Adv Physiol Educ 34: 25-34, 2010;
doi:10.1152/advan.00002.2010.
Thermoreception and nociception of the skin: a classic paper of Bessou and
Perl and analyses of thermal sensitivity during a student laboratory exercise
Johann P. Kuhtz-Buschbeck,1 Wiebke Andresen,1 Stephan Göbel,1 René Gilster,1 and Carsten Stick2
1
Physiologisches Institut and 2Medizinische Klimatologie, Universität Kiel, Kiel, Germany
Submitted 6 January 2010; accepted in final form 8 March 2010
Kuhtz-Buschbeck JP, Andresen W, Göbel S, Gilster R, Stick
C. Thermoreception and nociception of the skin: a classic paper of
Bessou and Perl and analyses of thermal sensitivity during a
student laboratory exercise. Adv Physiol Educ 34: 25–34, 2010;
doi:10.1152/advan.00002.2010.—About four decades ago, Perl
and collaborators were the first ones who unambiguously identified
specifically nociceptive neurons in the periphery. In their classic
work, they recorded action potentials from single C-fibers of a
cutaneous nerve in cats while applying carefully graded stimuli to
the skin (Bessou P, Perl ER. Response of cutaneous sensory units
with unmyelinated fibers to noxious stimuli. J Neurophysiol 32:
1025–1043, 1969). They discovered polymodal nociceptors, which
responded to mechanical, thermal, and chemical stimuli in the
noxious range, and differentiated them from low-threshold ther-
moreceptors. Their classic findings form the basis of the present
method that undergraduate medical students experience during
laboratory exercises of sensory physiology, namely, quantitative
testing of the thermal detection and pain thresholds. This diagnos-
tic method examines the function of thin afferent nerve fibers. We
collected data from nearly 300 students that showed that 1) women
are more sensitive to thermal detection and thermal pain at the
thenar than men, 2) habituation shifts thermal pain thresholds
during repetititve testing, 3) the cold pain threshold is rather
variable and lower when tested after heat pain than in the reverse
case (order effect), and 4) ratings of pain intensity on a visual
analog scale are correlated with the threshold temperature for heat
pain but not for cold pain. Median group results could be repro-
duced in a retest. Quantitative sensory testing of thermal thresholds
is feasible and instructive in the setting of a laboratory exercise and
is appreciated by the students as a relevant and interesting tech-
nique.
thermal detection thresholds; thermal pain thresholds; pain ratings;
reproducibility; quantitative sensory testing
THE QUESTION OF what the role of slowly conducting afferents is
was answered four decades ago by Perl and colleagues, who
proved, for the first time, that a distinctive set of primary
afferent units codes for painful stimuli in the periphery. Today,
it is basic physiological knowledge that A␦-fiber nociceptors,
excited by strong mechanical stimuli, and polymodal C-fiber
nociceptors are the principal afferents signaling cutaneous pain
(30). The discovery of these nociceptors is described in the
classic paper of Bessou and Perl (2). In anesthetized cats, they
exposed the posterior femoral nerve and prepared very thin
filaments by dissection under the microscope. Afferent fibers
with a conduction velocity under 2.2 m/s (C-fibers) were
identified by electrical nerve stimulation. The cutaneous recep-
tive fields of single afferent units were identified and action
Address for reprint requests and other correspondence: J. P. Kuhtz-Busch-
beck, Institute of Physiology, Christian-Albrechts-Universität Kiel, Olshausen-
strasse 40, Kiel D 24098, Germany (e-mail: kuhtz@physiologie.uni-kiel.de).
1043-4046/10 Copyright © 2010 The American Physiological Society
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Using Classic Papers To Teach Physiology
potentials were recorded while the skin was stimulated using
various methods: graded pressure (von Frey hairs), light touch,
puncture, application of acid, cooling, and heating. In this way,
the receptive characteristics of 131 unmyelinated fibers were
examined. Thirty percent of these fibers belonged to high-
threshold receptors, which were activated by intense mechan-
ical stimuli, irritant chemicals, and heat, with thresholds be-
tween 42 and 56°C. Since noxious stimulation was the common
denominator, they were designated “polymodal nociceptors.”
Two original graphs from the classic paper (2) show their re-
sponses to local heating of the skin with a thermode (Fig. 1). Some
of these nociceptors were also weakly excited by very low
temperatures (ice placed on the skin). Further high-threshold
unmyelinated afferent units were classified as mechanoreceptors
and subcutaneous receptors. Low-threshold sensory units com-
prised other mechanoreceptors and thermoreceptors. The latter
had some background activity at normal ambient skin temperature
(30 –34°C) and were highly responsive to slight thermal changes
(⬍2°C). Lightly myelinated afferent fibers (A␦-fibers) responding
to noxious mechanical stimuli had been described in an earlier
publication from the same research group (4).
Later experiments with human volunteers used microneu-
rography to record action potentials from single C-fibers in-
nervating the hairy skin of the leg and foot while heat stimuli
were applied to the receptive fields of these fibers (45). The
magnitude of the evoked pain sensation, as rated by the
volunteers, was closely related to the discharge rate of poly-
modal mechano-heat-sensitive C-fibers. Moreover, C-fibers
innervating the glabrous and hairy skin of the hand and forearm
were selectively excited by intraneural microstimulation in
awake human subjects (32). This evoked sensations of dull or
burning pain that were accurately projected to the receptive
fields of the respective fibers. These findings indicate that
polymodal nociceptors of the skin, as originally described in
cats in the aforementioned classic paper (2), have similar
characteristics in humans as well.
Nowadays, the function of thermosensitive cutaneous A␦-
and C-fibers can be examined in humans by measuring the
thermal pain thresholds and detection thresholds for tempera-
ture change with a computer-controlled thermode (40, 41).
Elevated thresholds indicate a loss or dysfunction of thin nerve
fibers, e.g., in patients with neuropathic pain (18). Undergrad-
uate medical students (first year) encounter this diagnostic
method in our laboratory exercise in physiology. The right
thenar eminence serves as a test region that is convenient to
examine during a teaching exercise. The thermal detection and
pain thresholds are determined, and the students rate the
perceived intensity of pain on a visual analog scale (VAS).
Data from 287 medical students have been collected since
2005. The results are summarized in the present article and
may serve as a database for teaching purposes. We evaluated
25
Using Classic Papers To Teach Physiology
26 THERMORECEPTION AND NOCICEPTION
Fig. 1. Original data of the classic paper by
Bessou and Perl (2), adapted from their Figs. 2 and
5. A: responses recorded from an afferent fiber
(conduction velocity: 1 m/s) of a polymodal noci-
ceptor of a cat. First heating of the skin was above
40°C. B: 10 s after A; now heating from 45 to
50°C. C: instantaneous discharge frequency (F) of
a polymodal nociceptor during skin heating over a
period of 150 s, with a parallel record of the
corresponding skin temperature (bottom curve).
sex-related differences, effects of habituation during repeated
testing of the pain thresholds, correlations between the thresh-
old temperatures and corresponding ratings of pain intensity,
and effects of the sequence of stimuli. Retest reliability was
examined in a subgroup of volunteers. The results of the
student collective are discussed in the context of the aforemen-
tioned classic paper (2).
METHODS
The thermal sensitivity of the right thenar was examined in 287
medical students (170 women and 117 men) during a laboratory
exercise in physiology. We always assessed the cold and warm
detection thresholds (WDT and CDT, respectively) first and then the
cold and heat pain thresholds (CPT and HPT, respectively). Students
were divided into three groups: groups A, B, and C. Group A consisted
of 141 subjects (90 women and 51 men, age: 22.9 ⫾ 4.7 yr, mean ⫾
SD), whose thermal thresholds were examined in the following
sequence: CDT-WDT-CPT-HPT. Group B consisted of 124 subjects
(69 women and 55 men, age: 23.1 ⫾ 3.5 yr), who were tested in the
following sequence: WDT-CDT-HPT-CPT, i.e., warm stimuli pre-
ceded cold stimuli in this group. Group C consisted of 22 subjects (11
women and 11 men, age: 21.8 ⫾ 2.6 yr), who were examined with
both test sequences at an interval of ⬃30 min.
Classes of ⬃20 students took part in the laboratory exercise, which
took place in one room during afternoon hours. They were informed
that data of normal thermal sensitivity were to be gathered from
healthy subjects. About five students per class volunteered to undergo
the noninvasive tests; the others performed different tasks (e.g.,
vibration thresholds and tactile acuity). Volunteers gave their in-
formed consent before the start of the experiments, which were
approved by the Ethical Committee of the Medical Faculty of Kiel
University (Kiel, Germany).
The student was seated at a table in a corner of the room, with the
right forearm comfortably resting on a padded splint. Before the test
started, the initial skin surface temperature of the right thenar was
measured with a thermistor (Testo 720 Pt 100, Lenzkirch, Germany)
in group A. With the hand in a prone position, the right thenar was
then placed on a computer-controlled Peltier-type thermode (size of
contact surface: 3 ⫻ 3 cm2) of a thermal sensory analyzer (TSA 2001,
Medoc). Testing started after an adaptation period of ⬃1 min. A
device with a response button was held in the left hand.
All tests started from a “thermal-neutral” (indifferent) baseline
thermode temperature of 32°C. Series of thermal stimuli that in-
creased or decreased from baseline were applied. The response button
was pressed with the left hand when the respective thermal sensation
was perceived, i.e., with the Method of Limits (54). This stopped the
heating up/cooling down. The respective temperature was recorded,
and the thermode was returned to baseline (32°C). CDT and WDT
were examined first, using ramp stimuli with a velocity of 1°C/s.
Students were instructed to press the button as soon as they detected
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a change of the temperature (“Press the response button immediately
when you perceive a change of the thermode temperature, i.e., warmer
or colder.”). In each subject, CDT and WDT were each averaged from
five consecutive trials delivered at 7- to 10-s intervals. Thereafter,
CPT and HPT were determined with ramp stimuli (1.5°C/s). Students
were now explicitly instructed to press the button as soon as the heat
or cold sensation became painful (“Press the stop button at the first
painful sensation! The temperature increase/decrease will then stop
immediately.”). We emphasized that it was not the goal to examine
pain tolerance. The lower temperature limit of the thermode was 0°C
due to technical limitations, and the upper limit was set to 53°C for
safety reasons. Again, five consecutive trials were performed per pain
threshold, and mean values of the CPT and HPT were calculated. This
approach and the rates of the thermal ramps were chosen in line with
previously published test protocols (1, 41). Immediately after the
respective fifth trial, students rated the perceived intensity of pain on
a 101-point VAS. The VAS was a ruler with a slide, which could be
adjusted between “no pain” (0) and the “worst imaginable pain” (100).
To minimize distraction, students wore ear muffs during the entire
testing session, which lasted ⬃5 min. They could not watch the
computer screen that indicated the current results. Experienced staff
members (S. Göbel, W. Andresen, and R. Gilster) operated the
thermal sensory analyzer (TSA 2001, Medoc) and gave the instruc-
tions.
Nonparametric statistical methods were applied because the detec-
tion thresholds and CPT were not distributed normally. We deter-
mined median values (50th percentile), interquartile ranges (25–75th
percentile), and normal ranges (95% reference interval), which was
defined as the interval between the 2.5th and 97.5th empirical per-
centiles (52). Data from men and women were contrasted with
Mann-Whitney U-tests. The dynamics of the five consecutive CPT
and HPT measurements were evaluated with nonparametric ANOVA
for repeated measures (Friedman ANOVA) followed by Wilcoxon
signed-rank tests. Relations between different measures were de-
scribed with Spearman’s rank correlation coefficients (␳). Possible
effects of the test sequence (cold-warm vs. warm-cold) were evaluated
by comparing the results of groups A and B with Mann-Whitney
U-tests. Sequence effects in group C (same subjects examined with
both test sequences) were evaluated with Wilcoxon tests. To assess
retest reliability, 33 students from group A (20 women and 13 men)
were reexamined one by one in a climatic chamber (22°C, relative
humidity: 50%) ⬃1 wk after the laboratory exercise. The test and
retest results were compared with Wilcoxon tests, and correlation
coefficients were calculated. The software package SPSS (version 15)
was used for statistical computations.
RESULTS
Thermal Detection and Pain Thresholds
The results from group A are shown in Table 1, and the
corresponding data of women and men are contrasted in Fig. 2.
 Using Classic Papers To Teach Physiology
THERMORECEPTION AND NOCICEPTION 27

Table 1. Thermal detection and pain thresholds in group A difference between the first and last trial was ⬃4°C for the
HPT and ⬃3°C for the CPT.
Percentile

Parameter Median 2.5% 25% 75% 97.5% Minimum Maximum Ratings of Pain Intensity on the VAS
CDT, °C 30.8 28.9 30.4 31.1 31.5 27.0 31.5 The ratings of heat pain intensity increased with the temper-
WDT, °C 33.5 32.9 33.2 33.9 35.3 32.7 36.2 ature of the HPT (Fig. 5A). No such correlation was found for
CPT, °C 9.0 0.8 4.9 15.2 22.7 0.0 25.4
HPT, °C 46.4 37.8 43.5 48.1 52.3 37.0 52.9 the ratings of cold pain intensity, which were rather variable
VAS and independent from the temperature of the CPT (Fig. 5B).
CPT 27.0 5.0 20.0 38.0 53.0 0.0 80.0 However, the ratings of cold and heat pain intensity were
HPT 37.0 10.0 27.0 50 77.0 0.0 80.0 positively correlated (␳ ⫽ 0.68, P ⬍ 0.01), so that students who
Skin temperature, °C 32.2 29.3 31.3 33.0 34.4 28.0 34.3
indicated the intensity of heat pain to be high tended to give
n ⫽ 141 students in group A. Shown are median values, percentiles, and high ratings of cold pain intensity as well.
minimum and maximum values. Results are combined data of women and
men. VAS, pain rating on visual analog scale (where no pain ⫽ 0 and the Effects of the Test Sequence
“worst imaginable pain” ⫽ 100). CDT, cold detection threshold; WDT, warm
detection threshold; CPT, cold pain threshold; HPT, heat pain threshold. The A comparison of the results of group A (Table 1) and group
order of testing was CDT-WDT-CPT-HPT in group A.
B (Table 2) suggested that the order of stimuli influences the
perception of cold pain. Students in group B, who were tested
Women detected temperature changes more sensitively than in the sequence WDT-CDT-HPT-CPT, had a significantly
men, as reflected by significant differences (P ⬍ 0.01) of the lower CPT (P ⬍ 0.01) than the members of group A (sequence
WDT and CDT. In addition, the HPT was lower in female CDT-WDT-CPT-HPT). Moreover, heat pain was rated to be
students than in male students (P ⬍ 0.05), whereas the CPT more intense (P ⬍ 0.05) by group B than by group A. The
and ratings of pain intensity did not significantly differ. Both results of group C confirmed the effect of the order of stimuli
women and men rated the intensity of heat pain stronger (P ⬍ on the CPT because the median CPT of 9.5°C (test sequence
0.01) than cold pain intensity. The HPT was less variable than HPT-CPT) was significantly lower than the median value
the CPT, whose normal range covered a span of ⬃20°C. (10.3°C) that was obtained with the reverse sequence (CPT-
A significant correlation (P ⬍ 0.01) existed between the HPT) in the same subjects (P ⬍ 0.05 by Wilcoxon test). The
HPT and CPT (Fig. 3), i.e., volunteers who did not perceive thermal detection thresholds and HPT were not influenced by
cold pain until the thermode reached very low temperatures the order of stimuli. Sex-related differences in group B were
had high (insensitive) thresholds of heat pain as well. Simi- similar to those described for group A (see Fig. 2).
larly, CDT and WDT were correlated. However, we found no
significant correlation between the thermal detection and pain Retest Reliability
thresholds. In addition, the initial skin temperature (measured The setting of a laboratory exercise includes the presence of
before testing) was not significantly correlated with any of the classmates, social interactions, and noise in a room where other
thresholds. tasks are performed at the same time. Distraction may be a
Short-Term Changes of Thermal Pain Thresholds relevant factor, which conceivably can affect data that are
obtained with a reaction time-dependent method. Furthermore,
Both thermal pain thresholds shifted gradually over the five the ambient room temperature and humidity could not be kept
consecutive trials (P ⬍ 0.05 by ANOVA), i.e., the response perfectly constant. To assess reproducibility, 33 students from
button that signaled the first painful sensation was pressed later group A were retested one by one in a quiet climatic chamber
from trial to trial (Fig. 4). Significant differences between (22°C, relative humidity: 50%) by the same examiner. Their
successive trials were found up to the fifth measurement of the thermal detection and pain thresholds did not differ signifi-
HPT and up to the fourth measurement of the CPT. The median cantly from the previous laboratory exercise (not significant by

Fig. 2. Warm and cold detection thresholds

(WDT and CDT, respectively) and heat and cold
pain thresholds (HPT and CPT, respectively) as
well as subjective ratings of pain intensity on a
visual analog scale (VAS). Box plots show me-
dians, quartiles, and minimum and maximum
values. Significant differences between women
and men are shown (*P ⬍ 0.05 and **P ⬍ 0.01
by Mann-Whitney U-tests). Data of the labora-
tory exercise (group A, n ⫽ 141 students) were
measured at the right thenar.

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Using Classic Papers To Teach Physiology
28 THERMORECEPTION AND NOCICEPTION

Fig. 3. Correlations. HPT and CPT were cor-

related, as were WDT and CDT. Spearman’s
rank correlation coefficients (␳) were significant
(P ⬍ 0.01). Each symbol indicates the results of
one student. The solid lines are regression lines;
the dashed lines indicate normal ranges (2.5th
and 97.5th percentiles). Data are from group A
(laboratory exercise).

Wilcoxon tests), and correlation coefficients between test and resting on the thermode is comfortable, and no straps are
retest results ranged between 0.4 and 0.7 (Table 3). necessary to fix the thermode. Regardless of the body region,
the detection and evaluation of a physical stimulus (e.g.,
DISCUSSION warmth) is a subjective experience. Especially, the perception
of pain varies from person to person and must be distinguished
The classic study of Bessou and Perl (2) characterized from the objective neural consequences of a noxious stimulus
polymodal nociceptors in cats by measuring the discharge rates as analyzed by Bessou and Perl, such as receptor potentials and
of single C-fibers (see Fig. 1) in response to thermal, mechan- discharge rates of afferent fibers. Psychophysical sensory
ical, and chemical stimulation of the skin. It is important for the thresholds are not fixed but can be influenced by practice,
students to understand that diagnostic determination of the
thermal detection and pain thresholds in humans (discovery
learning) not only involves peripheral receptors but the entire
afferent pathway: nociceptors and low-threshold thermorecep-
tors, their afferent C- and A␦-fibers, the synaptic relay in the
dorsal horn of grey matter of the spinal cord, the spinothalamic
pathway, the thalamus, and cortical regions engaged in the
processing and evaluation of thermal sensations and pain
(somatosensory, cingulate, and insular cortex).
As a further difference, Bessou and Perl (2) studied the hairy
skin of the cat hindlimb, whereas the glabrous skin of the
thenar was examined during the laboratory exercise. Potential
differences between hairy and glabrous skin with regard to
thermal sensitivity and nociception are an issue of current
research. Harrison and Davis (14) found that CDT and cold-
induced pain thresholds were lower (i.e., occurred at higher
absolute temperatures) for the hairy skin of the dorsal hand
compared with the thenar. Other researchers have reported that
the human palm has a higher HPT than the hairy skin of the
dorsal hand (9). A very recent study (7) varied the size of the
stimulated area and concluded that spatial summation depends
on skin type (more summation in glabrous skin) and on skin
sensitivity. However, Iannetti and colleagues (17) found that
laser heat stimulation of the dorsum as well as palm of the hand
elicited remarkably similar EEG brain responses (laser-evoked
potentials) with very similar psychophysical ratings of pain
intensity. They inferred that nociceptive afferents with compa-
rable properties mediate the first pain to heat stimulation of the
glabrous and hairy skin in humans. Besides the type of skin, the
body region seems to be relevant. Hagander et al. (13) found
significantly lower CDT and WDT at the dorsum of the hand
Fig. 4. Short-term habituation of thermal pain thresholds. Changes from the first to the
than at the dorsum of the foot. fifth measurement for the CPT and HPT are shown. Significant differences between
For a laboratory exercise, the thenar is a very convenient test successive measurements are shown (*P ⬍ 0.05 and **P ⬍ 0.01 by Wilcoxon tests
region. Students do not have to undress, the posture of the hand after a Bonferroni correction). Box plots are as in Fig. 2. ns, Not significant.

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 Using Classic Papers To Teach Physiology
THERMORECEPTION AND NOCICEPTION 29

Fig. 5. Correlation between pain intensity and thermal pain thresholds. A: relation between ratings for heat pain intensity (vertical axis) and temperature of the
HPT. B: relation between ratings for cold pain intensity and temperature of the CPT. Pain intensity was rated on a VAS. Each symbol shows the results from
one student. Data are from group A (laboratory exercise).

fatigue, and reaction time. Diurnal and situational variations of
the pain threshold have an influence (23); descending pain
control systems may, e.g., reduce sensitivity during competi-
tive sports.
Teaching Points
The present results, which were collected over several years,
lead to the following five questions that can be discussed with
the participating students after the laboratory exercise.
Question 1. What can explain differences in thermal sensi-
tivity between women and men (Fig. 2)? Female students
detected cold and warm stimuli more sensitively than male
students and had a lower HPT. Nine previous studies, con-
ducted in research laboratories, have reported similar differ-
ences (see Table 4). Women have a thinner epidermis at the
palm and fingers than men (27), which may result in better
peripheral temperature conductance and, therefore, a stronger
afferent input at the peripheral level. In the present study,
higher alertness of female students may have influenced the
results of the reaction time-dependent method as well. The
increased heat pain sensitivity (lower HPT) of the women
could furthermore be due a higher readiness of women to
report pain, gender role expectations, and sex-related differ-
Table 2. Thermal detection and pain thresholds in group B
ences in endogenous pain modulation (22, 37, 43, 51). Differ-
ences in the central processing of noxious input have been
reported in a recent neuroimaging study (15), where cutaneous
pain evoked stronger activity of the midcingulate cortex, dor-
solateral prefrontal cortex, and hippocampus in women than
men. A meta-analysis of published articles (39) showed that
sex differences in response to noxious experimental stimuli are
relatively small so that large sample sizes (n ⬎ 40) are
necessary to detect them. The skin temperature at the thenar,
which had been measured before the hand was placed on the
thermode, was lower in women than in men (Table 1). Al-
though a lower temperature reduces the nerve conduction
velocity (33), we found no significant influence of the skin
temperature on the thermal detection and pain thresholds,
probably because the effects were too small (48). In addition,
Hagander and collaborators (13) reported that WDT and CDT
are independent of the local skin temperature.
Question 2. What can explain the correlations of the WDT
and CDT and of HPT and CPT (Fig. 3)? The detection of small
changes in skin temperature depends crucially on the function
of low-threshold thermoreceptors. Bessou and Perl (2) de-
scribed sensory units that responded to mild cooling of the skin
and had the greatest tonic discharge between 23 and 32°C and
warm-sensitive receptors that responded to slight increases
(⬍2°C) of the skin temperature, with maximal tonic activity

Percentile
Table 3. Test and retest results of 33 students
Parameter Median 2.5% 25% 75% 97.5% Minimum Maximum
Laboratory Exercise Climatic Chamber
CDT, °C 30.9 29.3 30.5 31.1 31.5 28.0 31.7 Parameter (Test Results) (Retest Results) ␳
WDT, °C 33.5 32.8 33.1 33.9 34.8 32.6 35.4
CPT, °C† 5.2 0.0 1.6 11.3 20.4 0.0 25.5 CDT, °C 30.9 30.9 0.50
HPT, °C 46.8 39.9 44.7 48.7 51.7 37.4 52.3 WDT, °C 33.6 33.6 0.56
VAS CPT, °C 10.6 14.1 0.72
CPT 30.0 0.1 20.8 46.5 68.0 0.0 78.0 HPT, °C 46.1 46.1 0.59
HPT* 50.0 20.2 36.8 60.0 73.9 18.0 87.0 VAS
CPT 20.0 15.0 0.38
n ⫽ 124 students in group B. Shown are median values, percentiles, and HPT 29.0 22.0 0.59
minimum and maximum values. Results are combined data of women and
men. The order of testing was WDT-CDT-HPT-CPT in group B. Significant The 33 volunteers were first tested during the laboratory exercise and then
differences between group A (see Table 1) and group B are shown (ⴱP ⬍ 0.05 reexamined one by one ⬃1 wk later under standardized conditions in a climatic
and †P ⬍ 0.01 by Mann-Whitney U-test). The initial skin temperature was not chamber. Shown are median values of the group and Spearman’s correlation
measured in group B. coefficients (␳).

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 Table 4. Summary of published normal thermal thresholds at the thenar and hand 30

Number of
Repeated Sex-Related
Measurements Differences
Number Temperature Underlying the (more sensitive Pain
Tested of WDT, change CDT, change Change Rate, Averaged Thermode gender in Sequence of Rating
Year Reference Region Subjects Age, yr in °C in °C HPT, °C CPT, °C Baseline, °C °C/s Results Size, cm2 parentheses) Tests (VAS)

Results from the thenar

1986 Kenshalo (21) Thenar 27 19–31 0.3* ⫺0.2* 44.6 (1.6) ND 40 0.3 20 7.1 No differences Randomized No
1991 Lautenbacher Thenar 64 38 (12) 1.8 (0.9) ⫺0.9 (0.3) 45.5 (2.5) ND 32/40 0.7 5–7 5.8 WDT (women) WDT-CDT- No
and Strian but not HPT HPT
(24)†
1992 Verdugo and Thenar 61 17–72 1.5 (1.2) ⫺1.4 (0.4) 44.6 (1.9) 12.3 (4.4) 32 2–4 3–6 12.5 Not evaluated CDT-WDT- No
Ochoa (46) CPT-HPT
1994 Meh and Thenar 150 36 (17) ND ND 38.9 (4.5) 23.6 (4.8) 30 1 Unknown 12.5 HPT (women) CPT-HPT No
Denišlič but not CPT
(31)
1994 Yarnitsky and Thenar 46 20–39 1.6 ⫺1.6 ND ND 32 1 4 12.5 No differences Not reported No
Sprecher
(54)
1995 Yarnitsky et Thenar 46 20–39 ND ND 45.1 ND 32 2 3 13.8 No difference HPT only No
Using Classic Papers To Teach Physiology

al. (55)
1999 Liou et al. Thenar 23 22–30 2.4 (1.1) ⫺0.8 (0.6) 49.6 (2.2) 8.2 (2.3) 30 1 3–6 12.5 WDT (women) WDT-CDT- Yes
(29) and CDT HPT-CPT
(men)
1999 Hilz et al. Thenar 157 31 (9) 1.4 (0.6) ⫺1.9 (0.8) ND ND 32 1 5 3.75 WDT (women) Random No
(16)
2000 Hagander et Thenar 46 33 (10) 0.5* ⫺0.5* 43.4 9.8 32 1 6 13.3 Not evaluated Not reported No
al. (13)‡
2005 Lin et al. (28) Thenar 122 30 (6) 1.7 (0.7) ⫺1.4 (0.6) ND ND 32 1 4 9.0 WDT (women) Random No
2005 Kelly et al. Thenar 50 19–59 0.8* ⫺0.7* 45.6 6.7 32 1.5 4 6.25 No differences WDT-CDT- Yes
(19) HPT-CPT
2005 Palmer and Thenar 24 21 (3) 1.2 (0.4) ⫺1.1 (0.6) 40.7 (4.4) 21.6 (5.9) 32 0.5 3 9.0 Only female Randomized No
Martin subjects
(34)†
2008 Li et al. (27) Thenar 25 26 (4) 4.1 ⫺2.9 ND ND 32 2 3 2.0 WDT (women) Not reported No
THERMORECEPTION AND NOCICEPTION

and CDT

Advances in Physiology Education • VOL 34 • JUNE 2010

(women)
2009 Agostinho et Thenar 39 42 (15) 1.6 ⫺1.6 45.9 (3.1) 8.5 (6.4) 32 1–1.5 3–8 9.0 Not evaluated CDT-WDT- No
al. (1) CPT-HPT
2010 Present Thenar 141 23 (5) 1.7 (0.6) ⫺1.4 (0.7) 45.7 (3.6) 10.2 (6.4) 32 1–1.5 5 9.0 WDT (women) CDT-WDT- Yes
study§ and HPT CPT-HPT
(women)
Results from adjacent sites
1995 Ruffell and Third 10 26 (4) 6.5 (2.9) ⫺3.6 (1.6) ND ND 32 1 5 Unknown Only male Random No

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Griffin (42) finger subjects
1999 Fillingim et Volar 37 21 (1) ND ND 45.9 (4.0) ND 32 1 4 9.0 HPT (women) HPT only No
al. (8)† forearm
2002 Defrin et al. Dorsum of 18 36 (7) 4.0 (2.0) ⫺4.0 (2.0) 42.5 (2.5) 19.0 (6.5) 32/35 2 4 15.4 Not evaluated WDT-CDT- No
(6)† the hand HPT-CPT
2005 Lautenbacher Volar 20 27 (4) 3.3 (2.0) ⫺1.8 (1.0) 45.2 (2.1) ND 32/35 0.5–2 5 6.0–9.0 WDT (women) WDT-CDT- No
et al. (25)† forearm but not HPT HPT
2005 Watson et al. Volar 20 34 (5) 2.5 (1.1) ⫺2.2 (1.1) 45.2 (3.5) 11.9 (5.4) 32 1 4 9 Only male CDT-WDT- No
(50) forearm subjects CPT-HPT

Continued
 Using Classic Papers To Teach Physiology
THERMORECEPTION AND NOCICEPTION 31

Data are means (SD) where available; otherwise, data are ranges or exact values. Published values are of thermal thresholds in normal subjects arranged in chronological order for the thenar and adjacent

(SD) or as range depending on the available data. If a study included several age groups, data of the young subjects were selected, in accordance with the ages of the student groups in the present study. ND,
sites. Some studies report separate data of women and men but no combined results. In this case, the respective data have been averaged post hoc. The Method of Limits (41, 54) was always used to examine
pain thresholds and also for most detection thresholds. However, three studies (13, 19, 21) determined detection thresholds with the Method of Levels (indicated by ⴱ). Ages of subjects are given as means

no data available. Baseline, starting temperature of the thermode; v. forearm, volar forearm; dors. hand, dorsum of the hand. †Numerical values had to be read from figures (there were no tables available).
between 35 and 40°C. A change of temperature will, therefore,

Rating
(VAS)
Pain

Yes
No

No
increase the activity of one receptor population above back-
ground level and decrease the activity of the other receptors

Sequence of

CPT-HPT

CPT-HPT

CPT-HPT
below background level at the same time. The difference in

CDT-WDT-

CDT-WDT-

CDT-WDT-
Tests
activity between warm and cold receptors encodes the amount
of change. Since the CDT and WDT are both determined by
the combined information of the two receptor populations, the
correlation of both thresholds is plausible.
(more sensitive

No differences
parentheses)
Sex-Related

CPT (women)
Differences

Not evaluated
gender in

and HPT The correlation of the thermal pain thresholds may simply
(women) reflect that some people react more sensitively to noxious
stimuli than others, irrespective of the stimulus type (heat/
cold). Individual characteristics such as anxiety, attitude to-
ward pain, distraction, and pain coping strategies may be
Thermode
Size, cm2

‡Hagander et al. (13) and Wasner and Brock (49) reported median values, not mean values. §Data from the present study are results 关means (SD)兴 from group A.
9.0–12.5

7.8

9.0

underlying factors. As a possible peripheral mechanism, it has

been shown in humans that some high-threshold cold-sensitive
C-fibers are also heat sensitive and mechanosensitive (5). Since
Underlying the
Measurements

these afferent fibers will discharge at both the HPT and CPT,
Number of

Averaged
Repeated

Results

their information may contribute to the aforementioned

3

correlation.
Common factors affecting all thresholds are alertness and
attention, integration of sensory information from the stimu-
Change Rate,
Temperature

lated skin area (spatial summation), and skin thickness (7).

°C/s

Interestingly, however, we found no significant relationship

1

between the thermal detection and pain thresholds, most likely

due to the dissimilar nature of the tasks (detection of change vs.
Baseline, °C

perception of pain) and the fact that they involve different

receptor populations (low-threshold thermoreceptors vs. high-
32

32

32

threshold polymodal nociceptors).

Question 3. Why do the thermal pain thresholds shift grad-
ually when repeatedly tested (Fig. 4)? Habituation, the de-
14.3 (7.9)

7.7 (7.8)
CPT, °C

17.6

crease in a behavioral response to a repeated harmless stimu-

lus, is one likely explanation. A well-known example is the
decrease of the startle reaction in response to recurring irrele-
43.4 (3.0)

45.4 (3.6)
HPT, °C

vant noise (44). Volunteers stopped the increase/decrease of

42.9

the thermode temperature via the response button before heat

or cold could injure the skin, so that the categorization as a
harmless stimulus is justified. Increasing confidence certainly
CDT, change

⫺0.7 (0.3)

plays a role, as the students were often more uneasy when the
in °C

⫺1.1

ND

pain threshold was determined for the first time than during the
last trial. We never encountered adverse side effects such as
burns, blisters, or frostbite. Habituation has also been reported
WDT, change

by Agostinho and colleagues (1), who used eight repetitive

1.9 (0.8)
in °C

ND
1.6

measurements of thermal pain thresholds. As a peripheral

process, fatigue of cutaneous nociceptors, which refers to the
decrement in response to repeated stimulation, might be rele-
Age, yr

38 (14)

37 (15)

vant here. Fatigue to heat stimuli in C-fiber nociceptors prob-

17–40

ably results from transduction-spike initiation mechanisms

(35). Since heat pain perception and heat-evoked brain poten-
Subjects
Number

tials in humans show signs of more rapid habituation when the

90

18

10
of

site of stimulation is fixed compared with stimulation at vari-

able locations, Greffrath and colleagues (12) inferred that
the hand

the hand

the hand

fatigue of nociceptors is the underlying mechanism.

Dorsum of

Dorsum of

Dorsum of
Region
Tested

The opposite mechanism, namely, sensitization, was re-

ported by Bessou and Perl (2). Repeated heating (over ⬃10 s)
Table 1.—Continued

of the skin of a cat to 50°C lowered the threshold and increased

the discharge rate of polymodal nociceptors (Figs. 3–5 in Ref.
Reference

Wasner and
Rolke et al.

Rolke et al.

2). Sensitization was also observed in awake humans after a

Brock
(49)‡
(40)

(41)

mild experimental heat injury of the skin (thermode with 50°C

over 100 s), which caused hyperalgesia (45). Compared with
the uninjured skin, suprathreshold stimulation of the hyperal-
Year

2006

2006

2008

gesic skin was associated with elevated discharge rates of the

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Using Classic Papers To Teach Physiology
32 THERMORECEPTION AND NOCICEPTION
C-fiber nociceptors, as measured with microneurography, and
with higher ratings of pain intensity. As a teaching example,
most students will have experienced a similar hyperalgesia
after a sunburn. However, the heat and cold stimuli applied
during our laboratory exercise were not strong enough to cause
sensitization.
Question 4. Why are the ratings of pain intensity at the HPT
and CPT not invariable (Fig. 5)? Pain intensity at the thresh-
olds was rated on a VAS between “no pain” (0) and the “worst
imaginable pain” (100). One may theoretically expect low and
invariable scores (e.g., around a value of 10) for the thermal
stimuli that just surpass the threshold. Surprisingly, the ratings
were higher (⬃30 –50; see Tables 1 and 2). This is in line with
three previous studies (19, 29, 49) of normal volunteers that
used a VAS (see Table 4) and found that pain intensity at the
HPT and CPT was rated considerably higher than the lowest
perceptible pain. Therefore, it is unlikely that the explanations
concerning the VAS given to the students during the laboratory
exercise were misleading. Rather, three other reasons are
plausible. First, it is possible that some volunteers hesitated a
few seconds until they became clearly aware of the pain and
only then pressed the response button. The threshold depends
on the rate of temperature rise and reaction time (53). Second,
ratings of pain intensity are influenced by psychological factors
such as expectations, anxiety, and pain coping strategies,
which vary from individual to individual (19, 38). Third, some
late afferent signals of slow-conducting C-fibers reached the
brain even after the increase (or decrease) in the thermode
temperature had been stopped by the button press so that
delayed pain may have influenced the ratings. As a teaching
point, it is important to realize that these results are based on
the subject’s “answers” and not on objective neurophysiolog-
ical data (such as, e.g., receptor potentials and discharge rates
of afferent fibers).
Still, there is evidence that pain ratings of human subjects
largely match the response profile of C-fiber nociceptors (45).
Correspondingly, we found that higher temperatures of the
HPT, which are associated with stronger activity of the afferent
units, were associated with higher ratings of pain intensity (Fig.
5A). No such relation was found for the less-consistent CPT
(Fig. 5B). Yet, the strong positive correlation between the
ratings of cold and heat pain intensity indicates a general
tendency of the students to give either high or low ratings of
pain intensity irrespective of the type of noxious stimulus.
Green and Akirav (10) reported a high correlation between
separate ratings of the intensity of different thermal sensations
(warmth and cold) and hypothesized that warm-sensitive and
cold-sensitive spinothalamic pathways converge so that the
modalities undergo common processing in the central nervous
system.
Question 5. Why is the threshold for cold pain more variable
than the threshold for heat pain (Fig. 2 and Tables 1 and 2)?
Cold is a weaker stimulus than heat, at least within the limited
range of the thermode temperatures that we could apply (0 –
53°C). In addition, Bessou and Perl (2) reported that the
polymodal nociceptors of the skin in cats were distinctly
activated by noxious heat, intense mechanical stimuli, and
irritant chemicals, but only weakly (if at all) excited by low
temperatures. Cooling the skin down to 10°C had no effect
unless the nociceptors had been sensitized beforehand by other
stimuli (e.g., heat and irritant chemicals; see Table 1 in Ref. 2).
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In our study, cold pain at the threshold was rated less painful
than heat pain, conforming with two previous studies (19, 49).
This points to the fact that beyond the tested range, noxious
heat stimuli (of, e.g., ⫹60°C) would damage the skin faster
than painful cold stimuli (of, e.g., ⫺10°C), so that the warning
function of pain is more important when heat is applied.
A survey of previously published data shows inconsistent
values of the “normal” CPT (see Table 4). The span between
the lowest [⬃7°C (19)] and highest mean CPT [⬃24°C (31)]
amounted to nearly 17°C. The respective instructions (often
not published) may have differed from study to study, either
reinforcing or discouraging the subjects to classify uncom-
fortable cold as painful. Neurophysiologically, cold pain
involves the interaction of different afferent inputs because
signals from cold-specific A␦-fibers (low-threshold thermo-
receptors) inhibit the input from C-fiber nociceptors at the
cortical level and can thereby suppress the sensation of pain
(47, 48). The effectiveness of this central inhibition is
probably not constant but may depend on receptiveness and
selective attention to the painful components of the cold
stimulus. A variable inhibition will add to a high interindi-
vidual variability of the CPT.
Interestingly, the CPT was shifted slightly, but signifi-
cantly, toward lower temperatures when it was tested after
the HPT compared with the reverse order. The series of the
preceding five heat stimuli may have evoked some transient
hypoalgesia. Painful conditioning stimuli are known to
activate central endogenous pain modulation systems and
can thereby evoke pain-evoked hypoalgesia (26, 37). This
will reduce the painfulness of subsequent noxious stimuli,
even when delivered at different body sites (36).
Methodological factors that can influence the thermal
detection and pain thresholds are the rates of the tempera-
ture ramps and the thermode size (small thermode ⫽ little
spatial summation). These factors are shown in Table 4 for
previously published data and the present study. Due to the
phasic response characteristics of the thermoreceptors, rapid
changes of the temperature are usually detected earlier than
slow changes (20). However, very rapid rates may introduce
a bias, because the thermode temperature will continue to
increase/decrease during the reaction time until the response
button is pressed. This will, e.g., shift the HPT toward
higher temperatures and the CPT toward lower temperatures
(53). We chose the rates of the thermal ramps and thermode
size in accordance with previous related publications (see
Table 4). These methodical aspects were discussed with the
students.
Conclusions
Four decades after the pioneering studies of Perl and
collaborators, the role of C-fibers and A␦-fibers in nocicep-
tion and thermosensation is well established. Pain has been
recognized as a discrete sensory modality. Quantitative
sensory testing of thermal detection and pain thresholds in
the setting of a student laboratory course proved to be an
instructive method that yielded repeatable results. The re-
sults of nearly 300 students showed that women are more
sensitive to thermal detection and thermal pain than men,
thus adding to other sex-based differences in physiology (3).
Habituation shifted the thermal pain thresholds up to the

THERMORECEPTION AND NOCICEPTION
fourth or fifth trial. Ratings of pain intensity were correlated
with the HPT but not with the CPT. The CPT was lower
when tested after the HPT than in the reverse case. Quan-
titative sensory testing was appreciated by the students as a
relevant and interesting method, which complements other
well-known tasks (like two-point discrimination and map-
ping of warm and cool spots) of a laboratory exercise in
somesthesis (11).
ACKNOWLEDGMENTS
The help of R. Neumann in data collection and preparation of the manu-
script is gratefully acknowledged.
DISCLOSURES
No conflicts of interest are declared by the author(s).
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