Animal husbandry – Confining or housing – For experimental purposes
Reexamination Certificate
2001-12-05
2003-11-11
Abbott, Yvonne (Department: 3644)
Animal husbandry
Confining or housing
For experimental purposes
C119S421000
Reexamination Certificate
active
06644244
ABSTRACT:
BACKGROUND OF THE INVENTION
Pain is an experience that cannot be measured directly, either in humans, or in animals, but must be inferred from behaviors. The available repertoire of behaviors that consistently reveal pain includes verbalizations in humans and complex motor sequences that eliminate nociceptive stimulation (escape responses) in humans and other animals. A variety of other behaviors suggest the presence of pain but can be elicited by stimuli or situations that are not necessarily aversive or involve responses that do not require a conscious perception of pain. Pain tests for non-human animals have been reviewed extensively in the literature (Vierck, C. J., B. Y. Cooper,
Advances in Pain Research and Therapy [
1984], pp. 305-322; Chapman, C. R et al.,
Pain [
1985] 22:1-31; Dubner, R.
Textbook of Pain [
1989], pp. 247-256; Franklin, K. B. J and F. V. Abbott,
Neuronmethods, Psychopharmacology [
1989] 13:145-215; Vierck, C. J. et al.
Issues in Pain Measurement [
1989] pp. 93-115), and they can be classified according to two main criteria: (1) type of stimulus applied; and (2) type of response measured.
Some methods for evaluating phasic responses to nociceptive stimulation involve electrical stimulation, because it can be turned on and off instantly, making it easy for an animal to learn the temporal relationship between an escape response and elimination of an aversive sensation. Although electrical stimulation has been criticized because skin receptors are bypassed, and synchronous afferent firing patterns are generated (Dubner, R., 1989), it is possible to elicit natural sensations of predictable quality when electrode tissue coupling is tightly controlled (Vierck, C. J. et al.,
Animal Pain Perception and Alleviation: American Physiological Society [
1983] pp. 117-132; Vierck, C. J. et al., 1989; Vierck, C. J. et al.,
Somatosens Mot Res [
1995] 12:163-174). However, control over current density and stimulus location can be achieved only by restraining the subjects, and animals will tolerate restraint only after lengthy adaptation and training periods. Restraint without proper adaptation leads to high levels of stress and anxiety—factors that are known to have modulatory effects on pain sensitivity (Amir, S. and Z. Amit,
Life Sci [
1978] 23:1143-1151; Bhattacharya, S. K. et al.,
Eur J Pharmacol [
1978] 50:83-85; Basbaum, A. I. and H. L. Fields,
Annu Rev Neurosci [
1984] 7:309-338; Franklin, K. B. J. and F. V. Abbott, 1989; Maier, S. F. et al.,
APS J [
1992] 1:191-198; Tokuyama, S. et al.,
Jpn J Pharmacol [
1993] 61:237-242; Caceres, C. and J. W. Burns,
Pain [
1997] 69:237-244). Therefore, nociceptive tests that require restraint or extensive handling, which have an effect on pain processing, may produce contaminated results.
Thermal stimulation has been used previously for nociceptive tests (Dubner, R., 1989). Contact thermal stimulation provides the basis for the hotplate test (Woolfe, G and A. D. Macdonald,
J Pharmacol Exp Ther [
1944] 80:300-307), and extensive use of contact heat in psychophysical and neurophysiological studies has established the range of temperatures that produces heat nociception. Radiant heat is used in the tailflick test (D'Amour, F. E. and D. Smith,
J Pharmacol Exp Ther. [
1941] 72:74-79) and the Hargreaves hindlimb-withdrawal test (Hargreaves, K et al.,
Pain [
1988] 32:77-88). The absence of a concurrent mechanical stimulus is thought to be an advantage of radiant heat, but it is difficult to control and assess skin temperature. Observations of hindlimb withdrawal and/or guarding behavior have also been utilized to evaluate thresholds for reactivity to mechanical stimulation (Chaplan, S. R. et al.
J Neurosci Methods [
1994] 53:55-63) or the frequency of responsivity to chemical stimulation (Dubuisson, D and S. G. Dennis,
Pain [
1977] 4:161-174). A present difficulty with mechanical tests is that characteristics of von Frey filaments (e.g. combinations of diameter and force) which produce mechanical nociception have not been determined. Chemical stimuli can be varied in concentration, volume and method of application (injection or surface application), but it is difficult to characterize the effects of these agents on peripheral tissues, receptors and afferents. These different methods of nociceptive testing elicit responses that can be modulated differentially by a variety of treatments (Willer, J. C. et al.
Brain Res [
1979] 179:61-68; McGrath, P. A. et al.,
Pain [
1981] 10:1-17; Vierck, C. J. et al.,
Progress in Psychobiology and Physiological Psychology [
1983b] pp. 113-165; Sandkuhler, J. and G. F. Gebhart,
Brain Res [
1984] 305:67-76; Dubner, R., 1989), and it is often concluded that the method of stimulation is the determinant factor, without consideration of other aspects of the testing method and response measurement.
An important consideration in evaluation of nociceptive tests is the central circuitry that is interposed between the input and output stages. For example, the tail flick and paw withdrawal responses can be elicited in spinal animals (Franklin, K. B. J. and F. V. Abbott, 1989) and therefore can represent segmental spinal reflexes. Pawlicking in the hotplate test (Woolfe, G. and A. D. Macdonald, 1944; Eddy, N. B. et al.,
J Pharmacol Exp Ther [
1950] 98:121-137; Chapman, C. R et al., 1985) and vocalization (Carroll, M. N and R. K. S. Lim,
Arch Int Pharmacodyn [
1960] 125:383-403) can be elicited in chronic decerebrate rats (Woolf, C. J.,
Pain [
1984] 18:325-343; Berridge, K. C.,
Behav Brain Res [
1989] 33:241-253; Matthies, B. K. and K. B. Franklin,
Pain [
1992] 51:199-206) and can be modulated differentially from responses to the same stimulus that originate at higher levels of the neuraxis (Sandkuhler, J. and G. F. Gebhart, 1984; Cooper, B. Y. and C. J. Vierck,
Pain [
1986] 26:393-407; Dubner, R., 1989). Therefore, it is important to distinguish innate responses that can be segmental (spinal) reflexes or long-loop (spino-bulbospinal) reflexes from operant responses that necessarily employ complex learned motor actions (involving the cerebrum).
Animal models of pain are most useful when they are good predictors of the effect of disease states or therapeutic interventions on human clinical pain. The clinically most relevant consequence of nociceptive stimuli is the conscious experience of pain and suffering that the stimuli may elicit. Assays based upon short or long-loop reflexes (such as the tail-flick test, paw withdrawal test, or hotplate test) provide little or no insight into what goes on at the conscious level. Reflex tests and the few available assays of conscious responses to painful stimuli, such as the foot shock escape test, rely mostly on fast-conducting pain pathways. However, it is known that slow-conducting nociceptive systems are the major contributors to the conscious experience of clinical pain and they are primarily affected by powerful pain killers such as morphine.
Shuttle-box paradigms, using the operant response measure of learned escape have been popular models of conscious aspects of pain (Warner, L. H.,
J Genetic Psychol [
1932] 41:57-89; Bohus, B. and D. Wied,
J Comp Physiol Psychol [
1967] 64:26-29; Randall, P. K. and D. C. Riccio,
J Comp Physiol Psychol [
1969] 69:550-553; Cleary, A.
Instrumentation for Psychology [
1977] pp. 1-319). These methods are easy to implement, because the subjects are unrestrained. Electrical stimulation has been used in shuttle box paradigms because it can be regulated in intensity and switched between chambers. However, it is problematic in these situations, because movement of the animals across a grid floor switches polarities and varies current densities.
A shuttle-box test was developed which uses thermal
Mauderli Andre Paul
Vierck Charles J.
Abbott Yvonne
Saliwanchik Lloyd & Saliwanchik
University of Florida
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