Neuropharmacology: Opiates

  • View

  • Download

Embed Size (px)


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.

Text of Neuropharmacology: Opiates

  • 1. OpiatesBrian J. Piper, Ph.D.

2. GoalsHistoryExamplesPharmacodynamicsTreatmentEpidemiology 3. Terminology Opiate: family of substances Narcotic: class of drugs including opiates Opioid: family receptors Analgesics: drugs that decrease painwithout unconsciousness Anesthetic: drugs that decrease pain withunconsciousness Naloxone (Narcan): short acting opioid antagonist Naltrexone: long-acting opioid antagonist 4. History129-199 1783-18411817-1884 5. Widespread use of morphine in US between1865-1906 Mrs. Winslows Soothing Syrup wasan 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. OriginChemistryScheduleMorphineOpiumII (II-III)poppyFelix Hoffman, BayerAcetyl=OCOH3Heroin IProduction in 1898OH to AcetylDiacetylmorphineSynthesized in 1916,H to OHOxycodone Oxycontin produced in II (II-IV)OH to =O1995Codeine Identified in 1832? -OH to 0CH3IIMethylmorphine (III-IV) 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. Potency (x-axis) vs.Efficacy (y-axis)100Re 75spo 50 HydromorphinensMorphinee 25 Codeine Aspirin1 10100 Log dose (mg) 9. SafetyD gAru 100 Effective Dose 50ED 50 - Dose thatproduces an effect in50% of a population E 50 DTD 50L w o H hig L gd gd soru o eLethal/Toxic DoseLD 50 - Dose that kills 100 D gB ru50% of a population 50 Safety FactorLD 50 /ED 50E 50TD D50L w L gd gd s H h ooru o e ig 10. Pharmacodynamics Opioid Receptors Mu: Kappa: Delta: 11. Delta Opioid Receptor 12. Delta Opiate ReceptorTradham (2011) Trends in Pharmacological Science, 32, 581-590. 13. Mu Receptor Distribution 14. Kappa Opiate Receptor 15. More terminology Pro- larger precursor proteins (peptides) Protease- enzyme that cut propeptide 16. Endogenous Substances 17. Knock-out Knock-out: animal with Genotype Responsegene made inoperative Allele: alternative forms of +/+Fullgene +/-Partial Diploid: organism with -/-Absenttwo sets of genes foreach traitC57 Mouse Homozygote: +/+ or -/- Heterozygote: +/- 18. KO Example 1 2 3 4Different opiate receptor (OR) knock-outs were testedMale 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. KO ExampleASome 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 DMartin, M. (2003). Eur J. Neurosci, 17, 701-708. 20. Comparison of Opioid ReceptorsReceptor Ligand Location FunctionMu EndorphinStriatum, NAc, PAG AnalgesiaDeltaEnkepahlin Striatum, NAc, spinal cord Analgesia, olfactionKappaDynorphinStriatum, NAc,hypothalamus TemperaturePAG: periaqueductal grayNAc: nucleus accumbens 21. Periaqueductal Gray Midbrain structure Near cerebral aqueduct 22. OppositesEffectAdministration WithdrawalTemperature HypothermiaHyperthermiaBlood pressurePupilsconstriction dilationBreathing depressedpanting/yawningPainArousal relaxedrestlessG.I. function constipation diarrheaSex sex driveSpontaneous ejaculationMoodeuphoria depressionGrilly, D.M. (1998). Drugs and human behavior. Allyn: Needham Heights. 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. NaltrexoneThe opiate antagonistnaltrexone (5 ng/kg)blocks the conditionedplace preference tomorphine (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. Codeine Addiction 2D6 Codeine -----> Morphine Fluoxetine inhibits 2D6 Will fluoxetine helpcodeine addicts reducetheir use? All groups reducedcodeine intake byDaily 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. Opiate Addiction Therapies Narcotics Anonymous: 12 step program,limited effectiveness Methadone: long-acting opiate agonist(oral) LAAM: L-alpha-acetyl-methadol: longeracting opiate agonist 27. Tx: Methadone Pill form used toprevent opiatewithdrawal Pros: limits use ofother opiates Cons: philosophical 28. Epidemiology (MtF) 29. Epidemiology: HeroinMTF: 30. Epidemiology: HeroinMTF: 31. Epidemiology: VicodinMTF: 32. Urban vs. Rural 33. Epidemiology: College PlansMTF: 34. Epidemiology: Non-HeroinMTF: 35. Celebrity Overdoses1979-20081943-1970 1964-1997 1943-1971 1949-1982 1960-1988 36. Celebrity OverdosesHeath LedgerJanis Joplin Chris Farley Jim Morrison1979-20081943-19701964-1997 John BelushiJean-Michel Basquiat1943-19711949-19821960-1988 37. Overdose 38. Summary History/Examples Pharmacodynamics: Mu, Delta, Kappa Epidemiology3 min: