Animal husbandry – Confining or housing – For experimental purposes
Reexamination Certificate
2002-12-05
2003-10-28
Abbott, Yvonne (Department: 3644)
Animal husbandry
Confining or housing
For experimental purposes
C119S421000
Reexamination Certificate
active
06637372
ABSTRACT:
BACKGROUND OF THE INVENTION
The broad definition of pain includes neural processes that take place to identify internal or external environmental influences that pose a risk for tissues of the body. Neural systems first calculate the magnitude of the risk. Depending on this magnitude, the systems will generate the driving force for a battery of behaviors aimed at minimizing the risk of tissue damage. For localized high intensity stimuli (such as when a hot stove is touched) speed of the response is of highest priority. There is no time for an in-depth analysis of all aspects of the threat, and information about location and intensity of the stimulus dominate the process that leads to a stereotypical but rapid first response (reflex withdrawal). For lower intensity or diffuse stimuli, or for stimuli where reflexes have failed to bring the desired result, higher-order neural circuitry is recruited for an in-depth analysis of the threat and generation of a response adapted to the specific situation. The signal that arrives from the site of tissue insult will be temporally and spatially integrated because the risk (and thus urgency of response) is a function of intensity x duration x spatial extent of the stimulus. The experiential and behavioral result of this computation may be subject to modification to better adapt the response to situational factors that are important for the survival of the animal as a whole. For instance, surviving a fight or flight situation takes precedence over protecting an injured paw, and thus pain from the paw will be suppressed until the animal has reached a safer environment.
The clinical definition of pain relates to the net result of many steps of neural processing. Typically, the definition is limited to the input side of the phenomenon of pain, namely the conscious experiential aspects. The output stage (escape, vocalization, verbal response) is often not included in the narrow definition of pain, but merely considered a means to infer the magnitude of the sensory or affective experience. Conscious (clinically most relevant) aspects of pain are the result of many more steps of neural processing than simple withdrawal reflexes. Clinical pain may be generated under conditions that do not lead to activation or facilitation of reflexes. Furthermore, suppression of protective reflexes is not an objective of pain medicine and may not be in the interest of the patient at all. The goal is reduction of the conscious unpleasant, often persistent experience of pain. Animal models, to be clinically relevant, must be predictors of this conscious pain experience.
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,
Neuromethods, 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: (I) 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 [
1983a] 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 [
1983] 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 hot-plate test (Woolfe, G. and A. D. Macdonald, 1944; Eddy, N. B. et al.
Mauderli Andre Paul
Vierck Charles J.
Abbott Yvonne
Saliwanchik Lloyd & Saliwanchik
Unversity of Florida
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