J Neurophysiol 90: 100 –109, 2003;
10.1152/jn.01066.2002.
Relationships Between Skin Temperature and Temporal Summation of Heat
and Cold Pain
Andre P. Mauderli,2 Charles J. Vierck, Jr.,1 Richard L. Cannon,1 Anthony Rodrigues,1 and Chiayi Shen3
Departments of 1Neuroscience, 2Prosthodontics, and 3Dental Biomaterials, and McKnight Brain Institute, University of Florida
Colleges of Medicine and Dentistry, Gainesville, Florida 21610-0244
Submitted 31 December 2002; accepted in final form 17 February 2003
Temporal summation of pain occurs reliably when pulses of
heat or electrical stimulation are delivered repetitively at rates
as slow as one pulse in 3 s. Enhanced discharge of nocireceptive central neurons (“windup”) can be observed under these
conditions (Mendell 1966; Tommerdahl et al. 1998). Temporal
summation for psychophysical and neural responses to heat is
dependent on activation of unmyelinated (C) nociceptors and is
dependent in part on activation of central N-methyl-D-aspartate
(NMDA) receptors (Dickenson 1990; Graven-Nielsen et al.
2000; Price et al. 1994). Most investigations of heat pain
summation have utilized triangular ramps from a Peltier device
in constant contact with the skin. This method has the advantage of returning the skin to a baseline temperature between
each ramping heat stimulus. However, because of limitations
on the ramp speeds of Peltier thermodes (especially during
down ramps), distinct first and second pain sensations that are
attributable respectively to activation of myelinated (A-delta)
and C nociceptors are not produced. Possibly because of inhibitory influences on C nociceptor input from simultaneous
activation of A-delta afferents (Chung et al. 1984; Mackenzie
et al. 1975; Torebjork and Hallin 1973; Wahren et al. 1989),
triangular ramps to tolerable nociceptive temperatures produce
moderate temporal summation (Vierck et al. 1997).
An alternative method involving brief contacts with glabrous
skin by a preheated thermode that is advanced repetitively from
off the skin produces a distinct second pain sensation that
temporally summates substantially (Staud et al. 2001; Vierck et
al. 1997). Because thresholds of C nociceptors in glabrous skin
are lower than thresholds for A-delta nociceptors (Treede et al.
1995), temperatures can be delivered with brief contacts that
are sufficient to temporally summate second pain but do not
produce first pain. Thus inhibition by A-delta nociceptors is
presumed not to occur with this method. Also, tactile stimulation of A-beta afferents during skin contact is not likely to be
inhibitory to second pain sensations (Melzack and Wall 1965)
for the repetition rates used to demonstrate temporal summation, where sensations evoked by A-beta and C afferents are
separated by more than 1 s. This separation in time between
skin contact and a late sensation is highly advantageous for
unambiguous rating of sensations elicited by activation of C
nociceptors.
Although repetitive tapping of the skin with a preheated
thermode is optimal for demonstration of temporal summation,
skin temperature increases slightly during each ISI and across
a series of heat taps (Vierck et al. 1997). A potential peripheral
effect must be considered when interpreting the rate of increase
in heat pain. The present study addresses this issue using
several approaches. First, subcutaneous temperatures were
monitored with sufficient temporal resolution to determine the
time-course of changes in skin temperature in the interstimulus
intervals (ISIs) during long series of repetitive contacts of
glabrous skin with a preheated thermode. These recordings at
the site of stimulation provide information on local thermoregulatory compensations for applied heat, and they reveal any
Address for reprint requests: C. J. Vierck, Dept. of Neuroscience, Univ. of
Florida College of Medicine, Gainesville, FL 21610-0244 (E-mail:
[email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked ‘‘advertisement’’
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
INTRODUCTION
100
0022-3077/03 $5.00 Copyright © 2003 The American Physiological Society
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Mauderli, Andre P., Charles J. Vierck, Jr., Richard L. Cannon,
Anthony Rodriques, and Chiayi Shen. Relationships between skin
temperature and temporal summation of heat and cold pain. J Neurophysiol 90: 100 –109, 2003; 10.1152/jn.01066.2002. Temporal summation of heat pain during repetitive stimulation is dependent on C
nociceptor activation of central N-methyl-D-aspartate (NMDA) receptor mechanisms. Moderate temporal summation is produced by sequential triangular ramps of stimulation that control skin temperature
between heat pulses but do not elicit distinct first and second pain
sensations. Dramatic summation of second pain is produced by repeated contact of the skin with a preheated thermode, but skin temperature between taps is not controlled by this procedure. Therefore
relationships between recordings of skin temperature and psychophysical ratings of heat pain were evaluated during series of repeated skin
contacts. Surface and subcutaneous recordings of skin temperatures
revealed efficient thermoregulatory compensation for heat stimulation
at interstimulus intervals (ISIs) ranging from 2 to 8 s. Temporal
summation of heat pain was strongly influenced by the ISIs and
cannot be explained by small increases in skin temperature between
taps or by heat storage throughout a stimulus series. Repetitive brief
contact with a precooled thermode was utilized to evaluate whether
temporal summation of cold pain occurs, and if so, whether it is
influenced by skin temperature. Surface and subcutaneous recordings
of skin temperature revealed a sluggish thermoregulatory compensation for repetitive cold stimulation. In contrast to heat stimulation,
skin temperature did not recover between cold stimuli throughout ISIs
of 3– 8 s. Psychophysically, repetitive cold stimulation produced an
aching pain sensation that progressed gradually and radiated beyond
the site of stimulation. The magnitude of aching pain was well related
to skin temperature and thus appeared to be established primarily by
peripheral factors.
THERMAL PAIN AND SKIN TEMPERATURE
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METHODS
The human subjects in experiments 1 and 2, ranging in age from 18
to 63 years, gave prior assent to experimental procedures approved by
the University of Florida Institutional Review Board and were informed that they could withdraw from the study at any time. The
experiments conformed with the Helsinki accord on experimentation
in humans subjects, and the animal and human pain studies conformed
with the guidelines of the IASP.
Experiment 1
A primary purpose of experiment 1 was to obtain subcutaneous skin
temperature recordings with sufficient temporal resolution to determine thermoregulatory adaptations of the skin to applied heat or cold.
These recordings from anesthetized monkeys were used to describe
changes in skin temperature during individual ISIs of long series of
repetitive heat or cold stimulation. Also, skin temperature data obtained in this experiment were used to relate ratings of aching cold
pain throughout a series to subcutaneous recordings of skin temperature. Previously, we have related human psychophysical ratings of
heat pain to progressive changes in subcutaneous skin temperature
during repetitive stimulation (Vierck et al. 1997).
SUBCUTANEOUS SKIN TEMPERATURE RECORDING. Subcutaneous
skin temperature during pulsed stimulation was recorded from two
Macaca arctoides monkeys using pulsed stimulation with a probe
temperature of 50°C (700-ms duration and 3-s ISI) and from two
additional monkeys with a probe temperature of 0.3°C (at the parameters used for psychophysical testing; see PSYCHOPHYSICS). All recordings were obtained after induction with ketamine (10 mg/kg) and
maintenance of full surgical anesthesia with isofluorane. Heart and
respiratory rates and blood pressure were monitored continuously. A
Yellow Springs thermistor (model 524 in a 25-g needle) was inserted
beneath the epidermis, on glabrous skin of a hand at the site of thermal
stimulation. The analog record was digitized and stored for off-line
analysis. At the end of these recording sessions, the animals were
killed with an overdose (80 mg/kg) of sodium pentobarbital (Nembutal) for histological analysis of spinal tissue required by another
experiment.
PSYCHOPHYSICS. Seven subjects (5 male and 2 female) rated the
magnitude of thermal sensations produced by contact of a precooled
thermode with glabrous skin of the hand. A 2.3 ⫻ 2.3-cm square
Peltier thermode was mounted on the center shaft of a solenoid, which
when activated, brought the thermode into timed contact with the
thenar eminence of either hand. During testing, the thenar eminence
was positioned over a 3 ⫻ 3-cm square aperture in a plexiglass surface
that provided support for the hand. When the solenoid was energized,
the thermode protruded slightly above the surface of the plexiglass
hand rest, insuring reliable contact with the skin. The duration of each
thermode contact and the interval between the onset of sequential
stimuli (ISI) were varied. A thermistor sandwiched between the Peltier element and the copper thermode surface was used to monitor and
maintain stimulus temperature. For pulsed cold stimulation, the thermode was precooled to 0.3°C.
Psychophysical ratings of sensation magnitude in experiment 1
utilized a verbal rating scale ranging from 0 (no thermal sensation) to
100 (intolerable pain sensation) in increments of 5, with verbal descriptors assigned to sensation intensities. Nonpainful warmth or cold
sensations were rated in intensity from 0 to 15. A rating of 20 was
identified as pain threshold, and verbal descriptors at subsequent
intervals of 10 were as follows: 30 ⫽ very weak pain, 40 ⫽ weak
pain, 50 ⫽ moderate pain, 60 ⫽ slightly strong pain, 70 ⫽ strong pain,
80 ⫽ very strong pain, and 90 ⫽ nearly intolerable pain. This scale
was utilized for several reasons: 1) for comparison with our previously published ratings of heat pain (Vierck et al. 1997) and 2) for
comparison with the visual analog scale used in experiment 2, where
only pain is rated. Inclusion of ratings for nonpainful sensations
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changes (e.g., adaptation) in compensation for each stimulus as
the series progresses and skin temperature gradually changes.
Second, skin surface temperatures were recorded from the site
of stimulation as a series of repetitive contacts progressed, so
that relationships between skin temperature and the progression of psychophysical ratings within ISIs could be assessed in
individual subjects. In addition, recordings of skin temperature
permitted estimation of skin temperature thresholds for pain
under conditions of repetitive stimulation.
The same procedures were utilized to determine whether
temporal summation of cold pain occurs with repetitive stimulation, to monitor local thermoregulatory compensations for
cold and to assess relationships between skin temperature and
psychophysical ratings of cold pain. Focal cold stimulation
activates populations of A-delta and C afferents that overlap
only partially with those stimulated by heat, and it is not known
whether temporal summation of pain is produced by all forms
of stimulation that activate C nociceptors.
Available information on cold pain comes primarily from
ramp-and-hold stimulation from a resting skin temperature to
near freezing, which produces complex changes in sensory
quality that include cold, prickling, aching, numb, and burning
sensations, with a progressively more aversive quality as skin
temperature drops (Chery-Croze and Duclaux 1980; Croze and
Duclaux 1978; Davis 1998; Harrison and Davis 1999; Kunkle
1949). The variety of sensations induced by maintained cold
stimulation apparently derives from effects on many categories
of afferents (Simone and Kajander 1996, 1997). A-delta afferents presumed to subserve nonnociceptive cold sensations discharge within a range of 20 – 40°C, with peak discharge rates at
25–30°C. Input from these afferents is inhibitory to pain (Bini
et al. 1984; Davis 1998; Fruhstorfer 1984; Sandkuhler et al.
1997; Yarnitsky and Ochoa 1990). Other A-delta afferents with
high thresholds for cold activation (LaMotte and Thalhammer
1982) may produce a sensation of pricking cold (Davis 1998;
Yarnitsky and Ochoa 1990). Maintained cold stimulation can
induce a deep radiating sensation of ache (Croze and Duclaux
1978; Kunkle 1949; LaMotte and Thalhammer 1982;
Yarnitsky and Ochoa 1990). This is particularly apparent for
the cold pressor test involving immersion of a limb in ice
water, which cools a large surface area and affects subcutaneous receptors on blood vessels (Fruhstorfer and Lindblom
1983; Klement and Arndt 1992; Wolf and Hardy 1941). At
temperatures approaching freezing, cold can evoke a sensation
of burning pain, presumably from activation of a subpopulation
of C nociceptors that also respond to heat (Davis 1998; Fruhstorfer 1984; Kunkle 1949; Wahren et al. 1989; Yarnitsky and
Ochoa 1990). Finally, with prolonged stimulation near and
below freezing, most afferents are activated and then inactivated (Franz and Iggo 1968; Simone and Kajander 1996).
Blocking of afferent conduction by extreme cold accounts for
sensations of numbness.
In contrast to the complexity of cold sensations during ramp
and hold stimulation, repetitive cold taps produced only a
diffuse aching sensation in the intervals between brief stimuli.
This deep aching sensation can be masked by the traditional
method of ramp-and-hold stimulation, where focal sensations
of cutaneous cold and cold pain predominate. The magnitude
of aching cold pain was rated during series of repetitive stimuli.
101
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MAUDERLI, VIERCK, CANNON, RODRIGUES, AND SHEN
(0 –15) in the verbal rating scale provides useful information on pain
thresholds.
The subjects were instructed to attend to any painful sensation
present in the interval between stimuli. They were instructed that
sensation intensity could increase, decrease, or stay the same with
stimulus repetition, and it was made clear that they should remove
their hand from the apparatus before they would experience intolerable pain. In each testing session, a series of 50 stimuli was delivered
to the thenar eminence of the left hand. Data were averaged for each
subject from three sessions at each ISI of 3, 4, or 8 s for contact
durations of 700 ms. In addition, three sessions each were averaged at
an ISI of 4 s and contact durations of 900 and 1,100 ms. The order of
the 15 daily sessions for each subject was randomized.
stimuli on separate days of testing was 2, 4, 6, or 8 s for heat and 4,
6, or 8 s for cold. The temperature and pain measurements were
averaged for each experimental condition and subject. The skin temperatures for pulses after which no measurement was made (i.e., all
but pulses 5, 10, 15, and 20) were interpolated by a third order
polynomial fit. This approach was necessary because it was possible
to obtain skin temperature measurements only before and after (but
not during) a series. Each skin temperature measurement required
removal of the subject’s hand from the testing apparatus, and it would
have been difficult to precisely reposition the hand before the arrival
of the next pulse.
Statistical evaluation of psychophysical ratings and of skin temperatures across series of 20 stimuli at different ISIs utilized Statistica
software (Statsoft, Tulsa, OK) and repeated measures ANOVA.
Experiment 2
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RESULTS
Experiment 1
Relationships between the magnitude of aching pain and
subcutaneous skin temperature during cold stimulation can be
appreciated by comparing Fig. 1, A and B, where variations in
ISI are shown, and Fig. 1, C with D, where effects of contact
duration are depicted. It is apparent that subcutaneous skin
temperature decreases at a faster rate than ratings of aching
pain increase, but there are orderly relationships between the
relative rates and magnitudes of temperature decreases and
pain increases in series of 50 stimuli at different ISIs or contact
durations. These results of cold stimulation contrast with previous findings that temporal summation of heat pain was highly
dependent on ISI, but subcutaneous skin temperature increased
almost identically for ISIs of 3–7 s (Vierck et al. 1997; see
DISCUSSION).
The magnitude and time-course of subcutaneous temperature fluctuations between pulses of heat or cold stimulation are
shown in Fig. 2. Subcutaneous temperature was sampled during each ISI throughout a series of 50 stimuli. In Fig. 2A, the
peaks of temperature increase or decrease within ISIs of 3 s are
shown. For heat, a small temperature increase was observed
following each stimulus, and the magnitude of this response
did not vary across the series. Throughout the series of 50°C
stimuli, subcutaneous skin temperature increased by approximately 0.3°C and peaked at 1.1 s after activation of the solenoid (Fig. 2B). At the end of each 3 s ISI, skin temperature
returned nearly to the value recorded just prior to the previous
skin contact.
Figure 2A shows that peak temperature changes early in a
series of cold stimuli were considerably greater than for heat
stimulation. The responses to cold stimulation became smaller
as a series of stimuli progressed. Figure 2, C and D, compares
skin temperature profiles produced by the first and last of 50
contacts at 0.3°C. During 3 s ISIs (Fig. 2C) and 8 s ISIs (Fig.
2D), early responses in the series reached a peak near the end
of the interval. For either ISI, skin temperature changes following cold stimuli late in a series were small and less prolonged than early responses. In contrast, peak temperature
changes after heat pulses (Fig. 2B) occurred near the midpoint
of ISIs and were comparable for the first and last stimulus in a
series. These observations show that thermoregulatory compensation for contact with the skin of an object sufficiently cold
to induce aching pain is slow in comparison to clearing of heat
after contact with an object that produces temporal summation
of heat pain.
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The purpose of this experiment was to evaluate surface skin temperature changes in individual human subjects as they rated the
magnitude of sensations elicited by repetitive heat or cold stimulation.
Five subjects (2 male and 3 female) participated in sessions involving
heat stimulation, and four of these also rated sensations produced by
cold stimulation. Each daily session consisted of four series of thermal
contact stimuli. The series were separated by a delay long enough to
allow the skin temperature to return to baseline (typically 5 min). The
thermode temperature, duration of each contact, and interval between
stimuli in a series remained unchanged throughout a daily session. For
sessions involving heat stimulation, the temperature was customized
for each subject, based on preliminary testing. The temperatures
utilized for individual subjects were 45, 46, 49.5, 50, and 50°C. These
temperatures were selected following sessions of preliminary testing
in which the temperature was increased for successive series of 20
stimuli at the 2-s ISI, from 44°C, in 0.5°C increments, to a temperature that produced temporal summation to a rating of ⱖ40. Customization was necessary because the temperature that induces temporal
summation of heat pain within a specified range of ratings differs
between individuals. In contrast, cold stimulation of 0.3°C reliably
produced comparable levels of pain for all subjects. The duration of
each thermode contact was 0.7 s throughout experiment 2.
The number of stimuli increased from one series to the next (5, 10,
15, 20 taps). Skin surface temperature was measured before the first
series and after each series, leading to five data points per daily
session (baseline temperature and after 5, 10, 15, and 20 taps). This
method was used because it was not practical to measure skin temperature between each stimulus in a series. An Exergen Dermatemp
infrared temperature scanner model DT-1001 (Exergen, Watertown,
MA) was used to measure skin temperature at the stimulation site. The
temperature was scanned continuously for 3– 4 s, and the highest (or
lowest) reading during scans in heat (or cold) series was used. Pain
intensity ratings were obtained after each stimulus of the longest
series. The subjects were trained to attend to the intensity of second
pain between contacts by the heated probe and to the intensity a tonic
aching sensation during repetitive stimulation with a cold probe.
Pain intensity was measured in experiment 2 with an electronic
visual analog scale (eVAS). The eVAS consisted of a low-friction
linear sliding potentiometer of 100-mm travel that, in proportion to its
position, generated a voltage between 0 and 10 V DC. The subjects
were instructed about the meaning of the endpoints of the scale and
were told to rate the pain intensity following each stimulus by updating the position of the slider after each thermode contact. The left
endpoint of the scale was identified as “no pain,” whereas the right
endpoint was labeled as “intolerable pain intensity.” The scale had no
divisions between these two anchors and was automatically positioned
at the left endpoint before each series. Computer software sampled the
voltage generated by the slider and converted it into a pain rating
between 0 and 100%.
The interstimulus interval varied between days, and each ISI condition was repeated four times for each subject. The interval between
THERMAL PAIN AND SKIN TEMPERATURE
103
Experiment 2
The relationships between heat and cold pain intensities and
subcutaneous skin temperatures were corroborated by an experiment involving measurement of surface skin temperatures
in human subjects. Figure 3 shows psychophysical ratings of
sensation intensity and surface skin temperatures obtained
from each participant during series of repetitive stimuli at
different ISIs for heat and cold stimulation. Figure 3B shows
that surface skin temperature increased by 7– 8°C in response
to heat stimulation regardless of the ISI, which ranged from 2
to 8 s. ANOVA revealed no difference in the progression of
skin temperatures across ISIs, either as a main effect (F ⫽
0.31, df ⫽ 3, P ⫽ 0.82) or as an interaction with the number
of stimuli (F ⫽ 0.70, df ⫽ 38, P ⫽ 0.95). However, ratings of
sensation intensity depended critically on ISI (Fig. 3A; main
effect: F ⫽ 7.07, df ⫽ 3, P ⫽ 0.002; interaction: F ⫽ 8.55,
df ⫽ 38, P ⬍ 0.000). A maximal rating of moderate pain was
produced only by the 2-s ISI. Thus neither surface temperature
(present study) nor subcutaneous temperatures (Vierck et al.
1997) determine the rate of temporal summation of sensation
J Neurophysiol • VOL
intensity for repetitive stimulation at different ISIs with a
heated probe.
Figure 3, C and D, reveals a good correspondence between
sensation intensity and surface skin temperature for cold stimulation at ISIs of 4, 6, and 8 s. The maximal ratings and
temperatures were ordered appropriately with ISI, suggesting
that the magnitude of aching pain is inversely proportional to
skin temperatures produced by repetitive stimulation with a
cold probe. Statistical evaluation showed a significant effect of
ISI on psychophysical ratings (interaction: F ⫽ 1.6, df ⫽ 38,
P ⫽ 0.002) and on skin temperature (interaction: F ⫽ 4.33,
df ⫽ 38, P ⬍ 0.000) as the series of repetitive stimulation
progressed. For cold stimulation, ratings of sensation intensity
increased slowly and reached a plateau later than skin temperature readings for each ISI, in contrast to ratings of heat pain,
which increased at rates either faster or slower than skin
temperature, depending on the ISI.
Figure 4, A and B, shows plots of psychophysical ratings
against surface skin temperature for repetitive heat stimulation
of two subjects at the 2-s ISI that produced substantial temporal
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FIG. 1. Comparison of human psychophysical ratings of aching pain magnitude with subcutaneous temperatures of anesthetized
monkeys during repetitive series of 50 contacts of a precooled thermode with glabrous skin. Left: verbal ratings of sensory
magnitude (20 ⫽ pain threshold: dashed line; 100 ⫽ intolerable pain) for 700-ms contacts at interstimulus intervals (ISIs) of 3, 4,
and 8 s (A) and for different contacts durations at an ISI of 4 s (C). Right: changes in subcutaneous temperature from baseline (note
increasing negative values on the ordinate) obtained at the end of each interstimulus interval for series of 50 contacts at the same
durations and contacts used for human psychophysics (compare A with B and C with D).
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MAUDERLI, VIERCK, CANNON, RODRIGUES, AND SHEN
summation of pain. Ratings of heat intensity progressed only
slightly and gradually for the first 6 –10 stimuli, as skin temperature approached 38°C (Fig. 4B) or 40°C (Fig. 4A). This
linear relationship then broke down, and ratings accelerated
greatly as surface skin temperature increased little or even
decreased. In contrast, ratings of sensations produced by
slower repetition of heat taps (Fig. 4, C and D; ISI of 6 s)
remained minimal as skin temperature increased within the
range produced by the 2-s ISI, to values in excess of 40°C.
These plots show that temporal summation of heat pain occurs
at a minimum surface temperature of 38 – 40°C, but maintenance of skin temperature in this range is not a sufficient
condition.
Figure 5 shows relationships between surface skin temperature and visual analog scale (VAS) ratings of aching pain
sensations produced by repetitive cold stimulation. A salient
difference between relationships of heat and cold pain to stimulus repetitions is that both short and long ISIs produced
substantial increases of cold pain with stimulus repetition.
Also, the functions relating skin temperature decreases to psychophysical ratings of aching pain were similar for long and
short ISIs. Thus measurement of surface skin temperatures as
subjects rated sensation intensity confirmed conclusions drawn
from comparisons of psychophysical ratings with separate recordings of sub-surface skin temperatures. With stimulus repetition, aching cold pain intensity is more closely related to
J Neurophysiol • VOL
skin temperature than temporal summation of heat pain. In
contrast to functions relating skin temperature to temporal
summation of heat pain that were frequently positively accelerating late in a series, comparable ratings of cold pain were
often negatively accelerating in relation to decreasing skin
temperature late in a series. Adaptation of aching pain was
often observed late in series of 20 stimuli.
DISCUSSION
A goal of this investigation was to determine similarities and
differences between temporal progressions of pain sensations
produced by repetitive heat and cold simulation. Glabrous skin
of the hand was tapped repeatedly by a thermode preheated or
precooled to temperatures that would produce moderate to
strong pain during maintained contact. Each heat tap produced
a tactile sensation during contact and a distinct late sensation of
warmth or heat pain welled up and receded after the probe left
the skin. It is the late or second sensation of heat that summates
dramatically in magnitude. Temporally summated heat pain
was well localized to the skin surface and site of stimulation.
Repeated contact of a precooled thermode with palmar skin
produced a nonnociceptive cold sensation during contact, and
then a diffuse sensation of ache developed. The ache progressed gradually across a series of cold taps, was perceived as
deep to the skin, radiated substantially, and was not localized
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FIG. 2. Subcutaneous skin temperature responses to heat and cold stimulation. A: peak changes in skin temperature during 3-s
ISIs over 50 pulses (700 ms). Peak responses to heat (50°C) were consistently near 0.3°C. Peak responses to cold (0.3°C) ranged
from ⫺2°C early in the series to ⫺0.5°C during later stimuli in the series. B: maximum and final subcutaneous temperature changes
within the 1st and last ISIs for heat. Peak temperature increases occurred reliably near the midpoint of 3-s ISIs of 50°C stimulation.
C and D: progression of subcutaneous temperature changes for cold stimulation. Peak temperature decreases early in a series of
repetitive stimuli occurred near the end of both 3- and 8-s ISIs of 0.3°C stimulation, accounting for a substantial lowering of
baseline skin temperature across the series.
THERMAL PAIN AND SKIN TEMPERATURE
105
to the site of stimulus contact. The ache sensation could radiate
either proximally within the arm or distally to the fingers.
First pain can be produced during brief contact of a heated
probe with hairy skin but was not reported for 700-ms stimulation at the thermode temperatures utilized. Glabrous skin
lacks low threshold A-delta nociceptors (Treede et al. 1995)
that would mediate first pain for these temperatures. First
sensations of warmth were not produced, because warmth
depends on activation of unmyelinated (C) afferents (LaMotte
and Campbell 1978). Late sensations of warmth from activation of nonnociceptive C thermoreceptors could be produced
early in a series, but second pain was the dominant sensation as
a series of heat taps progressed. Second pain sensations from
heat stimulation are attributed to activation of C nociceptors,
and temporal summation of heat pain (or comparable windup
of nociceptive responses of central neurons) is dependent on
activation of C nociceptors (Price et al. 1977). Accordingly, the
sensation that temporally summated was painful and had a
burning quality characteristic of C nociceptor activation
(Ochoa and Torebjork 1983).
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The thermoreceptive afferents activated during contact of
the cold probe with the skin are certain to include nonnociceptive A-delta cold receptors (Rainville et al. 1999) and could
include A-delta nociceptors with thresholds below 27°C (LaMotte and Thalhammer 1982). The subjects did not rate the
intensity or attend to qualitative features of sensation during
skin contact but described it as cold. Pricking pain, which
results from stimulation of A-delta afferents (Davis 1998), was
not apparent. Sensations of cold or cold pain with distinct
peaks between skin contacts were not reported. Second pain
sensations from cold stimulation would likely have a burning
quality (Fruhstorfer 1984; Wahren et al. 1989), but it appears
that skin temperature did not become low enough to activate C
polymodal receptors (Burgess and Perl 1973; Simone and
Kajander 1996). The ache sensation that gradually developed
with repetitive stimulation is likely attributable to activation of
nociceptors located subcutaneously, on or near blood vessels
(Klement and Arndt 1992; Morin and Bushnell 1998). These
afferents appear to be distinct from C nociceptors that are
associated with burning pain.
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FIG. 3. Comparisons of human psychophysical ratings of sensation magnitude and surface recordings of skin temperature from
the same subjects during repetitive stimulation with heat (A and B) and cold (C and D). Variation of the ISI dramatically affected
psychophysical ratings of heat pain (A), but profiles of change in skin temperature varied little across ISIs of 2– 8 s. In contrast,
variation of the ISIs produced modest changes in psychophysical ratings of aching pain during cold stimulation, and profiles of skin
temperature change (D) corresponded with the psychophysical ratings (C).
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MAUDERLI, VIERCK, CANNON, RODRIGUES, AND SHEN
Comparisons of surface and subcutaneous skin temperatures
with psychophysical ratings addressed mechanisms of cold and
heat pain. Temporal summation of heat pain is not explained
by tonic changes in surface temperature (present study) or
escalating subcutaneous skin temperatures (Vierck et al. 1997).
The amplitude of phasic changes in skin temperature during
ISIs was consistent across stimuli within a series, but late
FIG. 5. Plots of surface skin temperature against psychophysical ratings of
aching pain for 2 subjects (left and right) and ISIs of 4 s (top) and 8 s (bottom).
Temporal summation of aching pain over series of 0.3°C stimulation was
related to surface skin temperatures until late in the series, when adaptation of
aching pain was observed for some subjects (e.g., B and D).
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FIG. 6. Storage of applied heat (50°C) and cold (0.3°C) by the skin are
schematically depicted, based on recordings of subcutaneous skin temperature
over 10 stimuli (700-ms duration; 3-s ISI). Timing of thermal pulses is shown
below the graph. Skin temperature drops quickly over the 1st 5 cold stimuli
(thin line), because there is little or no recovery in the ISIs. Thereafter, the peak
decreases in skin temperature become smaller, there is some recovery within
ISIs, and skin temperature drops gradually across repeated stimuli until a
plateau is reached. In contrast, small peak increases in skin temperature occur
consistently between heat stimuli (thick line), there is nearly total recovery
within each ISI, and subcutaneous skin temperature increases gradually across
the series of 10 stimuli.
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FIG. 4. Plots of surface skin temperature against psychophysical ratings of
heat pain for 2 subjects (left and right) and ISIs of 2 s (top) and 6 s (bottom).
Comparing the top and bottom panels, it is apparent that skin temperatures of
approximately 40°C are associated with considerable temporal summation of
2nd pain for the 2-s ISI but not for the 6-s ISI.
sensation magnitudes increased with stimulus repetition. Also,
changing the interval between stimuli (with ISIs of 2– 8 s)
dramatically influenced temporal summation of pain but did
not appreciably alter the tonic progression of skin temperatures. Therefore consistent with conclusions drawn from recordings of nociceptive afferent and spinal neuronal responses
(Price et al. 1977), temporal summation of heat pain depends
on C nociceptor activation of central NMDA receptor systems
(Price et al. 1994; Vierck et al. 1997).
In contrast to the transient increases in subcutaneous temperatures that recovered nearly to baseline within ISIs of 3 s for
heat taps, cold taps produced prolonged reductions of subcutaneous temperatures that did not recover within 8-s ISIs. Thus
local application of heat to the skin is cleared efficiently, but
skin temperature does not recover quickly from cold stimulation. These differences are depicted in Fig. 6, which utilizes
data from Figs. 1 and 2 (and Vierck et al., 1997), to show that
subcutaneous skin temperature drops quickly and substantially
during repetitive cold stimulation compared with a small and
gradual increase in skin temperature that occurs across a series
of heat stimuli of the same duration and ISI. A likely mechanism for heat dissipation is that contact of a heated probe with
the skin produces a somatosympathetic vasoconstrictor response of cutaneous vessels (Hirata et al. 1988; Janig 1975;
Nagasaka 1987), lowering skin temperature. A similar response appears to be elicited by cold stimulation (Kurosawa et
al. 1985), accounting for the prolonged reduction of skin temperature between cold taps.
Both superficial and deep skin temperature changes were
proportionate to increases in aching sensation magnitude with
repetition of the cold stimulus. Increases in aching sensation
magnitude lagged behind decreasing surface and subcutaneous
skin temperatures over the range of interstimulus intervals
presented. Also, cold pain persists considerably longer than
heat pain after maintained stimulation, and these differences
are related to rate of return of skin temperature (Morin and
Bushnell 1998). The delay in progression of aching cold mag-
THERMAL PAIN AND SKIN TEMPERATURE
J Neurophysiol • VOL
probes of different sizes and with widely varying ramp rates
and stimulus durations (Hamalainen et al. 1982; LaMotte 1984;
LaMotte et al. 1983; Morin and Bushnell 1998; Pertovaara et
al. 1996; Strigo et al. 2000; Wahren et al. 1989; Yarnitsky and
Ochoa 1991). Most of the mean threshold values cluster between 43 and 46°C (Craig and Bushnell 1994; Dyck et al.
1993; Hardy et al. 1952; Harju 2002; Magerl and Treede 1996;
Nielsen and Arendt-Nielsen 1998; Taylor et al. 1993; Tillman
et al. 1995; Torebjork et al. 1984; Verdugo and Ochoa 1992).
In experiment 2 of this study, eVAS ratings of 10 represent a
conservative estimate of threshold pain. For probe temperatures of 49.5 or 50°C (3 subjects), eVAS ratings of 10 were
obtained when skin surface temperatures reached 37.9 and
38.1°C within ISIs of 2 and 4 s. Stimulation at longer ISIs did
not produce ratings as high as 10, even though skin temperatures reached 40°C. Thus temporal summation during repetitive heat stimulation lowers thresholds for pain as well as
increasing suprathreshold intensities.
Thresholds for activation of presumed nociceptors by maintained cold stimuli have been estimated to be below 12°C and
generally near freezing (Burgess and Perl 1973; Georgopoulos
1976; LaMotte and Thalhammer 1982; Simone and Kajander
1996). Possibly because ramp-and-hold stimulation produces a
variety of cold sensations, psychophysical thresholds for cold
pain have been reported to be highly variable, depending on
stimulus parameters and location. When subjects are instructed
to report on cold pain, irrespective of qualitative distinctions,
thresholds range remarkably from 30 to 0°C (Davis 1998;
Fruhstorfer 1984; Harju 2002; Harrison and Davis 1999; Klement and Arndt 1992; Morin and Bushnell 1998; Ochoa and
Torebjork 1983; Strigo et al. 2000; Verdugo and Ochoa 1992;
Wahren et al. 1989; Wolf and Hardy 1941; Yarnitsky and
Ochoa 1990). However, thresholds for aching pain have been
reported at approximately 15°C (Davis 1998) and 18°C (Hardy
et al. 1952). In the present study, threshold aching cold pain
(eVAS ⱖ 10) during repetitive stimulation was established
when surface skin temperature reached 18.9, 19.8, and 20.4°C
for ISIs of 4, 6, and 8 s, respectively. Thus thresholds for
aching cold pain are within the upper range of reported cold
pain thresholds and appear to be increased only slightly by
slow rates of repetitive stimulation.
In conclusion, repetitive stimulation of glabrous skin with
heat selectively activated cutaneous C nociceptors and produced substantial temporal summation of second pain that
depends on central mechanisms rather than a storage of heat by
the skin. In contrast, repetitive stimulation with a cold probe
progressively elicited aching cold pain by decreasing subcutaneous temperature, with relatively more warming of the skin
surface between stimuli. This preferential effect on thermal
receptors deep to the skin isolates one of the sensations experienced during maintained cold stimulation, which produces a
thermal gradient with the lowest temperatures at the surface.
Prolonged cold stimulation effectively activates a variety of
cutaneous nociceptors and evokes sensations that include cold,
freezing, sharp, prickle, stinging, tingling, throbbing, aching,
and burning (Chery-Croze and Duclaux 1980; Croze and Duclaux 1978; Davis 1998; Fruhstorfer 1984; Harrison and Davis
1999; Kunkle 1949; Yarnitsky and Ochoa 1990). Repetitive
cold stimulation appears to provide a convenient and tolerable
model of visceral pain. The activated nociceptors are located
on or near blood vessels, and all forms of nociceptive visceral
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nitude and its persistence likely depend on development of
vascular reactions to cold and indirect mechanical excitation of
receptors in the walls of vessels (Arndt and Klement 1991;
Kunkle 1949; Minut-Soroktina and Glebova 1976). Thus it is
unnecessary to invoke a central process of temporal integration
to account for the increase in magnitude of aching pain during
series of cold taps. That is, repetitive cold stimulation appears
not to induce windup of central spinal neurons in a manner
comparable to the effects of C nociceptor activation by heat.
Plots of psychophysical ratings against skin surface temperatures across series of 50 heat taps (Fig. 4) revealed a dependency of temporal summation on rate of stimulation rather than
skin temperature. This is apparent from the disparity between
maximal ratings that were ⬎60 or less then 10 when surface
skin temperatures exceeded 40°C in series with 2- or 6-s ISIs,
respectively. Furthermore, for the 2-s ISI, ratings of heat pain
increased dramatically when skin temperature was stable, near
40°C. These results emphasize the dependency of heat pain
magnitude on mechanisms of central summation. Also, they
present practical considerations for investigations of temporal
summation of heat. For probe temperatures of 48 –56°C and
brief contacts (Vierck et al. 1997 and the present study),
increases in sensation intensity for stimuli early in a series are
well related to skin temperature and are much less dependent
on repetition rate than for stimuli late in a series, when increases in skin temperature are small relative to increases in
sensation magnitude. That is, temporal summation that is dependent on central processing might be missed or underestimated by short series of heat stimulation.
A related difficulty with short series of repetitive heat stimuli
that produce modest increases in sensation magnitude is revealed by the use of several rating scales in the present study.
In experiment 1, a rating scale linked to verbal descriptors
defined values of 1–15 as subthreshold for pain (i.e., levels of
warmth), and ratings of 20 –100 were used to describe intensities ranging from pain threshold to intolerable pain. Using
50°C stimulation, the first 3–10 stimuli in a series produced
late sensations that were rated below pain threshold on the
verbal descriptor scale (Fig. 1). In contrast, using a VAS scale
for pain intensity that did not include ratings of warmth, the
sensations early in a series were reliably rated above zero (as
slightly painful) for probe temperature of 50°C or less (Fig. 2).
Because subjects have difficulty discriminating faint pain from
warmth, there is a tendency to rate all near threshold sensations
as slightly painful on a scale that does not include the category
of warmth. This is of little importance when the goal is to rate
clearly suprathreshold levels of heat pain. However, short
series that are rated by a VAS scale and do not eventuate in
ratings of moderate pain could describe temporal summation of
nonnociceptive warmth.
When the skin is heated by repetitive brief contact with a
thermode, thresholds for nociception are near those reported
for excitation of C nociceptors by maintained cutaneous stimulation. The lowest threshold reported for activation of C
nociceptors is approximately 40°C (LaMotte and Thalhammer
1982; LaMotte et al. 1983; Torebjork et al. 1984; Yarnitsky et
al. 1992) and is well below thresholds as high as 53°C for
activation of A-delta thermal nociceptors in glabrous skin
(LaMotte and Campbell 1978; LaMotte et al. 1983; Treede et
al. 1995). Psychophysical thresholds for heat pain range from
40 to 49 for stimulation at glabrous and hairy skin sites with
107
108
MAUDERLI, VIERCK, CANNON, RODRIGUES, AND SHEN
stimulation appear to produce a diffuse, aching pain sensation
(Hardy et al. 1952).
This study was supported by National Institute of Neurological Disorders
and Stroke Grant NS-43435 and the Brain and Spinal Cord Injury and Rehabilitation Trust Fund of the University of Florida.
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