704 
PHARMACOLOGY 
a widely used technique that has as its major 
advantage its sensitivity to the analgesic action 
of the narcotic antagonists and as its major 
drawbacks its lack of specificity, since many 
nonanalgesic drugs also inhibit writhing. Also 
there appears to be a lack of correlation with 
potency of analgesics in man. It is of interest to 
point out that the analgesic activity of the nar- 
cotic antagonists is one property of this class of 
compounds that is relatively easy to demon- 
strate in man^^ and extremely difficult to show 
in almost any animal model that can be devised. 
Electrical methods, such as shock to the tooth 
pulp, or to the scrotal sac, or to the tail 
all suffer from serious drawbacks that make 
their use difficult. They give inconsistent re- 
sults, low sensitivity and variable response with 
age, strain, sex, etc. However, if one combines 
nociceptive stimuli with a response that is 
more complex than vocalization, such as turning 
the head or lifting of the stimulated limb, one 
gets what are known as "behavioral" methods, 
and these range from very simple "flinch-jump" 
techniques^'' to very complex operant proce- 
dures. Many of the operant procedures involve 
producing conditioned anxiety^" — a concept 
that must raise some eyebrows of investigators 
who find it difficult to conceive of anxious rats. 
Most of these procedures seem to tap properties 
of opiates other than analgesia and also give 
positive results with other CNS depressants. 
There is, however, a modification of an oper- 
ant procedure that may be suitable for the 
measurement of analgesic properties. This 
procedure, first described by Weiss and 
Laties,^^-^^ is called either "fractional escape 
and avoidance" or "shock-threshold titration". 
In essence, this allows an animal to reduce the 
level of electric shock to a threshold which can 
be tolerated by pressing a bar, or in a later re- 
finement, by turning a wheel.^* The training 
time is minimal and even mice can be taught to 
lower the shock threshold in one training ses- 
sion of 15-30 minutes. The procedure can be 
adapted for use in the monkey^^ and the shock 
can be delivered not only through the grid floor 
on which the animal stands but to electrodes im- 
planted in various discrete areas in the brain of 
the monkey and the rat. These techniques allow 
the expansion of the animal model and open the 
way for the study of reward and punishment 
areas in the cortex and midbrain and will allow 
us to make some inferences not only with re- 
gard to the site of action of the narcotic analge- 
sics but with regard to the control of human 
behavior as well. 
EVALUATION OF 
PHYSICAL DEPENDENCE 
The assessment of addiction liability poses 
problems of a different and much more compli- 
cated nature. The nature of the addictive illness 
is such that it poses extremely difficult and per- 
plexing problems for the clinician who has to 
treat it. Fortunately the disease model in ani- 
mals is strikingly similar to that seen in man 
and much of our knowledge and thinking about 
tolerance, physical dependence and, more re- 
cently, psychological dependence and drug-seek- 
ing behavior have come from the animal model. 
The evaluation of physical-dependence liabil- 
ity in animals uses procedures that were devel- 
oped expressly by pharmacologists when they 
began to study the abstinence phenomena in 
depth. Many of the procedures in general use in 
animal studies closely resemble and may indeed 
be patterned after methods developed for use in 
the experimental investigation of physical de- 
pendence in man, while some of the experimen- 
tal techniques in man were first developed in ani- 
mals. The final screening of physical dependence 
liability is done in the monkey, but preliminary 
inforniation can be obtained in smaller animals 
that has general applicability to man. 
The establishment of the addiction research 
center at the University of Michigan has made 
possible the measurement of opioid-like proper- 
ties in the monkey in a systematic and compre- 
hensive manner and the results have consistently 
paralled those obtained at the NIMH Ad- 
diction Research Center in Lexington Kentucky. 
In both these centers, investigations of the 
characteristics of the withdrawal syndrome in 
man and animals have led to the recognition of 
the fact that it has features that are common to 
most species, regardless of the identity of the 
addicting drug. At the same time, research at 
both centers has made it possible to measure 
quantitatively the intensity and duration of the 
