Lecture 14 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Includes pharmacokinetics, pharmacodynamics, and epidemiology.
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
5. 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
6. Origin Chemistry Schedule
Morphine Opium II (II-III)
poppy
Felix Hoffman, Bayer Acetyl=OCOH3
Heroin I
Production in 1898
OH to Acetyl
Diacetylmorphine
Synthesized in 1916, H to OH
Oxycodone Oxycontin produced in
II (II-IV)
OH to =O
1995
Codeine Identified in 1832? -OH to 0CH3 II
Methylmorphine
(III-IV)
7. History
In the following years, Heroin was a drug marketed by Bayer as
a cough syrup without the nasty side effects of morphine.
Source: Prof.
Anagnostaras, UCSD
8. Potency (x-axis) vs.
Efficacy (y-axis)
100
R
e 75
s
p
o 50 Hydromorphine
n
s Morphine
e 25 Codeine
Aspirin
1 10 100
Log dose (mg)
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
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. 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. 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. 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 gray
NAc: nucleus accumbens
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 depression
Grilly, D.M. (1998). Drugs and human behavior. Allyn: Needham Heights.
23. Dopamine & Behavior
Mice of different strains: C57 (black), 129SV (white), and DBA2 (grey) received 3 mg/kg
of 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. 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.
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.