Neuropharmacology: Opiates
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OpiatesBrian J. Piper, Ph.D.
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Goals
History
Examples
Pharmacodynamics
Treatment
Epidemiology
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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
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History129-199 1783-1841
1817-1884
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Widespread use of morphine in US between 1865-1906
Mrs. Winslow's 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 day's 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
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Origin Chemistry Schedule
Morphine Opium
poppyII (II-III)
Heroin Felix Hoffman, Bayer
Production in 1898
Acetyl=OCOH3
OH to Acetyl
Diacetylmorphine
I
Oxycodone Synthesized in 1916, Oxycontin produced in 1995
H to OH
OH to =OII (II-IV)
Codeine Identified in 1832? -OH to 0CH3
MethylmorphineII
(III-IV)
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History
Source: Prof. Anagnostaras, UCSD
In the following years, Heroin was a drug marketed by Bayer as a cough syrup without the nasty side effects of morphine.
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Potency (x-axis) vs. Efficacy (y-axis)
100
75
50
25
1Log dose (mg)
10 100
HydromorphineMorphineCodeineAspirin
Response
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Safety
• Effective Dose
ED50 - Dose that produces an effect in 50% of a population
Lethal/Toxic Dose
LD50 - Dose that kills 50% of a population
• Safety Factor
LD50 /ED50
Drug B100
50
Log drug doseLow HighED50 TD50
100Drug A
50
Low HighLog drug doseED50 TD50
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Pharmacodynamics
• Opioid Receptors• Mu: • Kappa:• Delta:
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Delta Opioid Receptor
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Delta Opiate Receptor
Tradham (2011) Trends in Pharmacological Science, 32, 581-590.
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Mu Receptor Distribution
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Kappa Opiate Receptor
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More terminology
• Pro- larger precursor proteins (peptides)
• Protease- enzyme that cut propeptide
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Endogenous Substances
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Knock-out
• Knock-out: animal with gene made inoperative
• Allele: alternative forms of gene
• Diploid: organism with two sets of genes for each trait
• Homozygote: +/+ or -/-• Heterozygote: +/-
Genotype Response
+/+ Full
+/- Partial
-/- Absent
C57 Mouse
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KO Example
• 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.
1 2 3 4
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KO Example
• Some evidence for sex difference A,D vs. B,C.
• Mu opiate receptor is important for thermal pain (males).
• Other receptors also play a role in females.
Martin, M. (2003). Eur J. Neurosci, 17, 701-708.
A
B
C
D
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Comparison of Opioid Receptors
Receptor Ligand Location Function
Mu Endorphin Striatum, NAc, PAG Analgesia
Delta Enkepahlin Striatum, NAc, spinal cord Analgesia, olfaction
Kappa Dynorphin Striatum, NAc,hypothalamus Temperature
PAG: periaqueductal grayNAc: nucleus accumbens
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Periaqueductal Gray
• Midbrain structure
• Near cerebral aqueduct
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OppositesEffect 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 depression
Grilly, D.M. (1998). Drugs and human behavior. Allyn: Needham Heights.
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Dopamine & Behavior
Murphy et al. J Neurochem (2001) 79, 626-635.
Mice 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.
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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 injections
Olmstead et al. (2005). Psychopharm, 181, 576-81.
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Codeine Addiction
• Codeine -----> Morphine• Fluoxetine inhibits 2D6• Will fluoxetine help
codeine addicts reduce their use?
• All groups reduced codeine intake by >40%.
2D6
Daily dose of codeine in people that receivedcounseling and fluoxetine (circles), quinidine (triangles), or placebo (squares).
Fernandes et al. (2002). J Clin Psychopharm, 22, 326-329.
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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
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Tx: Methadone
• Pill form used to prevent opiate withdrawal
• Pros: limits use of other opiates
• Cons: philosophical
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Epidemiology (MtF)
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Epidemiology: Heroin
MTF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
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Epidemiology: Heroin
MTF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
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Epidemiology: Vicodin
MTF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
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Urban vs. Rural
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Epidemiology: College Plans
MTF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
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Epidemiology: Non-Heroin
MTF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
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Celebrity Overdoses
1943-19701979-2008 1964-1997
1943-1971
1949-1982 1960-1988
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Celebrity Overdoses
1943-19701979-2008 1964-1997
1943-1971
Heath Ledger Janis Joplin Chris Farley Jim Morrison
1949-1982 1960-1988
John Belushi Jean-Michel Basquiat
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Overdose
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Summary
• History/Examples
• Pharmacodynamics: Mu, Delta, Kappa
• Epidemiology
3 min: http://www.npr.org/player/v2/mediaPlayer.html?action=1&t=1&islist=false&id=12131233&m=12131234