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Vol. 53, Issue 4, 597-652, December 2001
INSERM U-161, Paris, France (D.L.B.); Laboratoires UPSA
Bristol-Myers-Squibb, La Grande Arche Nord, Paris La Défense,
France (M.G.); and The Dental School, University of Dundee, Dundee,
Scotland (S.W.C.)
I. Introduction
II. Ethical Problems
III. Input and Output: the Stimulus and the Response
A. The Stimulus
1. Electrical Stimulation.
2. Thermal Stimulation.
3. Mechanical Stimulation.
4. Chemical Stimulation.
5. The Choice of Stimulus Parameters.
B. The Response
IV. Behavioral Models of Nociception
V. Use of Short-Duration Stimuli ("Phasic Pain")
A. Tests Based on the Use of Thermal Stimuli
1. The Tail-Flick Test.
a. The Tail-Flick Test Using Radiant Heat.
b. The Tail-Flick Test Using Immersion of the Tail.
2. The Paw Withdrawal Test.
3. The Hot Plate Test.
4. Tests Using Cold Stimuli.
B. Tests Based on the Use of Mechanical Stimuli
C. Tests Based on the Use of Electrical Stimuli
1. Use of Long-Lasting Trains of Electrical Stimuli.
a. Electrical Stimulation of the Tail.
b. Electrical Stimulation of the Paw (and Tail).
2. Use of Single Shocks or Very Short Trains of Electrical
Stimuli.
a. Stimulation of the Tail.
b. Stimulation of the Dental Pulp.
c. Stimulation of the Limbs.
VI. Tests Based on the Use of Long Duration Stimuli ("Tonic
Pain")
A. Intradermal Injections
B. Intraperitoneal Injections of Irritant Agents (the "Writhing
Test")
C. Stimulation of Hollow Organs
VII. Nociceptive Tests and Stimulus-Response Relationships
VIII. Nociceptive Tests and Motor Activity
A. Not All Flexion Reflexes Are Nociceptive
B. Not All Nociceptive Reflexes Are Flexion Reflexes
C. Spinal Shock
D. Excitatory Effects of Opioids on Motor Activity
IX. The Sensitivity of the Tests
A. Statement of the Problem
B. What Types of Fiber Underlie the Responses?
C. What Is the Significance of Measurements of Reaction Time When
the Stimulus Intensity Is Increasing?
D. Influence of Methods of Analysis
E. Influence of Species and Genetic Line
X. The Specificity of Tests
XI. Comparison with Clinical Situations and Predictiveness of the
Tests
XII. Perturbing Factors
A. Factors Linked to Pharmacokinetics
B. Interactions Between Stimuli
C. Environmental Factors
D. Related Psychophysiological and Psychological Factors
E. Related Physiological Functions
1. Thermoregulation.
2. Vasomotor Tone.
3. Systemic Arterial Blood Pressure.
4. Nociception and Homeostasis.
XIII. Conclusion
Acknowledgments
References
The study of pain in awake animals raises ethical, philosophical, and technical problems. We review the ethical standards for studying pain in animals and emphasize that there are scientific as well as moral reasons for keeping to them. Philosophically, there is the problem that pain cannot be monitored directly in animals but can only be estimated by examining their responses to nociceptive stimuli; however, such responses do not necessarily mean that there is a concomitant sensation. The types of nociceptive stimuli (electrical, thermal, mechanical, or chemical) that have been used in different pain models are reviewed with the conclusion that none is ideal, although chemical stimuli probably most closely mimic acute clinical pain. The monitored reactions are almost always motor responses ranging from spinal reflexes to complex behaviors. Most have the weakness that they may be associated with, or modulated by, other physiological functions. The main tests are critically reviewed in terms of their sensitivity, specificity, and predictiveness. Weaknesses are highlighted, including 1) that in most tests responses are monitored around a nociceptive threshold, whereas clinical pain is almost always more severe; 2) differences in the fashion whereby responses are evoked from healthy and inflamed tissues; and 3) problems in assessing threshold responses to stimuli, which continue to increase in intensity. It is concluded that although the neural basis of the most used tests is poorly understood, their use will be more profitable if pain is considered within, rather than apart from, the body's homeostatic mechanisms.
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