702 
PHARMACOLOGY 
assessment of drug-seeking behavior, of psycho- 
logical dependence to drugs. Nevertheless, 
workers in the area of drug addiction believe 
that these assessments, although quite difficult, 
are not impossible, and a number of animal 
techniques that are both sensitive and repro- 
ducible with which to make these assessments 
have been developed. 
Any discussion of screening methods for 
most classes of drugs is usually confined to as- 
says which define and delimit their potency, 
their site of action, their mode of action if at 
all possible, their efficacy, their toxicity and so 
forth. The narcotic analgesics, however, must 
be assayed not only for the properties listed, but 
also for the properties that are not solely phar- 
macological but which also have major legal 
and sociological import and impact. The profile 
of activity of the opiate analgesics includes the 
ability to initiate in animals and in man phys- 
iological and psychological states which are 
referred to as physical and psychological depend- 
ence, respectively. 
It is obvious that some of the effects produced 
by substances with addiction liability are de- 
monstrable only through prolonged clinical and 
social experience. However, tolerance, physical 
dependence and to some degree psychological 
dependence can be measured quantitatively in 
man and fortunately in animals as well. It is to 
animal models of these states that this report 
will be directed. 
There is little interest in the dependence lia- 
bility of a new drug unless the compound in 
question is also a useful analgesic. Once this has 
been established, its abuse potential is of some- 
what more than academic interest. Screening 
for analgesic potency is the first step in the long 
and complicated process of developing a new 
analgesic. A large number of techniques have 
been developed that are useful in assessing the 
antinociceptive activity, the activity that we 
refer to as analgesic activity in man. I shall out- 
line briefly the principal methods used in the 
assay of analgesics in animals, those methods 
that utilize so-called nociceptive (noxious) stim- 
uli to elicit a response in animals that we 
equate with a response to pain in man. 
METHODS FOR ASSESSING ANALGESIA 
The literature is filled with methods and po- 
lemic concerning these methods. All this seems 
to be beside the point since it becomes fairly ob- 
vious upon an examination of the literature that 
(a) there is no method that yields complete par- 
allelism between results in animals and clinical 
practice in man, and (b) for each investigator 
one or another of several assay methods of an- 
tinociceptive activity is successful and yields re- 
sults that are grossly comparable. As long as 
the results of a given assay technique are re- 
producible in one laboratory and are useful for 
that laboratory, then that method is a valid one. 
Whether or not we are actually measuring 
"pain threshold" or "analgesia", is not of great 
practical importance if we can relate the results 
to man and to the relief of his pain. A number 
of comprehensive reviews of this subject have 
appeared^"^ and the reader is referred to them. 
The animal techniques commonly used can be 
divided into thermal, mechanical, chemical and 
electrical and behavioral. The thermal methods 
are still the most widely used techniques in both 
the commercial and academic laboratory. All of 
them utilize the general principle of applying 
heat to the animal or human to elicit a response. 
The difference in time needed to elicit a re- 
sponse (a skin twitch, a tail flick, a lifting of a 
hind paw, a licking of a front paw) before and 
after administration of a drug is used as the 
measure of drug effect. This general method 
was adapted to the rat by D'Amour and Smith.* 
Heat is applied to the tail of a rat and the time 
that elapses before the rat flicks his tail away 
from the heat source is measured. Neither the 
original tail-flick method nor any of its many 
modifications have been able to assay with any 
degree of predictability in man the potency of 
compounds that have both agonist and antago- 
nist activity, compounds such as nalorphine or 
levallorphan. 
The tail-flick procedure has been modified to 
make it applicable to mice. In this modification, 
the tails are dipped into hot water and the end 
point is a flick or a rapid continuous movement 
of the tail.^ Methods such as those described by 
Andrews and Workman'' and by Winder'^ uti- 
lize the "skin-twitch" threshold after focusing 
