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A primate model for the study of tonic pain, pain tolerance and diffuse noxious inhibitory controls
388
Brain Research, 487 (1989) 388-391
Elsevier BRE23512
A primate model for the study of tonic pain, pain tolerance and diffuse noxious inhibitory controls Serge Marchand 2, Nathalie Trudeau 1, M. Catherine Bushnell 1'2 and Gary H. Duncan 1'2 l Facult~ de rnddecine dentaire and 2Centre de Recherche en sciences neurologiques, Universit~ de Montreal, Montreal, QuL (Canada)
(Accepted 7 February 1989) Key words: Primate; Cold pressor pain; Tonic pain; Pain tolerance; Diffuse noxious inhibitory control; Counterirritation
A primate model of cold pressor pain is described in which the animal itself initiates all trials, may terminate painful stimuli at any time, and controls the duration of the experimental session, thus avoiding the inadvertent administration of intolerable pain stimuli. Pain tolerance time varies directly with stimulus intensity and is sensitive to motivational factors. This model will facilitate the study of endogenous pain-modulatory pathways and the assessment of analgesic treatments in animals.
The development of animal pain models that parallel those used in humans is important for both practical and ethical reasons. Using such models, neurophysiological and pharmacological data can be obtained from animal studies under conditions in which the human perception is known, providing a clinical relevance that is frequently questioned with such tests as rodent tail flick, writhing response, hot plate reaction, shock titration and vocalization 5-7. In addition, by using the same painful stimuli that humans are willing to tolerate and by allowing the same control of stimulus presentations as is customary for human experimental pain subjects, one can better insure the ethical treatment of the animals. We have previously used, in both humans and monkeys, psychophysical paradigms which test their liminal ability to distinguish different intensities of painful heat4; we have also used other paradigms (adapted from the field of visual research 18) which assess the effects of attention on their nociceptive discriminative ability 3. These studies have shown that humans and monkeys perform even difficult psychophysical tasks in a similar fashion and more importantly that there are no demonstrable differ-
ences between the humans and monkeys in either their nociceptive discrimination thresholds or in the manner in which attention alters their ability to detect intensity changes in noxious heat stimuli. Thus, these results indicate that the perception of noxious heat must be similar for monkeys and humans. Because of these similarities in perception, the results of neurophysiological studies in monkeys, which investigate the neural substrates of nociceptive discrimination and its modulation by attention 1" 2,13,17 are directly relevant to the problems of pain and analgesia in humans. Another laboratory pain model frequently employed in humans to measure pain tolerance is the cold pressor test 8'1°'21, in which the subject is instructed to immerse a part of the body (usually the hand) in painfully cold water as long as possible; the duration of immersion is then given as a measure of pain tolerance. This type of pain measure is thought to approximate clinical acute pain states better than most laboratory stimulation procedures, because the pain stimulus is persisting rather than discrete, and the pain experience involves arousal and anxiety in addition to nociception 5. Cold pressor pain is also
Correspondence: M.C. Bushnell, Facult6 de m6decine dentaire, Universit6 de Montr6al, Montr6al, Quebec, Canada H3C 3J7.
0006-8993/89/$03.50 (~ 1989 Elsevier Science Publishers B.V. (Biomedical Division)
389 used in human studies investigating the phenomenon of counterirritation, in which the presence of one painful stimulus reduces the pain caused by other noxious stimuli 14'19'2°. A neurophysiological phenomenon, termed diffuse noxious inhibitory controls (DNICs), has been identified in anesthetized rats and monkeys, which probably underlies counterirritation 9'12'15A6. In this phenomenon, noxious stimuli applied to widespread areas of the body inhibit t h e nociceptive responses of wide dynamic range (WDR) neurons in the spinal and medullary dorsal horn. An animal model equivalent to the human cold pressor test could provide a useful tool for neurophysiological and pharmacological studies of pain states that approximate clinical acute pain, as well as presenting a potential model for the neurophysiological study of DNICs in unanesthetized animals. In the present study, one adult female monkey (Macaca mulatta) was trained to press a button installed in the floor of a 3-inch deep pan attached to the left side of the primate chair. At first, each time the monkey pressed the button it received a liquid reward. After this initial training, the pan was filled with room-temperature water (25 °C), and the monkey was taught to submerge its hand and press the button in order to obtain reward. For the remainder of the training, the pan was connected to a circulating refrigeration unit and the temperature of the water was gradually decreased to 10 °C*. Through successive approximations, the monkey was required to keep the button depressed for longer and longer periods, until it received reward only after depressing the button for 10 s. The monkey could then receive an additional reward every 5 s, if it continued to keep the button depressed. However, if it released the button and withdrew its hand from the water, a new behavioral trial could not be initiated for 90 s. A red light mounted on the primate chair was illuminated after the 90 s intertrial interval, signalling the monkey to initiate the next trial. If the monkey pressed the button during the intertrial interval, no reward was given, and a buzzer sounded to indicate that this was an inappropriate response. There was no limit on the number of trials that a
monkey could initiate during a session. However, when the monkey waited for at least 3 min before initiating 3 sequential trials, the session was terminated. When the monkey's performance was stable, a series of testing sessions were begun. During this series the water temperature was kept at 35 °C one day, 10 °C the next, and 0 °C the last day. This 3-day sequence was repeated 5 times. A minicomputer controlled the presentation of the trial-initiation stimulus (red light) as well as the frequency and quantity of liquid reward. The dependent variable, duration of each appropriate button press (i.e. the time that the monkey kept its hand submerged in the cold water), was recorded to disk for subsequent off-line analysis. Throughout the training and testing period, the monkey was kept in its home cage except for the approximately 2-h experimental period, during which it was seated in a primate chair. The monkey's weight and the amount of liquid intake during the experiment were monitored each day. The monkey was visited regularly by the university veterinarian and received vitamins and fruit daily as well as free access to primate chow. In addition to the liquid earned during the experiment, the monkey was given supplemental liquids so that it gradually gained weight (4%) during the 10 weeks of the study. Fig. 1 shows that the average duration that the monkey kept its hand in the water was influenced by water temperature (Kruskal-Wallis test, )~2 = 8.12, df = 2, P < 0.02). The monkey's withdrawal latency was greater than 3 min when the water was near skin temperature (35 °C), but decreased to 78 s for 10 °C water and 33 s for 0 °C water. These data indicate that the monkey was withdrawing its hand sooner from the colder water because of its painfulness, since all other variables were held constant across the 3 experimental conditions. As is expected for any measure of pain tolerance 11, the monkey's latency for withdrawing its hand from the cold water was influenced by motivational level. Fig. 2 compares data collected from the first 3 trials to that of the last 3 trials of each experimental session. During the earliest trials (solid
* Constant recirculation of the water reduces laminar warming around the submerged hand and insures a more consistent and controlled cold stimulus.
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Fig. 1. Withdrawal latency (mean of the median scores for each session) for each water temperature, i.e. 35 °C, 10 °C, and 0 °C. Error bars represent the standard error of the mean. The non-parametric Kruskal-Wallis test (equivalent to analysis of variance) revealed a significant effect of temperature on withdrawal latency (P < 0•02).
Fig. 2. Comparison of median withdrawal latencies for the first 3 trials (solid line) and the last 3 trials (dashed line) at each water temperature. The Kruskal-Wallis test revealed a significant temperature effect for the late trials (P < 0.05) but not for the early trials (P = 0.79)•
line), when the m o n k e y had not received fluids for 12 h, the withdrawal latencies were much longer than during the last 3 trials of the session (dashed line), when the monkey was satiated. This was true for the non-painful 35 °C water, as well as for the two cold-water conditions. Further, while there was a significant effect of water temperature on withdrawal latency for the late trials (Kruskal-Wallis, ;(2 = 6.04, df = 2, P < 0.05), there was no significant temperature effect during the earliest trials (P = 0.79). We also assessed, in two humans, subjective reports of cold pain for 10 °C and 0 °C water using the same behavioral paradigm used for the monkeys, but asking the subjects to indicate verbally when they first felt pain (pain threshold) and to withdraw their hand when they could no longer tolerate the pain. Their pain thresholds at 10 °C and 0 °C, respectively, were 51.2 s and 17.5 s, both being shorter than the monkey's mean withdrawal latencies (78 s and 34 s, respectively). However, the humans' mean tolerance time was higher than that of the m o n k e y for both 10 °C water (humans = 218 s, m o n k e y = 78 s) and 0 °C water (humans = 51 s, m o n k e y = 34 s). As was true for the monkey,
humans tended to tolerate the 10 °C cold for a longer period during the first 3 trials than during the last 3 (374 vs 234 s), but this relationship did not hold for 0 °C (43 vs 43 s). The fact that the early-late differences were not as great as those observed for the monkey is not surprising, since the humans received no reward for keeping their hand in the water, and thus were less influenced by changes in motivation across the experimental session. The present data suggest that the cold pressor test can be used successfully in monkeys as a pain tolerance measure• Since motivational level appears to have a large influence on tolerance time, it is important, when using the model to test analgesic manipulations, to maintain motivation at the same level during each experimental condition. Since some analgesic manipulations, such as morphine, may also produce motor, cognitive, or appetitive effects, a non-painful control temperature (such as 35 °C) provides a useful method to evaluate nonspecific changes in the monkey's performance. Finally, the fact that the animal initiates all painful stimuli and sustains the painful stimulus with an active response eliminates a problem inherent in most escape paradigms, i.e. motor or cognitive
391
deficits could interfere with the animal's ability to terminate a noxious stimulus. The primate cold pressor pain model will also be useful for c o m b i n e d neurophysiological and behavioral evaluations of DNICs. Changes in n e u r o n a l activity produced by the tonic noxious stimulus (i.e. the cold pain) can be evaluated in conjunction with observations of the animal's perception of phasic noxious and non-noxious stimuli, in a m a n n e r similar 1 Bushnell, M.C. and Duncan, G.H., Sensory and affective aspects of pain perception: is medial thalamus restricted to emotional issues? Exp. Brain Res., submitted. 2 Bushnell, M.C., Duncan, G.H., Dubner, R. and He, L.F., Activity of trigeminothalamic neurons in medullary dorsal horn of awake monkeys trained in a thermal discrimination task, J. Neurophysiol., 52 (1984) 170-187. 3 Bushnell, M.C., Duncan, G.H., Dubner, R., Jones, R.L. and Maixner, W., Attentional influences on noxious and innocuous cutaneous heat detection in humans and monkeys, J. Neurosci., 5 (1985) 1103-1110. 4 Bushnell, M.C., Taylor, M.B., Duncan, G.H. and Dubner, R., Discrimination of noxious and innocuous thermal stimuli in human and monkey, Somatosen. Res., 1 (1983) 119-129. 5 Chapman, C.R., Casey, K.L., Dubner, R., Foley, K.M., Gracely, R.H. and Reading, A.E., Pain measurement: an overview, Pain, 22 (1985) 1-31. 6 Cooper, B.Y. and Vierck, C.J. Jr., Vocalizations as measures of pain in monkeys, Pain, 26 (1986) 393-393. 7 Cooper, B.Y. and Vierck, C.J. Jr., Measurement of pain and morphine hypalgesia in monkeys, Pain, 26 (1986) 361-392. 8 Davidson, P.O. and McDougall, C.E.A., The generality of pain tolerance, J. Psychosom. Res., 13 (1969) 69-76. 9 Dickenson, A.H. and Le Bars, D., Diffuse noxious inhibitory controls (DNIC) involve trigeminothalamic and spinothalamic neurones in the rat, Exp. Brain Res., 49 (1983) 174-280. 10 Dowling, J., Autonomic measures and behavioral indices of pain sensitivity, Pain, 16 (1983) 193-200. 11 Dubner, R., Beitel, R.E. and Brown, F.J., A behavioral animal model for the study of pain mechanisms in primates. In M. Weisenberg and B. Tursky (Eds.), Pain: New Perspectives in Therapy and Research, Plenum, New York, 1976, pp. 155-170. 12 Gerhart, K.D., Yezierski, R.P., Giesler, G.J. and Willis,
to that used to evaluate attentional m o d u l a t i o n in pain pathways 1'2. We would like to thank Dr. A l l e n Smith for his critical comments on this manuscript. This research was supported by the Medical Research Council of Canada. Mr. Marchand was supported by the Quebec 'Fonds pour la formation de chercheurs et l'aide la recherche'.
13
14 15
16
17
18 19
20
21
W.D., Inhibitory receptive fields of primate spinothalamic tract cells, J. Neurophysiol., 46 (1981) 1309-1325. Hayes, R.L., Price, D.D., Ruda, M.A. and Dubner, R., Neuronal activity in medullary dorsal horn of awake monkeys trained in a thermal discrimination task. II. Behavioral modulation of responses to thermal and mechanical stimuli, J. Neurophysiol., 46 (1981) 428-443. Jungkunz, G., Engel, R.R., King, U.G. and Kuss, H.J., Endogenous opiates increase pain tolerance after stress in humans, Psychiatry Res., 8 (1983) 13-13. Le Bars, D., Dickenson, A.H. and Besson, J.-M., Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat, Pain, 6 (1979) 283-304. Le Bars, D., Dickenson, A.H. and Besson, J.-M., Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on non-convergent neurones, supraspinal involvement and theoretical implications, Pain, 6 (1979) 305-327. Maixner, W., Dubner, R., Bushnell, M.C., Kenshalo, D.R. and Oliveras, J.-L., Wide-dynamic-range dorsal horn neurons participate in the encoding process by which monkeys perceive the intensity of noxious heat stimuli, Brain Research, 374 (1986) 385-388. Posner, M.E., Orienting of attention, Q. J. Exp. Psychol., 32 (1980) 3-25. Talbot, J.D., Bushnell, M.C. and Boyer, M., Psychophysical evidence in man for intersegmental suppression of noxious heat perception by cold pressor pain, Pain, 30 (1987) 221-232. Talbot, J.D., Duncan, G.H. and Bushnell, M.C., Effects of diffuse noxious inhibitory controls (DNICs) on the sensory-discriminative dimension of pain perception, Pain, 36 (1989) 231-238. Wolf, S. and Hardy, J.D., Studies on pain: observations on pain due to local cooling and on factors involved in the 'cold pressor' effect, J. Clin. Invest., 20 (1941) 521-533.
Brain Research, 487 (1989) 388-391
Elsevier BRE23512
A primate model for the study of tonic pain, pain tolerance and diffuse noxious inhibitory controls Serge Marchand 2, Nathalie Trudeau 1, M. Catherine Bushnell 1'2 and Gary H. Duncan 1'2 l Facult~ de rnddecine dentaire and 2Centre de Recherche en sciences neurologiques, Universit~ de Montreal, Montreal, QuL (Canada)
(Accepted 7 February 1989) Key words: Primate; Cold pressor pain; Tonic pain; Pain tolerance; Diffuse noxious inhibitory control; Counterirritation
A primate model of cold pressor pain is described in which the animal itself initiates all trials, may terminate painful stimuli at any time, and controls the duration of the experimental session, thus avoiding the inadvertent administration of intolerable pain stimuli. Pain tolerance time varies directly with stimulus intensity and is sensitive to motivational factors. This model will facilitate the study of endogenous pain-modulatory pathways and the assessment of analgesic treatments in animals.
The development of animal pain models that parallel those used in humans is important for both practical and ethical reasons. Using such models, neurophysiological and pharmacological data can be obtained from animal studies under conditions in which the human perception is known, providing a clinical relevance that is frequently questioned with such tests as rodent tail flick, writhing response, hot plate reaction, shock titration and vocalization 5-7. In addition, by using the same painful stimuli that humans are willing to tolerate and by allowing the same control of stimulus presentations as is customary for human experimental pain subjects, one can better insure the ethical treatment of the animals. We have previously used, in both humans and monkeys, psychophysical paradigms which test their liminal ability to distinguish different intensities of painful heat4; we have also used other paradigms (adapted from the field of visual research 18) which assess the effects of attention on their nociceptive discriminative ability 3. These studies have shown that humans and monkeys perform even difficult psychophysical tasks in a similar fashion and more importantly that there are no demonstrable differ-
ences between the humans and monkeys in either their nociceptive discrimination thresholds or in the manner in which attention alters their ability to detect intensity changes in noxious heat stimuli. Thus, these results indicate that the perception of noxious heat must be similar for monkeys and humans. Because of these similarities in perception, the results of neurophysiological studies in monkeys, which investigate the neural substrates of nociceptive discrimination and its modulation by attention 1" 2,13,17 are directly relevant to the problems of pain and analgesia in humans. Another laboratory pain model frequently employed in humans to measure pain tolerance is the cold pressor test 8'1°'21, in which the subject is instructed to immerse a part of the body (usually the hand) in painfully cold water as long as possible; the duration of immersion is then given as a measure of pain tolerance. This type of pain measure is thought to approximate clinical acute pain states better than most laboratory stimulation procedures, because the pain stimulus is persisting rather than discrete, and the pain experience involves arousal and anxiety in addition to nociception 5. Cold pressor pain is also
Correspondence: M.C. Bushnell, Facult6 de m6decine dentaire, Universit6 de Montr6al, Montr6al, Quebec, Canada H3C 3J7.
0006-8993/89/$03.50 (~ 1989 Elsevier Science Publishers B.V. (Biomedical Division)
389 used in human studies investigating the phenomenon of counterirritation, in which the presence of one painful stimulus reduces the pain caused by other noxious stimuli 14'19'2°. A neurophysiological phenomenon, termed diffuse noxious inhibitory controls (DNICs), has been identified in anesthetized rats and monkeys, which probably underlies counterirritation 9'12'15A6. In this phenomenon, noxious stimuli applied to widespread areas of the body inhibit t h e nociceptive responses of wide dynamic range (WDR) neurons in the spinal and medullary dorsal horn. An animal model equivalent to the human cold pressor test could provide a useful tool for neurophysiological and pharmacological studies of pain states that approximate clinical acute pain, as well as presenting a potential model for the neurophysiological study of DNICs in unanesthetized animals. In the present study, one adult female monkey (Macaca mulatta) was trained to press a button installed in the floor of a 3-inch deep pan attached to the left side of the primate chair. At first, each time the monkey pressed the button it received a liquid reward. After this initial training, the pan was filled with room-temperature water (25 °C), and the monkey was taught to submerge its hand and press the button in order to obtain reward. For the remainder of the training, the pan was connected to a circulating refrigeration unit and the temperature of the water was gradually decreased to 10 °C*. Through successive approximations, the monkey was required to keep the button depressed for longer and longer periods, until it received reward only after depressing the button for 10 s. The monkey could then receive an additional reward every 5 s, if it continued to keep the button depressed. However, if it released the button and withdrew its hand from the water, a new behavioral trial could not be initiated for 90 s. A red light mounted on the primate chair was illuminated after the 90 s intertrial interval, signalling the monkey to initiate the next trial. If the monkey pressed the button during the intertrial interval, no reward was given, and a buzzer sounded to indicate that this was an inappropriate response. There was no limit on the number of trials that a
monkey could initiate during a session. However, when the monkey waited for at least 3 min before initiating 3 sequential trials, the session was terminated. When the monkey's performance was stable, a series of testing sessions were begun. During this series the water temperature was kept at 35 °C one day, 10 °C the next, and 0 °C the last day. This 3-day sequence was repeated 5 times. A minicomputer controlled the presentation of the trial-initiation stimulus (red light) as well as the frequency and quantity of liquid reward. The dependent variable, duration of each appropriate button press (i.e. the time that the monkey kept its hand submerged in the cold water), was recorded to disk for subsequent off-line analysis. Throughout the training and testing period, the monkey was kept in its home cage except for the approximately 2-h experimental period, during which it was seated in a primate chair. The monkey's weight and the amount of liquid intake during the experiment were monitored each day. The monkey was visited regularly by the university veterinarian and received vitamins and fruit daily as well as free access to primate chow. In addition to the liquid earned during the experiment, the monkey was given supplemental liquids so that it gradually gained weight (4%) during the 10 weeks of the study. Fig. 1 shows that the average duration that the monkey kept its hand in the water was influenced by water temperature (Kruskal-Wallis test, )~2 = 8.12, df = 2, P < 0.02). The monkey's withdrawal latency was greater than 3 min when the water was near skin temperature (35 °C), but decreased to 78 s for 10 °C water and 33 s for 0 °C water. These data indicate that the monkey was withdrawing its hand sooner from the colder water because of its painfulness, since all other variables were held constant across the 3 experimental conditions. As is expected for any measure of pain tolerance 11, the monkey's latency for withdrawing its hand from the cold water was influenced by motivational level. Fig. 2 compares data collected from the first 3 trials to that of the last 3 trials of each experimental session. During the earliest trials (solid
* Constant recirculation of the water reduces laminar warming around the submerged hand and insures a more consistent and controlled cold stimulus.
390 240 -
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Fig. 1. Withdrawal latency (mean of the median scores for each session) for each water temperature, i.e. 35 °C, 10 °C, and 0 °C. Error bars represent the standard error of the mean. The non-parametric Kruskal-Wallis test (equivalent to analysis of variance) revealed a significant effect of temperature on withdrawal latency (P < 0•02).
Fig. 2. Comparison of median withdrawal latencies for the first 3 trials (solid line) and the last 3 trials (dashed line) at each water temperature. The Kruskal-Wallis test revealed a significant temperature effect for the late trials (P < 0.05) but not for the early trials (P = 0.79)•
line), when the m o n k e y had not received fluids for 12 h, the withdrawal latencies were much longer than during the last 3 trials of the session (dashed line), when the monkey was satiated. This was true for the non-painful 35 °C water, as well as for the two cold-water conditions. Further, while there was a significant effect of water temperature on withdrawal latency for the late trials (Kruskal-Wallis, ;(2 = 6.04, df = 2, P < 0.05), there was no significant temperature effect during the earliest trials (P = 0.79). We also assessed, in two humans, subjective reports of cold pain for 10 °C and 0 °C water using the same behavioral paradigm used for the monkeys, but asking the subjects to indicate verbally when they first felt pain (pain threshold) and to withdraw their hand when they could no longer tolerate the pain. Their pain thresholds at 10 °C and 0 °C, respectively, were 51.2 s and 17.5 s, both being shorter than the monkey's mean withdrawal latencies (78 s and 34 s, respectively). However, the humans' mean tolerance time was higher than that of the m o n k e y for both 10 °C water (humans = 218 s, m o n k e y = 78 s) and 0 °C water (humans = 51 s, m o n k e y = 34 s). As was true for the monkey,
humans tended to tolerate the 10 °C cold for a longer period during the first 3 trials than during the last 3 (374 vs 234 s), but this relationship did not hold for 0 °C (43 vs 43 s). The fact that the early-late differences were not as great as those observed for the monkey is not surprising, since the humans received no reward for keeping their hand in the water, and thus were less influenced by changes in motivation across the experimental session. The present data suggest that the cold pressor test can be used successfully in monkeys as a pain tolerance measure• Since motivational level appears to have a large influence on tolerance time, it is important, when using the model to test analgesic manipulations, to maintain motivation at the same level during each experimental condition. Since some analgesic manipulations, such as morphine, may also produce motor, cognitive, or appetitive effects, a non-painful control temperature (such as 35 °C) provides a useful method to evaluate nonspecific changes in the monkey's performance. Finally, the fact that the animal initiates all painful stimuli and sustains the painful stimulus with an active response eliminates a problem inherent in most escape paradigms, i.e. motor or cognitive
391
deficits could interfere with the animal's ability to terminate a noxious stimulus. The primate cold pressor pain model will also be useful for c o m b i n e d neurophysiological and behavioral evaluations of DNICs. Changes in n e u r o n a l activity produced by the tonic noxious stimulus (i.e. the cold pain) can be evaluated in conjunction with observations of the animal's perception of phasic noxious and non-noxious stimuli, in a m a n n e r similar 1 Bushnell, M.C. and Duncan, G.H., Sensory and affective aspects of pain perception: is medial thalamus restricted to emotional issues? Exp. Brain Res., submitted. 2 Bushnell, M.C., Duncan, G.H., Dubner, R. and He, L.F., Activity of trigeminothalamic neurons in medullary dorsal horn of awake monkeys trained in a thermal discrimination task, J. Neurophysiol., 52 (1984) 170-187. 3 Bushnell, M.C., Duncan, G.H., Dubner, R., Jones, R.L. and Maixner, W., Attentional influences on noxious and innocuous cutaneous heat detection in humans and monkeys, J. Neurosci., 5 (1985) 1103-1110. 4 Bushnell, M.C., Taylor, M.B., Duncan, G.H. and Dubner, R., Discrimination of noxious and innocuous thermal stimuli in human and monkey, Somatosen. Res., 1 (1983) 119-129. 5 Chapman, C.R., Casey, K.L., Dubner, R., Foley, K.M., Gracely, R.H. and Reading, A.E., Pain measurement: an overview, Pain, 22 (1985) 1-31. 6 Cooper, B.Y. and Vierck, C.J. Jr., Vocalizations as measures of pain in monkeys, Pain, 26 (1986) 393-393. 7 Cooper, B.Y. and Vierck, C.J. Jr., Measurement of pain and morphine hypalgesia in monkeys, Pain, 26 (1986) 361-392. 8 Davidson, P.O. and McDougall, C.E.A., The generality of pain tolerance, J. Psychosom. Res., 13 (1969) 69-76. 9 Dickenson, A.H. and Le Bars, D., Diffuse noxious inhibitory controls (DNIC) involve trigeminothalamic and spinothalamic neurones in the rat, Exp. Brain Res., 49 (1983) 174-280. 10 Dowling, J., Autonomic measures and behavioral indices of pain sensitivity, Pain, 16 (1983) 193-200. 11 Dubner, R., Beitel, R.E. and Brown, F.J., A behavioral animal model for the study of pain mechanisms in primates. In M. Weisenberg and B. Tursky (Eds.), Pain: New Perspectives in Therapy and Research, Plenum, New York, 1976, pp. 155-170. 12 Gerhart, K.D., Yezierski, R.P., Giesler, G.J. and Willis,
to that used to evaluate attentional m o d u l a t i o n in pain pathways 1'2. We would like to thank Dr. A l l e n Smith for his critical comments on this manuscript. This research was supported by the Medical Research Council of Canada. Mr. Marchand was supported by the Quebec 'Fonds pour la formation de chercheurs et l'aide la recherche'.
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16
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W.D., Inhibitory receptive fields of primate spinothalamic tract cells, J. Neurophysiol., 46 (1981) 1309-1325. Hayes, R.L., Price, D.D., Ruda, M.A. and Dubner, R., Neuronal activity in medullary dorsal horn of awake monkeys trained in a thermal discrimination task. II. Behavioral modulation of responses to thermal and mechanical stimuli, J. Neurophysiol., 46 (1981) 428-443. Jungkunz, G., Engel, R.R., King, U.G. and Kuss, H.J., Endogenous opiates increase pain tolerance after stress in humans, Psychiatry Res., 8 (1983) 13-13. Le Bars, D., Dickenson, A.H. and Besson, J.-M., Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat, Pain, 6 (1979) 283-304. Le Bars, D., Dickenson, A.H. and Besson, J.-M., Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on non-convergent neurones, supraspinal involvement and theoretical implications, Pain, 6 (1979) 305-327. Maixner, W., Dubner, R., Bushnell, M.C., Kenshalo, D.R. and Oliveras, J.-L., Wide-dynamic-range dorsal horn neurons participate in the encoding process by which monkeys perceive the intensity of noxious heat stimuli, Brain Research, 374 (1986) 385-388. Posner, M.E., Orienting of attention, Q. J. Exp. Psychol., 32 (1980) 3-25. Talbot, J.D., Bushnell, M.C. and Boyer, M., Psychophysical evidence in man for intersegmental suppression of noxious heat perception by cold pressor pain, Pain, 30 (1987) 221-232. Talbot, J.D., Duncan, G.H. and Bushnell, M.C., Effects of diffuse noxious inhibitory controls (DNICs) on the sensory-discriminative dimension of pain perception, Pain, 36 (1989) 231-238. Wolf, S. and Hardy, J.D., Studies on pain: observations on pain due to local cooling and on factors involved in the 'cold pressor' effect, J. Clin. Invest., 20 (1941) 521-533.