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Noxious cold evokes multiple sensations with distinct time courses

Davis, Karen D.a,b,∗; Pope, Geoffrey E.b

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doi: 10.1016/S0304-3959(02)00043-X
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Abstract

1. Introduction

Healthy individuals can easily distinguish different types of noxious stimuli because of the characteristic qualities of sensation evoked by each stimulus type. The heterogeneity of pain sensations suggest the existence of a distinct pattern of neural activity that signals each type of pain sensation. As a first step toward understanding different qualities of pain, we studied the time courses of several sensations elicited by a noxious cold stimulus. A noxious cold stimulus is particularly well suited for this purpose because it can elicit a myriad of painful and non-painful sensations. In addition to the expected cold feelings, low temperature stimuli can also evoke a feeling of heat (referred to as paradoxical heat), non-thermal sensations such as prickling and aching (Hamalainen et al., 1982; Greenspan et al., 1993; Beise et al., 1998; Davis, 1998; Harrison and Davis, 1999; Susser et al., 1999), and/or responses associated with the so-called motivational-affective aspects of pain (Melzack and Casey, 1968).

In addition to its utility for evoking a multidimensional sensory experience, a noxious cold stimulus is an ideal probe for investigating the interaction between thermoreceptive and nociceptive systems. This interaction has been observed in both clinical and experimental settings. In normal individuals, a cold stimulus delivered during experimental A-fiber block feels hot and burning, suggesting a complex interaction between A- and C-fiber primary afferents (Mackenzie et al., 1975; Fruhstorfer, 1984; Wahren et al., 1989; Yarnitsky and Ochoa, 1990; Davis, 1998). A strong interaction between thermoreceptive and nociceptive systems in normal individuals is also suggested by the thermal grill illusion, wherein pain is evoked by alternating warm and cool metal bars (Craig and Bushnell, 1994). This also illustrates a dissociation between the feelings evoked by a stimulus and the physical attributes of the stimulus.

The ability to correctly distinguish and identify stimulus types can also be severely impaired in patients with multiple sclerosis (Hansen et al., 1996) or chronic pain. Abnormal cold perception is common in patients with some neuropathic pains and neurological conditions. In diabetic neuropathy, the abnormality is one of loss of thermal sensitivity despite ongoing burning pain. In other conditions such as some central pains and complex regional pain syndrome (Meh and Denislic, 1994), there is a heightened sensitivity to cold resulting in severe cold-evoked pains. A disruption in the normal thermo- and nociceptive systems and their interaction is at the core of these disorders. However, little is known of the mechanisms underlying such phenomena. An understanding of the complexity of normal cold-evoked sensations is needed to begin to construct a framework to understand these abnormalities.

Previous psychophysical studies of noxious cold have typically concentrated on the overall magnitude of a particular sensation evoked by the stimulus, such as pain intensity or unpleasantness. More recently, there have been some descriptions of the temporal characteristics of cold-evoked pain intensity, unpleasantness and prickle (Davis, 1998; Morin and Bushnell, 1998; Harrison and Davis, 1999). We now extend these findings to reveal in greater depth, the temporal properties of five types of noxious cold-evoked sensations: cold, prickle, pain, ache and heat. The unique temporal pattern of these sensations provide insight into the neurophysiological mechanism of such perceptions. Furthermore, these findings provide a psychophysical framework for imaging cortical correlates of cold-evoked sensory sensations (Davis et al., 2001).

2. Materials and methods

2.1. Subjects

A total of 17 healthy normal subjects (eight males, nine females) between the ages of 20 and 37 were recruited from the University of Toronto, Toronto Western Hospital, and the general public. All subjects were given a general description of the study protocol, were informed of their right to withdraw from the study at any time and they gave informed consent to procedures given ethics approval by the University of Toronto Human Subjects Review Committee.

2.2. Experimental protocol

A computer-controlled peltier-type contact thermal stimulator (TSA 2001, Medoc Ltd, Israel) with a 20×25mm thermode was used to deliver cold stimuli to the right thenar eminence. For each cold stimulus, the thermode temperature was lowered from a baseline of 32 to 3°C at a rate of 0.5°C/s, held at 3°C for 10s, then brought back up to the 32°C baseline at a rate of 10°C/s. The thermode temperature was maintained at the 32°C baseline for at least 120s between stimuli.

Each subject underwent a psychophysical session of approximately 1.5h in duration. At the beginning of the session the subject was trained to use rating scales (see below) and was exposed to practice stimuli to become acquainted with the protocol prior to the start of the experiment. Five separate experimental runs were used to obtain ratings of each of the five sensations in a consistent order: cold, prickle, pain, ache and heat. Within each experimental run, the cold stimulus was presented four times (except for one subject that received only three stimuli in the ache and heat runs). A stimulus-free period of at least 4min was maintained between runs.

2.3. Ratings

Subjects were asked to distinguish and rate the sensations of cold, prickle, pain, ache and heat in separate experimental runs. They were told to focus on one particular sensation for each run, but it was made clear that they may not experience that sensation at all. Although this instruction was meant to avoid false reports of unfelt sensations due to demand, we cannot totally exclude the possibility of such reports. In each run, subjects were instructed to rate a single sensation in isolation from the others. Throughout each run, subjects gave continuous ratings of sensation intensity on a 0–100 visual analog scale (VAS) by moving a slider with their left hand. Ratings data were recorded with 0.2-s temporal resolution using COVAS 2.3 software (Medoc Ltd, Israel).

The sensation of cold (including non-painful cool) was sufficiently intuitive as to need little explanation. Prickle was described as a sensation of ‘pins and needles’ or pin-pricks which could be isolated in time or be clustered together in time. As a demonstration of pin prick sensations, a mechanical prick was delivered to the subject's forearm skin using a 0.5-mm metal wire. Subjects were asked to distinguish prickle from numbness, and to refrain from reporting numbness itself. Pain was defined as overall pain intensity including any and all painful sensations (e.g. painful prickle, painful ache, painful heat, etc.). Ache was defined as a type of pain. Toothache, headache and menstrual cramps were used as examples of common sensations that often include ache. Heat was defined as a sensation of ‘skin temperature that is above neutral’. Subjects were also asked to refrain from reporting ‘heat’ when they felt that the temperature was merely returning from cold to neutral. Furthermore, subjects were given the opportunity to distinguish between non-painful heat (0–50 on the VAS), and painful heat (51–100 on the VAS).

2.4. Data and statistical analysis

The threshold temperature for each quality was defined as the temperature at which a rating rose above 2 on the non-normalized scale of 0–100. All averaged data are depicted as means±standard error (SE). Individual data were averaged at each time point to construct average group responses. An analysis of variance (ANOVA) was applied across the cold, pain and ache group average thresholds to detect any statistically significant difference in threshold across these three sensations. The differences between specific group average thresholds were assessed using paired t-tests.

To determine the incidence of prickle and heat responses, we used the following procedure. For a given subject, the stimulus time course was divided into four contiguous, non-overlapping phases: (1) the cooling phase was defined as the time when the temperature was dropping and the subject felt cold but not pain, (2) the pain phase was defined as the time from the onset of the pain experience to the beginning of the re-warming phase, (3) the re-warming phase was defined as the time during which the temperature rose from 3 to 32°C and (4) the interstimulus interval (ISI) began when the temperature reached the 32°C baseline and ended at the beginning of the next cooling phase. For each phase, the percentage of stimulus trials (i.e. incidence) in which prickle (or paradoxical heat) was experienced could then be determined for each subject. For a given phase, all the subjects' incidence values were pooled, to determine a group average incidence. A one-way ANOVA test was applied across the four phases to test for any significant change, and post hoc paired t-tests were applied to test the significance of between-phase differences in group average incidence values.

3. Results

3.1. General features

All subjects were able to consistently rate the cold-evoked sensations of cold, pain, ache, heat and prickle. An example of the ratings obtained in one subject is shown in Fig. 1 which illustrates the consistency of ratings obtained across the four trials for each sensation. This example also illustrates the general features of the five cold-evoked sensations assessed. Not surprisingly, as the thermode temperature cooled by a few degrees, the first and most intense sensation evoked was that of cold. As the thermode temperature cooled below ∼15°C, pain and ache sensations were additionally provoked. At the coldest temperature and/or as the thermode temperature began to return to baseline, brief jabs of prickle were detected. Then, as the pain, ache and cold sensations were subsiding and the thermode temperature had returned to 32°C, a modest intensity heat sensation was reported for ∼1min. The onset and occurrence of the prickle and heat sensations across subjects were somewhat variable and are described in greater detail below.

F1-20
Fig. 1:
Example of the time course of various sensations evoked during cooling of the skin. Data is taken from a single subject. Each type of sensation was rated in a separate cold trial consisting of four presentations of the cooling stimulus to the thenar eminance.

3.2. Thresholds

Threshold data are shown in Table 1. The mean group thresholds for cold, ache and pain sensations were 28.2±5°C, 16.4±1.8°C and 14.9±1.5°C, respectively. The mean cold threshold was significantly lower (i.e. less cold) than the pain and ache thresholds (P<0.001) but there was no statistically significant difference between the pain and ache thresholds (P>0.1).

T1-20
Table 1:
Sensation thresholds (n=17)

3.3. Group responses: temporal profiles

The time course of the mean group responses to the cold stimuli are shown in Fig. 2. These data reveal that the overall profile of cold-evoked cold sensations preceded the pain and ache. The pain and ache profiles were similar and consistent across subjects, as exemplified by the relatively small standard errors in the mean curves. This indicates that ache feelings dominated the overall pain experience. The peak of each of the pain, ache and cold sensations occurred during peak cold temperature level of 3°C. In contrast, the cold-evoked heat and prickle sensations were variable across subjects and occurred at various phases of the stimulus (see below).

F2-20
Fig. 2:
Temporal profile of cold-evoked sensations. Group average data (mean±SE) are shown for the pain, ache, cold, heat and prickle sensations evoked by the cold stimulus in 17 subjects. Data represent normalized ratings based on each subject's maximal response. The bottom panel depicts the cold stimulus.

3.4. Prickle

All 17 subjects reported the sensation of prickle. The mean group prickle rating plotted as a function of thermode temperature (Fig. 3a) indicates that the intensity of prickle increased throughout cooling and was maximal at the coldest temperature and during re-warming. To further assess the dependence of prickle on stimulus temperature, the prickle incidence was determined according to the stimulus phase. Fig. 4 reveals that the prickle sensations were most often reported when the thermode temperature was painful and during the re-warming phase.

F3-20
Fig. 3:
Temporal profile of cold-evoked prickle (A) and heat (B) sensations. Curves indicate the mean percent of maximal ratings across all subjects when the thermode temperature was cooling, re-warming or in the interstimulus (ISI) period.
F4-20
Fig. 4:
Incidence of paradoxical heat and prickle during different phases of the cold pain cycle. (A) Phases of cold stimulus cycle. The cold stimulus cycle was divided into four non-overlapping phases: the cold phase corresponded to the time during which the subject perceived non-painful cold. The pain phase began when the subject first perceived pain. The re-warming phase began at the end of the cold stimulus and encompassed the time during which the stimulus was returning to the baseline temperature. The ISI bridged the re-warming phase and the next cold phase. Incidence of cold-evoked prickle (B) and paradoxical heat (C). Each bar depicts the mean number of trials per subject in which the sensation was reported for each of the phases of the cold stimulus (see Section 2).

A one-way ANOVA test confirmed that the mean incidence of prickle sensations differed significantly across the four phases (P<0.001). Prickle incidence was significantly higher in the pain and re-warming phases than in the ISI (both at P<0.005). The incidence of prickle in the cold phase was found to be significantly lower than in either the pain phase, the re-warming phase or the ISI (all at P<0.05). However, there was no significant difference in prickle incidence between the pain and re-warming phases (P>0.1).

3.5. Paradoxical heat

Despite the fact that the thermode temperature did not rise above 32°C, 13 of the 17 subjects (76%) reported feeling a heat sensation during the experimental runs. These heat sensations were rated as non-painful in 11 subjects, and painful in two subjects. The intensity of the heat sensations rose slightly as the thermode temperature became colder, but was most pronounced during re-warming, and was the greatest during the ISI (see Fig. 3). More than half of the heat sensations were reported during the ISI, while the remainder occurred during the cooling, pain and re-warming phases (Fig. 4).

The incidence of the paradoxical heat sensation was also found to change significantly across the four phases (one-way ANOVA, P<0.01). The incidence of heat sensations in the ISI was significantly higher than in the cold, pain and re-warming phases (all at P=0.001). In contrast, there was no statistically significant difference in heat sensation incidence between the cold and pain phases (P>0.5), the cold and re-warming phases (P>0.1) or the pain and re-warming phases (P>0.5).

4. Discussion

Early studies of human pain observed the perceptual outcome of noxious stimuli using very simple measurement tools (see Lewis, 1942). Yet there have been scant detailed reports of the temporal response profile to noxious cold stimuli. Continuous ratings of components of the pain experience (intensity, affect, prickle, etc.) throughout a stimulus are valuable because they can provide clues to the underlying neural mechanisms responsible for eliciting that sensation. Classic studies more than 50 years ago laid the foundation of the study of cold-evoked sensations. Wolf and Hardy (1941), reported that cold water immersion evoked deep aching pain followed by a sensation of ‘pins and needles’ after about 1min of immersion that was most pronounced at the coldest (0–5°C) temperatures. Kunkle (1949) described a series of sensations evoked by placing a finger in a 0°C water bath for at least 20min: immediate cold followed by aching pain within 10–60s with ‘distressing tingling’ accompanying the maximum pain, and then after about 10 min a second wave of pain with a burning and deep ache quality. Upon removal of the finger from the water bath, subjects reported an ‘after pain’ that included deep ache, burning, throbbing and local heat. Both of these interesting reports considered the contribution of vasoconstriction but Kunkle concluded that the ‘pain can be attributed to direct injury to the chilled tissues or nerves and may be mediated by a metabolite locally released’.

Over the last 50 years, psychophysical studies of cold pain have noted cold-evoked sensations and differences between hairy and glabrous skin, effects of cold stimulation parameters (e.g. cooling rate, stimulation area) and the effect of A-fibre blocks (Mackenzie et al., 1975; Croze and Duclaux, 1978; Chery-Croze and Duclaux, 1980; Hamalainen et al., 1982; Fruhstorfer, 1984; Wahren et al., 1989; Yarnitsky and Ochoa, 1990; Greenspan et al., 1993; Handwerker and Kobal, 1993; Davis, 1998; Morin and Bushnell, 1998; Harrison and Davis, 1999). These studies demonstrate the complex interplay between peripheral noci- and thermoreceptors and the central nervous system (CNS). Furthermore, profound hot and prickle sensations were reported during re-warming to a neutral temperature following a cold stimulus (Dostrovsky and Sherman, 1997; Davis, 1998). In addition, there are interesting and clinically important phenomena that occur during repetitive stimuli. For instance, brief repetitive heat stimuli applied to normal skin produce temporal summation of second pain (Vierck et al., 1997). In inflamed skin, repeated touch stimuli produce progressive tactile hypersensitivity characterized by exquisite allodynia (Ma and Woolf, 1996). Thus, psychophysical response profiles can provide clues to the underlying mechanisms of acute pain, neuropathy and other chronic pain conditions.

The present study expands on our previous reports of the temporal profiles of cold-evoked pain intensity, unpleasantness and prickle and provides further data documenting the complex perceptual outcome of an intense cold stimulus delivered to the skin. The temporal pattern of the prickle and heat sensations indicate that intense cooling and re-warming can trigger the sensations. However, prickle and heat sensations had different patterns of occurrence throughout the cooling/re-warming cycle. The greatest incidence of prickle occurred during both the pain and re-warming phases but heat was most pronounced following the re-warming (i.e. during the ISI). These findings suggest a different underlying mechanism for prickle and heat. The re-warming effect on these sensation is a curious finding since the thermode temperature only re-warmed to a neutral level of 32°C. Noxious cold stimuli are capable of exciting a variety of primary afferents, including cold thermoreceptors, and A- and C-fiber nociceptors (Chery-Croze, 1983; Campero et al., 1996; Simone and Kajander, 1997). Furthermore, some primary afferent nociceptors can encode fabric prickliness (Garnsworthy et al., 1988a). Peripheral warm receptors are thought to require an absolute temperature of 30–35°C and fire maximally at 40–44°C (Hensel, 1974; Konietzny and Hensel, 1977; Darian-Smith et al., 1979; Duclaux and Kenshalo, 1980; Sumino and Dubner, 1981; Kenshalo, 1990). Therefore, warm receptors are unlikely to be responsible for the effects noted, although the response of warm receptors to a large temperature step from 3°C has not been specifically examined. Alternatively, the perception of heat could be attributed to a decrease in the activity of cold thermoreceptors and cold-responsive nociceptors. This is supported by the finding that a shift in temperature from 16 to 24°C evoked a feeling of warmth (Dostrovsky and Sherman, 1997). Susser et al. (1999) showed that paradoxical heat sensations and warm sensations are C-fiber mediated and suggested that paradoxical heat sensations occur when there is a ‘malfunction of the cold-sensing pathway’ such that there is a disinhibition of peripheral and/or central components of the heat-sensing pathway. This concept is based on the thermal grill illusion and the behavior of lamina I cells responsive to heat, pinch and cold (HPC) stimuli described by Craig and coworkers (Craig, 1994; Craig and Bushnell, 1994). Another consideration to the mechanism of paradoxical heat is the contribution of cold-induced vasodilation, such as occurs during a cold pressor test (Wolf and Hardy, 1941; Kunkle, 1949; Kreh et al., 1984). However, this effect requires the skin temperature to be held at cold temperatures (typically <5°C) for several minutes. Thus it is unlikely that such vasodilation occurred in our experiments given that our cold stimuli were maintained at 3°C for only 10s and our runs were separated by 4min of neutral temperature.

The mechanism underlying the cold-evoked prickle sensation is unknown but data derived from heat pain and TENS studies provide some insight. Garnsworthy et al. (1988a,b) observed that prickle sensations could be elicited during and after removal of a TENS stimulus to the forearm. This is consistent with our findings of prickle occurrence during noxious cold and rewarming. Electrophysiological studies of prickle and the related sensation of itch (Tuckett and Wei, 1987; Schmelz et al., 1997; Andrew and Craig, 2001) suggest the involvement of A-delta and/or C polymodal nociceptors (Garnsworthy et al., 1988a,b). It is generally accepted that A fibers play a role in superficial pricking pain in contrast to the C fibers which are thought to mediate deep, aching pain (Handwerker and Kobal, 1993). This is corroborated by the first pain–second pain phenomena whereby noxious heat stimuli evoke a fast A-mediated prickling/stinging sensation followed by a C-mediated dull, warm/burning sensation (Price and Dubner, 1977; Campbell and LaMotte, 1983; Itskovich et al., 2000). A lack of laser-evoked double pain sensation in the glabrous skin (Campbell and LaMotte, 1983) has been attributed to the absence of type II A-mechanoheat nociceptors in that skin type (Treede et al., 1995).

Since the superficially applied cold stimulus was applied for ∼1min, one should also consider the possibility that the tissues beneath the skin were cooled as well as the skin. Based on recordings of cold-evoked pain and intracutaneous temperature, Morin and Bushnell (1998) suggested that cold pain involved receptors located deeply (i.e. below the subcutaneous level). The pain evoked by activation of muscle nociceptors is characterized by a deep, cramping feeling (Simone et al., 1994; Marchettini et al., 1996). Therefore, muscle afferents may partially contribute to the cold-evoked aching observed in the present study. Activation of polymodal vascular nociceptors may contribute to the cold-evoked prickle and aching sensations. Intravenous cooling can evoke pain with dull, sharp, deep or even a burning quality (Fruhstorfer and Lindblom, 1983; Arndt and Klement, 1991; Klement and Arndt, 1991). Block experiments demonstrate that intravenously evoked pain sensations depend on vascular receptor activity whereas the non-painful thermal sensations derive from activation of cutaneous receptors (Arndt and Klement, 1991; Klement and Arndt, 1991). Early work by Kunkle (1949) also suggests activation of vascular receptors from superficial cooling. These interesting findings suggest that in the present study, the sensations evoked during cold stimulation of the skin could be attributed to activation of the underlying vascular nociceptors.

In conclusion, the disparate time courses of achy pain from prickle and heat sensations demonstrate that different patterns of central activity are evoked by an intense cold stimulus. The separation of these perceptions in time provides a framework to study cortical networks underlying particular flavors of sensation.

Acknowledgements

This study was funded by the Canadian Institutes of Health Research (formally the Medical Research Council of Canada). K.D.D. is a Canada Research Chair in Brain and Behaviour.

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Keywords:

Thermoreception; Cold pain; Psychophysics; Prickle; Paradoxical heat

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