Modeling of nociceptor transduction in skin thermal pain sensation

All biological bodies live in a thermal environment with the human body as no exception, where skin is the interface with protecting function. When the temperature moves out of normal physiological range, skin fails to protect and pain sensation is evocated. Skin thermal pain is one of the most common problems for humans in everyday life as well as in thermal therapeutic treatments. Nocicetors (special receptor for pain) in skin play an important role in this process, converting the energy from external noxious thermal stimulus into electrical energy via nerve impulses. However, the underlying mechanisms of nociceptors are poorly understood and there have been limited efforts to model the transduction process. In this paper, a model of nociceptor transduction in skin thermal pain is developed in order to build direct relationship between stimuli and neural response, which incorporates a skin thermomechanical model for the calculation of temperature, damage and thermal stress at the location of nociceptor and a revised Hodgkin-Huxley form model for frequency modulation. The model qualitatively reproduces measured relationship between spike rate and temperature. With the addition of chemical and mechanical components, the model can reproduce the continuing perception of pain after temperature has returned to normal. The model can also predict differences in nociceptor activity as a function of nociceptor depth in skin tissue.     

Focused ultrasound in studies of somatic reception

Focused ultrasound has been used to elicit cutaneous tactile, thermal, specific and nonspecific pain sensations, and also subcutaneous (deep) sensations which included tactile and some pain sensations (muscular and periosteal etc.). It has been found that somatic reception can be attributed to mechanoreception, that the same receptive structures are involved in the sensations of warmth and cold, and that ultrasound has a sensitizing action. Studies have been made of sensation differences from corporal and auricular acupuncture points, and from some chosen skin and subcutaneous points.I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Saint Petersburg. I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, Saint Petersburg. Translated from Neirofiziologiya, Vol. 24, No. 5, pp. 529–534, September–October, 1992.     

Brain activation associated with ratings of the hedonic component of thermal sensation during whole-body warming and cooling

Thermal sensation has both discriminative and hedonic components. The neural network associated with thermal discrimination has been described, but the representation of the hedonic component of thermal sensation in the brain has yet to be demonstrated. This study measured regional cerebral blood flow (rCBF) with Positron Emission Tomography in human participants during whole-body cooling and warming. Ratings of the hedonic dimension of thermal sensation were correlated with rCBF and compared to brain activation maps of skin and core temperature changes. The hedonic dimension of thermal sensation was represented in a widely distributed network that included somatosensory, limbic, paralimbic, and associative cortices. Changes in rCBF associated with ratings of the hedonic dimension of thermal sensation were contrasted with changes in rCBF associated with skin and core temperature to identify brain regions that were uniquely activated by the hedonic dimension of thermal sensation. The contrast between the correlates of the hedonic dimension of thermal sensation and the correlates of skin and core temperatures identified a region in the posterior part of the mid cingulate cortex (pMCC). The independent relationship between rCBF changes in the pMCC with ratings of the hedonic dimension of thermal sensation may indicate an important role for the pMCC in the integration of temperature-related signals from receptors in the skin and core.     

Sensory recovery in a split skin graft: pinprick or a thermal sensory analyzer?

Sensory return in a split skin graft is an important factor in the protection of this graft from injury. Hence, three tests were compared: (1) the standard pain test using a simple pin, (2) the cold pain test, and (3) the hot pain test. Both the hot and cold pain tests were performed using the thermal sensory analyzer device. Thirteen patients were investigated; all had split skin grafts applied directly onto deep fascia after malignant melanoma excision on the lower limb. The period after grafting ranged from 4 to 15 years, and the mean age was 46.5 years. The normal contralateral side of each patient was used as the control for that patient. The results were collected in simple data tables and were analyzed using paired t tables for small samples with the level of significance set at p < 0.05. The standard pain test demonstrated that the split skin grafts applied on deep fascia did not recover sensation, even 15 years after surgery (p < 0.001). The hot and cold pain tests were both in agreement with the standard pain test at p < 0.001 and p < 0.03, respectively. The standard pain test is usually performed, as described in this study, using a pin, which is cheap and readily available in any plastic surgery and burn clinic. However, the cold and hot pain tests as performed here using the thermal sensory analyzer device are accurate but are costly, cumbersome, and not available in all clinics except for highly specialized units. Hence, the author would like to dispel the myth that the standard pain test is inaccurate. This might be so in testing sensation in "normal" skin but not in testing the recovery of sensation in a skin graft.     

Case study of skin temperature and thermal perception in a hot outdoor environment

Focusing on the understanding and the estimation of the biometeorological conditions during summer in outdoor places, a field study was conducted in July 2010 in Athens, Greece over 6 days at three different sites: Syntagma Square, Ermou Street and Flisvos coast. Thermo-physiological measurements of five subjects were carried out from morning to evening for each site, simultaneously with meteorological measurements and subjective assessments of thermal sensation reported by questionnaires. The thermo-physiological variables measured were skin temperature, heat flux and metabolic heat production, while meteorological measurements included air temperature, relative humidity, wind speed, globe temperature, ground surface temperature and global radiation. The possible relation of skin temperature with the meteorological parameters was examined. Theoretical values of mean skin temperature and mean radiant temperature were estimated applying the MENEX model and were compared with the measured values. Two biometeorological indices, thermal sensation (TS) and heat load (HL)—were calculated in order to compare the predicted thermal sensation with the actual thermal vote. The theoretically estimated values of skin temperature were underestimated in relation to the measured values, while the theoretical model of mean radiant temperature was more sensitive to variations of solar radiation compared to the experimental values. TS index underestimated the thermal sensation of the five subjects when their thermal vote was ‘hot’ or ‘very hot’ and overestimated thermal sensation in the case of ‘neutral’. The HL index predicted with greater accuracy thermal sensation tending to overestimate the thermal sensation of the subjects.     

Location of heat sensitive region in human skin

Heat sensitive points on the body skin were investigated in the course of psychophysiological research using thermal and mechanical stimulation on 98 volunteers residing under conditions of pronounced continental climate, in the town of Alma-Ata, with an age range of 20 to 46. Heat sensitive and cold sensitive points were divided into four and two classes respectively on the basis of minimum arousal threshold and nature of the sensation. Receptors of each class were located in the skin at the areas of greatest concentration. Comparison of the thermal range of activity and numbers of active points at different cutaneous sites in humans revealed their differing capacity for perception of different temperature levels.Institute of Physiology, Kazakhstan Academy of Sciences, Alma-Ata. Translated from Neirofiziologiya, Vol. 24, No. 5, pp. 591–598, September–October, 1992.     

Thermal sensation. A comparison of rating scales and cross modality matching

Studies of thermal sensation in man commonly use a 7 point category scale. Such scales have disadvantages, and an experiment was carried out to apply the methods of the new psychophysics to whole body thermal sensation. Ten sedentary subjects were exposed singly to a temperature T_o near their comfort level, then to (T_o + 3) and (T_o –3)°C. The subject responded both by giving a warmth vote, and by gripping a dynamometer so that the strength of his grip was equal to his thermal sensation: this is the method of cross modality matching. For each subject the strength of grip was consistently related to thermal sensation vote, but the range of grips employed by different subjects was very high, making between subjects comparison impossible. The experiment was repeated with the subjects unclothed and heavily clothed. No effect of clothing was found on the rate of change of thermal sensation with temperature; conventional theories which relate sensation to heat load would predict a factor of 2.     

The Response of Human Thermal Sensation and Its Prediction to Temperature Step-Change (Cool-Neutral-Cool)

This paper reports on studies of the effect of temperature step-change (between a cool and a neutral environment) on human thermal sensation and skin temperature. Experiments with three temperature conditions were carried out in a climate chamber during the period in winter. Twelve subjects participated in the experiments simulating moving inside and outside of rooms or cabins with air conditioning. Skin temperatures and thermal sensation were recorded. Results showed overshoot and asymmetry of TSV due to the step-change. Skin temperature changed immediately when subjects entered a new environment. When moving into a neutral environment from cool, dynamic thermal sensation was in the thermal comfort zone and overshoot was not obvious. Air-conditioning in a transitional area should be considered to limit temperature difference to not more than 5°C to decrease the unacceptability of temperature step-change. The linear relationship between thermal sensation and skin temperature or gradient of skin temperature does not apply in a step-change environment. There is a significant linear correlation between TSV and Q_loss in the transient environment. Heat loss from the human skin surface can be used to predict dynamic thermal sensation instead of the heat transfer of the whole human body.     

Thermal sensation at index finger while applying external pressure at upper arm

In this study we focused on thermal sensation at fingertip under the influence of applied external pressure via a tourniquet at the upper arm. The perceived thermal sensation has found to be closely related to the skin temperature (Tsk) that is regulated by the skin blood flow (SkBF), whereas SkBF is easily influenced by external pressure. We thus hypothesized that the perceived thermal sensation, the Tsk and SkBF form such a cross-coupled triad that jointly affects our feeling of thermal comfort. Such interconnections among them were examined in this study using two protocols to investigate the perceived thermal sensation from a given heat stimulus under an exerted external pressure: (1) the SkBF and Tsk, at the right hand index finger under different external pressures at the right upper arm of one male subject, were monitored by a laser-Doppler flowmeter (LDF); (2) subjective thermal feelings (cold, normal and warm) at the right index fingertip of 10 test takers were recorded, while contacting a glass tube filled with water at different temperatures, with/without 50 mm Hg external pressure at the upper arm, while the temperatures of the glass tube and the index fingertip were recorded by an infrared camera. First, it is found that the SkBF and Tsk at the index fingertip reduced significantly with high external pressure applied at the upper arm, while the pressure from our daily clothing is not large enough to generate such an effect. Next, the applied pressure suppresses the variations in subjective sensory responses towards the thermal stimuli. Our hypothesis on the interconnections among the perceived thermal sensation, the Tsk and SkBF is thus confirmed. Overall, females appear more discerning to temperature change under the given conditions compared to males.     

Effects of ambient temperature steps on thermal comfort requirements

The purpose of this study was to determine the thermal comfort requirements for steps in temperature. Thirty male subjects were exposed for 50 min to a 34 or 37°C condition, and then quickly transferred to a cooler environment of 31, 28, 25, and 22°C for 50 min. Mean skin temperature was continuously measured, and the subjects reported their thermal sensation and comfort sensation every 2 min. Just after the step changes, the mean skin temperature immediately decreased, while the thermal sensation overshot and gradually rose again. Both the skin temperature and the thermal sensation seemed to reach a constant level within about 20 min. However, there were differences in the mean skin temperature and the neutral temperature derived from the correlation between the ambient temperature and the thermal sensation even 50 min after the steps, due to the thermal environmental condition before the changes of temperature. The change in the neutral temperature with time was expressed as two attenuating equations. These equations indicate that there is an obvious difference between the neutral temperatures due to the thermal condition before step changes, and that it takes >50 min after the step changes to reach the steady state. It is expected that these equations predict in quantitative terms the thermal comfort requirements within a given experimental condition.     

Developing a new individualized 3-node model for evaluating the effects of personal factors on thermal sensation

Individual differences, such as weight, height, gender, age, and Basal Metabolic Rate (BMR), between human subjects can significantly affect body thermoregulatory mechanisms. Therefore, application of common population-based thermal comfort models cannot provide accurate results for an individual's thermal sensation. Based on the standard thermal models, including those of Fanger and Gagge, individual parameters are not considered in the evaluation of thermal sensations. Thus, these simplified standard models have some limitations under varied individual conditions. In this study, a new individualized thermal comfort model is presented on the basis of a simplified 3-node model. This model was developed by regarding the effects of individual characteristics, such as age, gender, Body Mass Index (BMI), and BMR on the thermal sensations of the bare and clothed parts of the body. A good agreement was found in the current model, which was verified based on the experimental data. In conclusion, the results indicated that the mean error in the prediction of skin temperature decreased from 1.2 °C to 0.4 °C when using the new individual model instead of a non-individualized 3-node model.     

The role of activin in neuropeptide induction and pain sensation

Signals from target tissues play critical roles in the functional differentiation of neuronal cells, and in their subsequent adaptations to peripheral changes in the adult. Sensory neurons in the dorsal root ganglia (DRG) provide an excellent model system for the study of signals that regulate the development of neuronal diversity. DRG have been well characterized and contain both neurons that convey information from muscles about limb position, as well as other neurons that provide sensations from skin about pain information. Sensory neurons involved in pain sensation can be distinguished physiologically and antigenically, and one hallmark characteristic is that these neurons contain neuropeptides important for their functions. The transforming growth factor (TGF) beta family member activin A has recently been implicated in neural development and response to injury. During sensory neuron development, peripheral target tissues containing activin or activin itself can regulate pain neuropeptide expression. Long after development has ceased, skin target tissues retain the capacity to signal neurons about changes or injury, to functionally refine synapses. This review focuses on the role of activin as a target-derived differentiative factor in neural development that has additional roles in response to cutaneous injuries in the adult.     

Thermosensation and pain

We feel a wide range of temperatures spanning from cold to heat. Within this range, temperatures over about 43 degrees C and below about 15 degrees C evoke not only a thermal sensation, but also a feeling of pain. In mammals, six thermosensitive ion channels have been reported, all of which belong to the TRP (transient receptor potential) superfamily. These include TRPV1 (VR1), TRPV2 (VRL-1), TRPV3, TRPV4, TRPM8 (CMR1), and TRPA1 (ANKTM1). These channels exhibit distinct thermal activation thresholds (>43 degrees C for TRPV1, >52 degrees C for TRPV2, > approximately 34-38 degrees C for TRPV3, > approximately 27-35 degrees C for TRPV4, < approximately 25-28 degrees C for TRPM8 and <17 degrees C for TRPA1), and are expressed in primary sensory neurons as well as other tissues. The involvement of TRPV1 in thermal nociception has been demonstrated by multiple methods, including the analysis of TRPV1-deficient mice. TRPV2, TRPM8, and TRPA1 are also very likely to be involved in thermal nociception, because their activation thresholds are within the noxious range of temperatures.     

Influence of skin temperature distribution on thermal sensation in a cool environment

Thermal sensation and distribution of skin temperatures in persons exercising at 36.5 W on a bicycle ergometer and resting in a cool environment (10 degrees C) in two different clothings, one with the insulation mainly over the trunk (1.22 clo), and one with well insulated limbs (1.67 clo), were studied. Their general thermal sensations varied from slightly warm to slightly cool. The placing of the insulation had a decisive influence on skin temperature distribution, so that skin temperature was always high in well-insulated areas. When the insulation was placed over the limbs, a greater amount of heat was lost than if a similar insulation was placed on the trunk. Neither Tsk nor skin temperature distribution correlated with general thermal sensation. Instead, mean body temperature seemed to be the determinant of general thermal sensation in these conditions. The best prediction of general thermal sensation was obtained by adding Tre with a weighting factor of 0.8-0.9 and Tsk with a weighting factor of 0.1-0.2.     

Skin and core temperature response to partial- and whole-body heating and cooling

1. Human subjects were exposed to partial- and whole-body heating and cooling in a controlled environmental chamber to quantify physiological and subjective responses to thermal asymmetries and transients.

2. Skin temperatures, core temperature, thermal sensation, and comfort responses were collected for 19 local body parts and for the whole body.

3. Core temperature increased in response to skin cooling and decreased in response to skin heating.

4. Hand and finger temperatures fluctuated significantly when the body was near a neutral thermal state.

5. When using a computer mouse in a cool environment, the skin temperature of the hand using the mouse was observed to be 2–3 °C lower than the unencumbered hand.     

Thermal sensation and thermophysiological responses to metabolic step-changes

This study investigated the effect on thermal perception and thermophysiological variables of controlled metabolic excursions of various intensities and durations. Twenty-four subjects were alternately seated on a chair or exercised by walking on a treadmill at a temperature predicted to be neutral at sedentary activity. In a second experimental series, subjects alternated between rest and exercise as well as between exercise at different intensities at two temperature levels. Measurements comprised skin and oesophageal temperatures, heart rate and subjective responses. Thermal sensation started to rise or decline immediately (within 1 min) after a change of activity, which means that even moderate activity changes of short duration affect thermal perceptions of humans. After approximately 15–20 min under constant activity, subjective thermal responses approximated the steady-state response. The sensitivity of thermal sensation to changes in core temperature was higher for activity down-steps than for up-steps. A model was proposed that estimates transient thermal sensation after metabolic step-changes. Based on predictions by the model, weighting factors were suggested to estimate a representative average metabolic rate with varying activity levels, e.g. for the prediction of thermal sensation by steady-state comfort models. The activity during the most recent 5 min should be weighted 65%, during the prior 10–5 min 25% and during the prior 20–10 min 10%.     

From chills to chilis: mechanisms for thermosensation and chemesthesis via thermoTRPs

Six highly temperature-sensitive ion channels of the transient receptor potential (TRP) family have been implicated to mediate temperature sensation. These channels, expressed in sensory neurons innervating the skin or the skin itself, are active at specific temperatures ranging from noxious cold to burning heat. In addition to temperature sensation thermoTRPs are the receptors of a growing number of environmental chemicals (chemesthesis). Recent studies have provided some striking new insights into the molecular mechanism of thermal and chemical activation of these biological thermometers.     

Quantification of gender specific thermal sensory and pain threshold before and after laser needle stimulation]

Quantitative thermal sensory and pain threshold testing (QST) was performed in 29 adult healthy volunteers (mean age 24.2 +/- 2.7 years; range: 18-29 years; 20 females, 9 males) using the Thermal Sensory Analyser TSA-II (Medoc Advanced Medical Systems, Ramat Yishai, Israel, and Minneapolis, Minnesota, USA) before and after laser needle acupuncture and placebo stimulation, respectively. Significant (p < or = 0,001; t-test) gender-specific differences were seen on cold pain threshold analysis. No significant changes in parameters of thermal sensory and pain thresholds were found before and after laser needle or placebo stimulation at acupuncture points for acute pain. However, a trend towards change in the median value of cold pain sensation after laser needle stimulation (p = 0.479; paired t-test; n.s.) was seen within the group of healthy females. The influence of stimulation of acupuncture points for chronic pain on the various parameters needs to be clarified in future studies.     

The Fine Tuning of Pain Thresholds: A Sophisticated Double Alarm System

Two distinctive features characterize the way in which sensations including pain, are evoked by heat: (1) a thermal stimulus is always progressive; (2) a painful stimulus activates two different types of nociceptors, connected to peripheral afferent fibers with medium and slow conduction velocities, namely Aδ- and C-fibers. In the light of a recent study in the rat, our objective was to develop an experimental paradigm in humans, based on the joint analysis of the stimulus and the response of the subject, to measure the thermal thresholds and latencies of pain elicited by Aδ- and C-fibers. For comparison, the same approach was applied to the sensation of warmth elicited by thermoreceptors. A CO₂ laser beam raised the temperature of the skin filmed by an infrared camera. The subject stopped the beam when he/she perceived pain. The thermal images were analyzed to provide four variables: true thresholds and latencies of pain triggered by heat via Aδ- and C-fibers. The psychophysical threshold of pain triggered by Aδ-fibers was always higher (2.5–3°C) than that triggered by C-fibers. The initial skin temperature did not influence these thresholds. The mean conduction velocities of the corresponding fibers were 13 and 0.8 m/s, respectively. The triggering of pain either by C- or by Aδ-fibers was piloted by several factors including the low/high rate of stimulation, the low/high base temperature of the skin, the short/long peripheral nerve path and some pharmacological manipulations (e.g. Capsaicin). Warming a large skin area increased the pain thresholds. Considering the warmth detection gave a different picture: the threshold was strongly influenced by the initial skin temperature and the subjects detected an average variation of 2.7°C, whatever the initial temperature. This is the first time that thresholds and latencies for pain elicited by both Aδ- and C-fibers from a given body region have been measured in the same experimental run. Such an approach illustrates the role of nociception as a “double level” and “double release” alarm system based on level detectors. By contrast, warmth detection was found to be based on difference detectors. It is hypothesized that pain results from a CNS build-up process resulting from population coding and strongly influenced by the background temperatures surrounding at large the stimulation site. We propose an alternative solution to the conventional methods that only measure a single “threshold of pain”, without knowing which of the two systems is involved.     

辣椒素及其受体

可以感受痛觉刺激的初级感觉神经元的周围末梢被称为伤害性感受器。这些小直径神经元的末梢可将化学、机械和热刺激信号转化为动作电位,并将这些信息上传到中枢,最后使机体产生痛觉或不舒服的感受。但到目前为止,人们对这些可探测到伤害性刺激的分子所知甚少。1997年成功克隆的辣椒素受体亚型1（vanilloid receptor subtype1,VR1)是近年来科学家们研究的“热点分子”,它是表达于伤害性感受器上的非选择性阳离子通道,已有诸多证据表明其可探测和整合诱发痛觉的化学和热刺激信号,基因敲除小鼠的研究分析也有力证明了该离子通道参与了疼痛及组织损伤后痛觉过敏的产生,而且是热诱发疼痛发生过程的关键分子。