •  compounds are not self-administered • psychomimetic and aversive in humans

  42. Opioid/DA interaction • Intra-VTA opioid support SA and CPP • DA antagonist or 6-OHDA lesion impair SA • DA antagonist into VTA or ACC impair SA

  43. Mechanism µ compounds: • Increase DA cell firing • Increase DA release in ACC • Accompanied by locomotor activation

  44. Model for reinforcing effects Site of action • VTA – accumbens DA system “Disinhibition”  12.16

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