Neuropharmacology: Opiates


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Lecture 14 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. ( at Willamette University. Includes pharmacokinetics, pharmacodynamics, and epidemiology.

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Neuropharmacology: Opiates

  1. 1. OpiatesBrian J. Piper, Ph.D.
  2. 2. GoalsHistoryExamplesPharmacodynamicsTreatmentEpidemiology
  3. 3. Terminology• Opiate: family of substances• Narcotic: class of drugs including opiates• Opioid: family receptors• Analgesics: drugs that decrease pain without unconsciousness• Anesthetic: drugs that decrease pain with unconsciousness• Naloxone (Narcan): short acting opioid antagonist• Naltrexone: long-acting opioid antagonist
  4. 4. History129-199 1783-1841 1817-1884
  5. 5. Widespread use of morphine in US between 1865-1906 Mrs. Winslows Soothing Syrup was an indispensable aid to mothers and child-care workers. Containing one grain (65 mg) of morphine per fluid ounce, it effectively quieted restless infants and small children. It probably also helped mothers relax after a hard days work. The company used various media to promote their product, including recipe books, calendars, and trade cards such as the one shown here from 1887 (A calendar is on the reverse side.).Source: Prof. Anagnostaras, UCSD
  6. 6. Origin Chemistry ScheduleMorphine Opium II (II-III) poppy Felix Hoffman, Bayer Acetyl=OCOH3Heroin I Production in 1898 OH to Acetyl Diacetylmorphine Synthesized in 1916, H to OHOxycodone Oxycontin produced in II (II-IV) OH to =O 1995Codeine Identified in 1832? -OH to 0CH3 II Methylmorphine (III-IV)
  7. 7. HistoryIn the following years, Heroin was a drug marketed by Bayer asa cough syrup without the nasty side effects of morphine. Source: Prof. Anagnostaras, UCSD
  8. 8. Potency (x-axis) vs. Efficacy (y-axis) 100Re 75spo 50 Hydromorphinens Morphinee 25 Codeine Aspirin 1 10 100 Log dose (mg)
  9. 9. Safety D gA ru 100• Effective Dose 50 ED 50 - Dose that produces an effect in 50% of a population E 50 D TD 50 L w o H h ig L gd gd s o ru o e Lethal/Toxic Dose LD 50 - Dose that kills 100 D gB ru 50% of a population 50• Safety Factor LD 50 /ED 50 E 50TD D 50 L w L gd gd s H h o o ru o e ig
  10. 10. Pharmacodynamics• Opioid Receptors • Mu: • Kappa: • Delta:
  11. 11. Delta Opioid Receptor
  12. 12. Delta Opiate ReceptorTradham (2011) Trends in Pharmacological Science, 32, 581-590.
  13. 13. Mu Receptor Distribution
  14. 14. Kappa Opiate Receptor
  15. 15. More terminology• Pro- larger precursor proteins (peptides)• Protease- enzyme that cut propeptide
  16. 16. Endogenous Substances
  17. 17. Knock-out• Knock-out: animal with Genotype Response gene made inoperative• Allele: alternative forms of +/+ Full gene +/- Partial• Diploid: organism with -/- Absent two sets of genes for each trait C57 Mouse• Homozygote: +/+ or -/-• Heterozygote: +/-
  18. 18. KO Example 1 2 3 4• Different opiate receptor (OR) knock-outs were tested• Male and female mice were placed on hot plate and time until jumping was recorded.• Filled Star: p < .05 sex difference within genotype (e.g. 1 vs. 2)• Open Star: p < .05 genotype difference within sex (e.g. 1 vs. 3)• What do you conclude? Martin, M. (2003). Eur J. Neurosci 17, 701-708.
  19. 19. KO Example A• Some evidence for sex difference A,D vs. B,C.• Mu opiate receptor is important for B thermal pain (males).• Other receptors also play a role in females. C D Martin, M. (2003). Eur J. Neurosci, 17, 701-708.
  20. 20. Comparison of Opioid ReceptorsReceptor Ligand Location FunctionMu Endorphin Striatum, NAc, PAG AnalgesiaDelta Enkepahlin Striatum, NAc, spinal cord Analgesia, olfactionKappa Dynorphin Striatum, NAc,hypothalamus TemperaturePAG: periaqueductal grayNAc: nucleus accumbens
  21. 21. Periaqueductal Gray• Midbrain structure• Near cerebral aqueduct
  22. 22. Opposites Effect Administration Withdrawal Temperature Hypothermia Hyperthermia Blood pressure ↓ ↑ Pupils constriction dilation Breathing depressed panting/yawning Pain ↓ ↑ Arousal relaxed restless G.I. function constipation diarrhea Sex ↓ sex drive Spontaneous ejaculation Mood euphoria depressionGrilly, D.M. (1998). Drugs and human behavior. Allyn: Needham Heights.
  23. 23. Dopamine & BehaviorMice of different strains: C57 (black), 129SV (white), and DBA2 (grey) received 3 mg/kgof morphine or saline (arrows). Motor-activity (left) and dopamine in the striatum (right)was recorded. Murphy et al. J Neurochem (2001) 79, 626-635.
  24. 24. Naltrexone• The opiate antagonist naltrexone (5 ng/kg) blocks the conditioned place preference to morphine (5 mg/kg).• Conditioned Place Preference (CPP) – Pretest: Drug Treatment – Test: no Drug, animals choose whether to spend time in environment associated with drug injectionsOlmstead et al. (2005). Psychopharm, 181, 576-81.
  25. 25. Codeine Addiction 2D6• Codeine -----> Morphine• Fluoxetine inhibits 2D6• Will fluoxetine help codeine addicts reduce their use?• All groups reduced codeine intake by Daily dose of codeine in people that received >40%. counseling and fluoxetine (circles), quinidine (triangles), or placebo (squares).Fernandes et al. (2002). J Clin Psychopharm, 22, 326-329.
  26. 26. Opiate Addiction Therapies• Narcotics Anonymous: 12 step program, limited effectiveness• Methadone: long-acting opiate agonist (oral)• LAAM: L-alpha-acetyl-methadol: longer acting opiate agonist
  27. 27. Tx: Methadone• Pill form used to prevent opiate withdrawal• Pros: limits use of other opiates• Cons: philosophical
  28. 28. Epidemiology (MtF)
  29. 29. Epidemiology: HeroinMTF:
  30. 30. Epidemiology: HeroinMTF:
  31. 31. Epidemiology: VicodinMTF:
  32. 32. Urban vs. Rural
  33. 33. Epidemiology: College PlansMTF:
  34. 34. Epidemiology: Non-HeroinMTF:
  35. 35. Celebrity Overdoses1979-2008 1943-1970 1964-1997 1943-1971 1949-1982 1960-1988
  36. 36. Celebrity OverdosesHeath Ledger Janis Joplin Chris Farley Jim Morrison 1979-2008 1943-1970 1964-1997 John Belushi Jean-Michel Basquiat 1943-1971 1949-1982 1960-1988
  37. 37. Overdose
  38. 38. Summary • History/Examples • Pharmacodynamics: Mu, Delta, Kappa • Epidemiology3 min: