CHAPTER 1

Animal Models of Analgesia

A. TJ0LSEN and K. HOLE

A. Introduction
Measurement of pain and analgesia in animals poses a variety of problems. In
addition to the fact that pain itself constitutes a multiplicity of sensory entities,
the term pain is poorly defined in relationship to animals and animal
behaviour.
Pain is defined by the International Association for the Study of Pain as
"an unpleasant sensory and emotional experience associated with actual or
potential tissue damage, or described in terms of such damage" (MERSKEY
1984). A noxious stimulus is one which is damaging to normal tissue, and a
nociceptor is a receptor that is preferentially sensitive to a noxious stimulus or
to a stimulus which would become noxious if prolonged (SHERRINGTON 1947).
Activity in the nociceptor and nociceptive pathways and other neurophysi-
ological processes induced by a noxious stimulus is called nociception. Analge-
sia is the absence of pain in response to stimulation which would normally be
painful, while hypoalgesia is diminished pain. An increased response to a
stimulus which is normally painful is called hyperalgesia, the basic concept of
inflammatory pain.
According to the above definitions, the term pain is often avoided when
describing animal models of nociception. In general, pain tests in animals are
in fact tests of nociception. Pain is a sUbjective and personal psychological
experience that at best can be measured only indirectly in animals. Animal
models of analgesia must hence be animal models of nociception and
antinociception.

B. Animal Models and Ethics

Over the years many tests of nociception and pain in animals have been
developed, and the species most frequently used in pain research are rats and
mice. We describe some of the most commonly used methods, which may
illustrate important aspects of investigations on pain in animals. Special em-
phasis is put on methodological problems in the tests.
While the use of anaesthetics and analgesics is standard in invasive bio-
medical research involving intact animals, analgesics cannot be used in models
for studying behavioural responses to nociceptive stimulation. Therefore spe-
A. Dickenson et al. (eds.), The Pharmacology of Pain
© Springer-Verlag Berlin Heidelberg 1997
2 A. TJOLSEN and K. HOLE

cial considerations must be given to the approval of models and protocols for
pain research in animals. The type and intensity of noxious stimulation and the
duration of the stimulus should be examined thoughtfully. In addition, the
ability of the animal to terminate or limit the noxious stimulus may be an
important factor in evaluating models for acute pain.
The Committee for Research and Ethical Issues of the International As-
sociation for the Study of Pain has published the following guidelines for
investigations of experimental pain in conscious animals:
- Experiments must be reviewed by scientists and laypersons, and the poten-
tial benefit must be made clear.
- If possible, the investigator should try the pain stimulus on himself.
- A careful assessment of the animal's deviation from normal behaviour
should be given.
- A minimal pain stimulus necessary for the purposes of the experiment
should be used.
- Pain-relieving agents or procedures should be used, as long as this does not
interfere with the aim of the investigation.
- The duration must be as short as possible, and the number of animals kept
to a minimum.
Several tests of nociception measuring acute pain at or close to the pain
threshold do not pose problems with respect to these guidelines, while there
may be difficulties in applying the present guidelines to chronic pain models.
It is not always possible to try the pain stimulus on the experimenter himself,
and pain-relieving agents generally interfere with the purpose of the experi-
ments. Adequate evaluations of the intensity and duration of pain necessary to
achieve the experimental objective are also difficult (ROBERTS 1989). For these
reasons improved guidelines are needed for use in models of chronic pain.

c. Factors Affecting Measurements of Nociception

When an animal model of nociception or pain has been chosen, many factors
affect the outcome of the measurements. Conflicting results in various studies
may be explained by differences in nociceptive model or study design that are
not necessarily obvious. Because of this one should be aware that the animal
model used must be characterized as well as possible, and results should be
evaluated critically with regard to the exact conditions under which testing has
been performed.
The choice of species and strain of animals is among the more obvious
factors that influence the results of tests. The time of day when testing is
performed is another factor, there being considerable diurnal variation in
nociceptive sensitivity. Factors concerning the nociceptive stimulus used may
be important for the test result. It is of importance which area on the body is
used for the test, as nociceptive thresholds vary from one area to another. The