Noxious Temperatures Research Articles

Mechanisms of TREK-2 Potassium Channel Gating

The K2P channel TREK-2 is an archetypal polymodal potassium channel which acts to couple a diverse range of regulatory stimuli to cellular electrical excitability. Alongside the other thermo-and mechano-gated K2P channels (TREK-1 and TRAAK) the TREK-2 channel is critical for discrimination of innocuous and noxious temperature and touch sensation. Guided by novel X-ray crystal structures, we have used a variety of electrophysiological, pharmacological and kinetic studies to demonstrate a mechanism of action for the state-dependent inhibition of TREK-2 by norfluoxetine, a biologically active metabolite of the anti-depressant Prozac. These studies also enable us to propose a structural basis for activation of TREK-2 by membrane stretch, temperature and arachidonic acid.

The Anoctamin Family Channel Subdued Mediates Thermal Nociception in Drosophila

Calcium-permeable and thermosensitive transient receptor potential (TRP) channels mediate the nociceptive transduction of noxious temperature in Drosophila nociceptors. However, the underlying molecular mechanisms are not completely understood. Here we find that Subdued, a calcium-activated chloride channel of the Drosophila anoctamin family, functions in conjunction with the thermo-TRPs in thermal nociception. Genetic analysis with deletion and the RNAi-mediated reduction of subdued show that subdued is required for thermal nociception in nociceptors. Further genetic analysis of subdued mutant and thermo-TRP mutants show that they interact functionally in thermal nociception. We find that Subdued expressed in heterologous cells mediates a strong chloride conductance in the presence of both heat and calcium ions. Therefore, our analysis suggests that Subdued channels may amplify the nociceptive neuronal firing that is initiated by thermo-TRP channels in response to thermal stimuli.

Human TRPA1 is intrinsically cold- and chemosensitive with and without its N-terminal ankyrin repeat domain.

We have purified and reconstituted human transient receptor potential (TRP) subtype A1 (hTRPA1) into lipid bilayers and recorded single-channel currents to understand its inherent thermo- and chemosensory properties as well as the role of the ankyrin repeat domain (ARD) of the N terminus in channel behavior. We report that hTRPA1 with and without its N-terminal ARD (Δ1-688 hTRPA1) is intrinsically cold-sensitive, and thus, cold-sensing properties of hTRPA1 reside outside the N-terminal ARD. We show activation of hTRPA1 by the thiol oxidant 2-((biotinoyl)amino)ethyl methanethiosulfonate (MTSEA-biotin) and that electrophilic compounds activate hTRPA1 in the presence and absence of the N-terminal ARD. The nonelectrophilic compounds menthol and the cannabinoid Δ(9)-tetrahydrocannabiorcol (C16) directly activate hTRPA1 at different sites independent of the N-terminal ARD. The TRPA1 antagonist HC030031 inhibited cold and chemical activation of hTRPA1 and Δ1-688 hTRPA1, supporting a direct interaction with hTRPA1 outside the N-terminal ARD. These findings show that hTRPA1 is an intrinsically cold- and chemosensitive ion channel. Thus, second messengers, including Ca(2+), or accessory proteins are not needed for hTRPA1 responses to cold or chemical activators. We suggest that conformational changes outside the N-terminal ARD by cold, electrophiles, and nonelectrophiles are important in hTRPA1 channel gating and that targeting chemical interaction sites outside the N-terminal ARD provides possibilities to fine tune TRPA1-based drug therapies (e.g., for treatment of pain associated with cold hypersensitivity and cardiovascular disease).

Modulation of the startle reflex by heat pain: does threat play a role?

Previous studies have indicated that the startle reflex is potentiated by phasic, but not by tonic, heat pain, although the latter is seen as more strongly associated with emotional responses and more similar to clinical pain. The threat value of pain might be a decisive variable, which is not influenced alone by stimulus duration. This study aimed at comparing startle responses to tonic heat pain stimulation with varying degrees of threat. We hypothesized that the expectation of unpredictable temperature increases would evoke higher threat and thereby potentiate startle compared with the expectation of constant stimulation. Healthy, pain-free subjects (n = 40) underwent painful stimulation in two conditions (low/high threat) in balanced order. The only difference between the two conditions was that in the high-threat condition 50% of the trials were announced to include a short further noxious temperature increase at the end. Startle tones were presented prior to this temperature increase still in the phase of anticipation. We observed startle potentiation in the high-threat compared with the low-threat condition, but only in those participants who took part first in the high-threat condition. Habituation could not account for these findings, as we detected no significant decline of startle responses in the course of both conditions. Our results suggest that subjective threat might indeed be decisive for the action of pain on startle; the threat level appears not only influenced by actual expectations but also by previous experiences with pain as threatening or not.

TRPM3 - A Promising Target for Analgesic Treatment

According to the American Pain Society, pain is one of the most common symptoms why patients search medical attention. A recent achievement in pain research was the identification of Transient Receptor Potential (TRP) channels as analgesic targets. The superfamily of TRP ion channels consists of 28 different members in mammalians. The sensitivity of TRP channels to a broad array of stimuli allows them to function as biological sensors involved in processes ranging from vision to taste, and tactile sensation. The so-called thermoTRPs (temperature sensitive) are typically expressed in sensory neurons, where they act as primary thermosensors for the detection of innocuous and noxious temperatures. Recently, our research group identified high TRPM3 expression in nociceptor neurons, where it plays a decisive role in the nocifensive response to pregnenolone sulphate (PS) and heat and in the development of heat hyperalgesia during inflammation. This project aims to validate TRPM3 as a potential target for the development of new analgesics. Therefore, we purpose to identify new potent and selective TRPM3 blockers, and show their ability to cure different pain conditions in vivo. In collaboration with the Center for Drug Design and Development (CD3) we identified a new potent TRPM3 blocker (CIM056741) that showed a high selectivity for TRPM3 compared to other related TRP channels. The blocker was able to inhibit PS induced [Ca2+]i signals in isolated DRG neurons. Furthermore, CIM056741 significantly reduced the sensitivity of mice and rats to noxious heat and PS-induced chemical pain. Interestingly, injection of CIM056741 strongly reduced the inflammatory induced mechanical hyperalgesia and was without effect on body core temperature, heart rate and locomotor activity. In conclusion, the obtained results validate TRPM3 as a potential target for new analgesic treatments in humans.

Molecular Adaptations to Extreme Thermogenesis in Mammalian Hibernators

Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) are obligate mammalian hibernators that make the transition from deep torpor- where body temperatures can be as low as 2°C- to the fully active state within as little as two hours. During arousal from hibernation, squirrels undergo an extreme thermogenesis phase, where core body temperatures can increase above normal (37°C) and reach 45°C, without causing distress or discomfort to the animal. To elucidate protective mechanisms that enable tolerance to hyperthermia, we examined the functional properties of TRPV1, the capsaicin- and heat-activated channel that senses noxious heat (>42°C). Sequence alignment showed a high level of identity between rat and squirrel homologues. Histological examination showed no changes in the neuronal profile of squirrel sensory ganglia or decreases in the number of neurons expressing TRPV1. Electrophysiological recordings revealed that both channels are activated by acidic pH and capsaicin. However, whereas rat TRPV1 is also activated by heat at ∼43°C, we detected no thermal activation of the squirrel homologue even at temperatures as high as 48°C. Furthermore, in accord with the electrophysiological data, we found that squirrels fail to clearly discriminate between innocuous (25oC) and noxious (50oC) temperatures in behavioral tests. These experiments provide a molecular mechanism for hyperthermia tolerance in mammals at the level of the somatosensory system, and present a novel TRPV1 homologue, which can be used to delineate protein region(s) important for thermal activation.

Thermotaxis navigation behavior

This chapter describes four different protocols used to assay thermotaxis navigation behavior of single, or populations of, C. elegans hermaphrodites on spatial thermal gradients within the physiological temperature range (15-25°C). A method to assay avoidance of noxious temperatures is also described.

How and why Caenorhabditis elegans uses distinct escape and avoidance regimes to minimize exposure to noxious heat.

Minimizing the exposure to deleterious extremes of temperature is essential for animals to avoid tissue damages. Because their body temperature equilibrates very rapidly with their surroundings, small invertebrates are particularly vulnerable to the deleterious impact of high temperatures, which jeopardizes their growth, fertility, and survival. The present article reviews recent analyses of Caenorhabditis elegans behavior in temperature gradients covering innocuous and noxious temperatures. These analyses have highlighted that worm uses two separate, multi-componential navigational strategies: an avoidance strategy, aiming at staying away from noxious heat, and an escape strategy, aiming at running away after exposure. Here, I explain why efficient escape and avoidance mechanisms are mutually exclusive and why worm needs to switch between distinct behavioral regimes to achieve efficient protective thermoregulation. Collectively, these findings reveal some largely unrecognized strategies improving worm goal-directed navigation and the fascinating level of sophistication of the behavioral responses deployed to minimize the exposure to noxious heat. Because switching between avoidance and escape regimes circumvents constraints that are valid for navigation behaviors in general, similar solutions might be used by worms and also other organisms in response to various environmental parameters covering an innocuous/noxious, non-toxic/toxic range.

Cellular and Molecular Mechanisms of Dental Nociception

Due, in part, to the unique structure of the tooth, dental pain is initiated via distinct mechanisms. Here we review recent advances in our understanding of inflammatory tooth pain and discuss 3 hypotheses proposed to explain dentinal hypersensitivity: The first hypothesis, supported by functional expression of temperature-sensitive transient receptor potential channels, emphasizes the direct transduction of noxious temperatures by dental primary afferent neurons. The second hypothesis, known as hydrodynamic theory, attributes dental pain to fluid movement within dentinal tubules, and we discuss several candidate cellular mechanical transducers for the detection of fluid movement. The third hypothesis focuses on the potential sensory function of odontoblasts in the detection of thermal or mechanical stimuli, and we discuss the accumulating evidence that supports their excitability. We also briefly update on a novel strategy for local nociceptive anesthesia via nociceptive transducer molecules in dental primary afferents with the potential to specifically silence pain fibers during dental treatment. Further understanding of the molecular mechanisms of dental pain would greatly enhance the development of therapeutics that target dental pain.

Role of endogenous TRPV1 agonists in a postburn pain model of partial-thickness injury

Oxidized linoleic acid metabolites (OLAMs) are a class of endogenous transient receptor potential vanilloid 1 (TRPV1) channel agonists released on exposure of tissue to transient noxious temperatures. These lipid compounds also contribute to inflammatory and heat allodynia. Because persistent pain after a burn injury represents a significant clinical challenge for treatment, we developed an in vivo rat model of partial-thickness cutaneous thermal injury and examined whether TRPV1 and specific OLAM metabolites play a role in mediating postburn pain injury. This peripheral model of burn injury had marked thermal allodynia peaking at 24h after thermal injury, with allodynia being maintained for up to 7d. Immunohistochemical characterization of tissue taken from injury sites revealed an increase in leukocyte/macrophage infiltration that was colocalized with TRPV1-positive fibers. Using this peripheral thermal injury model, we found that pharmacological blockade of peripheral TRPV1 receptors reduced thermal allodynia by about 98%. Moreover, there was a significant increase in OLAM levels compared to naive controls in hind paw skin biopsies. Additional studies of the metabolism of [C14]-linoleic acid in skin biopsies revealed the role of the cytochrome P450 (CYP) system in mediating the metabolism of linoleic acid after thermal injury. Finally, we demonstrated that direct inhibition of OLAMs using OLAM antibodies and indirect inhibition using the CYP inhibitor ketoconazole significantly reduced postburn thermal allodynia. Collectively, these findings point to a novel role of the OLAMs and CYP-related enzymes in generating postburn allodynia via activation of peripheral TRPV1.

Self-reported physical activity predicts pain inhibitory and facilitatory function

The prevalence estimates of chronic pain among adults in the United States may be as high as 40%, affecting approximately 100 million adults (15). Pain increases physical disability (32), reduces quality of life, and is costly to both the individual experiencing pain and the nation (15). Alarmingly, a recent study reported that the national cost of pain exceeds the cost of the nation’s priority health conditions (e.g., cardiovascular disease, neoplasms, endocrine, nutritional and metabolic diseases), with costs ranging from $560 to $635 billion annually (15). Clearly, a need exists for effective methods to prevent and treat chronic pain. A rapidly growing body of evidence suggests that exercise may be a viable means to aid in the prevention of chronic pain and reduce ongoing pain symptoms in chronic pain populations. Indeed, data from observational studies (23), randomized controlled trials (19), and laboratory studies suggest a relationship between levels of physical activity and chronic pain (12, 26). For example, RCTs demonstrate that systematic aerobic exercise reduces pain symptoms and improves physical function in multiple chronic widespread (19) and regional pain conditions (17). Additionally, recent laboratory studies have showed that subjective and objective measures of physical activity are negatively related to suprathreshold pain sensitivity of painful heat stimuli in FMS patients (13, 26). A few studies have examined the relationship between pain sensitivity and physical activity in healthy adults. Most recently, Ellingson and colleagues found that greater vigorous physical activity as measured by accelerometers was significantly related to reduced pain intensity and unpleasantness ratings to noxious thermal stimuli in healthy, younger women (12). Similarly, Adrzejewski et al. revealed that pressure pain thresholds at a variety of skeletal muscles sites were higher in younger adults who reported engaging in vigorous physical activity compared to those who reported participation in only moderate physical activity (3). Anshel and Russel demonstrated that an aerobic training intervention increased pressure pain tolerance compared to a control group with no exercise training (4). While these studies suggest a link between physical activity and pain sensitivity, it is not known whether levels of physical activity are related to the functionality of pain modulatory processes. Importantly, several studies have shown that regular physical exercise exerts beneficial effects on several biological mediators (e.g., serotonin, endogenous opioids) of pain inhibition and facilitation (1,14,34). Pain is modulated by complex endogenous systems that both facilitate and inhibit pain. Alterations in the function of these systems have been implicated in multiple chronic pain conditions (24) and in older adults (31). Several sophisticated tests of pain modulatory mechanisms exist in the pain literature. Dysfunction of pain facilitation has often been assessed by the method of temporal summation. This procedure consists of the administration of short-duration repeated noxious stimuli of a constant intensity and measuring the consequent increase in pain as an indirect method of evaluating sensitization of the central nervous system (11). Endogenous pain inhibition has typically been assessed by a “pain inhibits pain” model termed conditioned pain modulation (CPM) or a model called offset analgesia (offset). CPM is the central inhibition of pain in a local area by a second pain that can be experienced anywhere in the body (38). Offset is an inhibitory temporal sharpening mechanism characterized by a pronounced reduction in perceived pain intensity evoked by slight decreases in noxious temperatures compared to those of equal magnitude increases (16). To date, no studies have investigated whether individuals who are more physically active exhibit enhanced descending pain modulatory function using the tests of temporal summation of pain, CPM, or offset analgesia. The purpose of this study was threefold. We sought to determine whether self-reported levels of physical activity in healthy adults predicted 1) pain sensitivity to heat and cold stimuli, 2) pain facilitory function as tested by temporal summation of pain, and 3) pain inhibitory function as tested by CPM and offset analgesia. We hypothesized that participants who reported relatively greater levels of physical activity would exhibit less pain sensitivity to thermal stimuli, reduced temporal summation of pain, and greater inhibition of pain via CPM and offset analgesia.

Mammalian Thermosensation: A Product of Two Lines of Aversive Input

Detection of environmental temperature is essential for survival as it allows for attraction to optimal, as well as avoidance of potentially dangerous temperatures. Normally, mammals are able to detect subtle variation in a broad range of temperatures. However, upon injury or with chronic pain syndromes, innocuous temperatures can become extremely painful. In this study we look at the neuronal inputs responsible for both innocuous and noxious temperature sensation. Recently, we generated mutant mice that are insensate to all thermal cues. These mice lack various sensory cells including those that express TRPV1, TRPM8 and Mrgprd. To dissect the thermosensory functional roles of these cell types, we engineered mice where these cell populations can be conditionally ablated with diphtheria toxin treatment. Our data show that non-overlapping, aversive inputs from TRPM8 and TRPV1 neurons are responsible for accurate temperature sensation from 0°C to 50°C. In addition, we find that avoidance of extreme temperatures is the result of an additional population of nociceptors that express Mrgprd, and that these responses are likely mediated through sensing of tissue damage rather than temperature. Together these studies give us a better understanding of how humans and other mammals are able to navigate a wide range of environments effectively and safely. The data show how only few types of neurons can encompass the full range of mammalian temperature sensation.

Analysis of Transient Receptor Potential Ankyrin 1 (TRPA1) in Frogs and Lizards Illuminates Both Nociceptive Heat and Chemical Sensitivities and Coexpression with TRP Vanilloid 1 (TRPV1) in Ancestral Vertebrates

Transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (V1) perceive noxious temperatures and chemical stimuli and are involved in pain sensation in mammals. Thus, these two channels provide a model for understanding how different genes with similar biological roles may influence the function of one another during the course of evolution. However, the temperature sensitivity of TRPA1 in ancestral vertebrates and its evolutionary path are unknown as its temperature sensitivities vary among different vertebrate species. To elucidate the functional evolution of TRPA1, TRPA1s of the western clawed (WC) frogs and green anole lizards were characterized. WC frog TRPA1 was activated by heat and noxious chemicals that activate mammalian TRPA1. These stimuli also activated native sensory neurons and elicited nocifensive behaviors in WC frogs. Similar to mammals, TRPA1 was functionally co-expressed with TRPV1, another heat- and chemical-sensitive nociceptive receptor, in native sensory neurons of the WC frog. Green anole TRPA1 was also activated by heat and noxious chemical stimulation. These results suggest that TRPA1 was likely a noxious heat and chemical receptor and co-expressed with TRPV1 in the nociceptive sensory neurons of ancestral vertebrates. Conservation of TRPV1 heat sensitivity throughout vertebrate evolution could have changed functional constraints on TRPA1 and influenced the functional evolution of TRPA1 regarding temperature sensitivity, whereas conserving its noxious chemical sensitivity. In addition, our results also demonstrated that two mammalian TRPA1 inhibitors elicited different effect on the TRPA1s of WC frogs and green anoles, which can be utilized to clarify the structural bases for inhibition of TRPA1.

A hot new channel

How do we feel temperature? A study now finds that a recently discovered anion channel is a temperature sensor that, like previously identified cation channels, mediates the perception of noxious hot temperatures.

20-Hydroxyeicosatetraenoic Acid (20-HETE) Is a Novel Activator of Transient Receptor Potential Vanilloid 1 (TRPV1) Channel

TRPV1 is a member of the transient receptor potential ion channel family and is gated by capsaicin, the pungent component of chili pepper. It is expressed predominantly in small diameter peripheral nerve fibers and is activated by noxious temperatures >42 °C. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 4A/4F-derived metabolite of the membrane phospholipid arachidonic acid. It is a powerful vasoconstrictor and has structural similarities with other TRPV1 agonists, e.g. the hydroperoxyeicosatetraenoic acid 12-HPETE, and we hypothesized that it may be an endogenous ligand for TRPV1 in sensory neurons innervating the vasculature. Here, we demonstrate that 20-HETE both activates and sensitizes mouse and human TRPV1, in a kinase-dependent manner, involving the residue Ser(502) in heterologously expressed hTRPV1, at physiologically relevant concentrations.

Temperature- and Touch-Sensitive Neurons Couple CNG and TRPV Channel Activities to Control Heat Avoidance in Caenorhabditis elegans

BackgroundAny organism depends on its ability to sense temperature and avoid noxious heat. The nematode Caenorhabditis elegans responds to noxious temperatures exceeding ∼35°C and also senses changes in its environmental temperature in the range between 15 and 25°C. The neural circuits and molecular mechanisms involved in thermotaxis have been successfully studied, whereas details of the thermal avoidance behavior remain elusive. In this work, we investigate neurological and molecular aspects of thermonociception using genetic, cell biological and physiological approaches.Methodology/Principal FindingsWe show here that the thermosensory neurons AFD, in addition to sensing temperature within the range within which the animals can thrive, also contribute to the sensation of noxious temperatures resulting in a reflex-like escape reaction. Distinct sets of interneurons are involved in transmitting thermonociception and thermotaxis, respectively. Loss of AFD is partially compensated by the activity of a pair of multidendritic, polymodal neurons, FLP, whereas laser ablation of both types of neurons abrogated the heat response in the head of the animals almost completely. A third pair of heat sensory neurons, PHC, is situated in the tail. We find that the thermal avoidance response requires the cell autonomous function of cGMP dependent Cyclic Nucleotide-Gated (CNG) channels in AFD, and the heat- and capsaicin-sensitive Transient Receptor Potential Vanilloid (TRPV) channels in the FLP and PHC sensory neurons.Conclusions/SignificanceOur results identify distinct thermal responses mediated by a single neuron, but also show that parallel nociceptor circuits and molecules may be used as back-up strategies to guarantee fast and efficient responses to potentially detrimental stimuli.

Mast-Cell Degranulation Induced by Physical Stimuli Involves the Activation of Transient-Receptor-Potential Channel TRPV2

A characteristic of mast cells is the degranulation in response to various stimuli. Here we have investigated the effects of various physical stimuli in the human mast-cell line HMC-1. We have shown that HMC-1 express the transient receptor potential channels TRPV1, TRPV2 and TRPV4. In the whole-cell patch-clamp configuration, increasing mechanical stress applied to the mast cell by hydrostatic pressure (-30 to -90 cm H(2)O applied via the patch pipette) induced a current that could be inhibited by 10 microM of ruthenium red. This current was also inhibited by 20 microM SKF96365, an inhibitor that is among TRPV channels specific for the TRPV2. A characteristic of TRPV2 is its activation by high noxious temperature; temperatures exceeding 50 °C induced a similar ruthenium-red-sensitive current. As another physical stimulus, we applied laser light of 640 nm. Here we have shown for the first time that the application of light (at 48 mW for 20 min) induced an SKF96365-sensitive current. All three physical stimuli that led to activation of SKF96365-sensitive current also induced pronounced degranulation in the mast cells, which could be blocked by ruthenium red or SKF96365. The results suggest that TRPV2 is activated by the three different types of physical stimuli. Activation of TRPV2 allows Ca(2+) ions to enter the cell, which in turn will induce degranulation. We, therefore, suggest that TRPV2 plays a key role in mast-cell degranulation in response to mechanical, heat and red laser-light stimulation.

Inflammatory stimuli up-regulate transient receptor potential vanilloid-1 expression in human bronchial fibroblasts

ABSTRACTLung fibroblasts are involved in interstitial lung disease, chronic asthma, and chronic obstructive pulmonary disease (COPD). The expanded fibroblast population in airway disease leads to airway remodeling and contributes to the inflammatory process seen in these diseases. The cation channel transient receptor potential vanilloid-1 (TRPV1) is activated by noxious stimuli, including capsaicin, protons, and high temperatures and is thought to have a role in inflammation. Although TRPV1 expression is primarily reported to be neuronal, some extraneuronal expression has been reported. The authors therefore sought to determine whether human primary bronchial fibroblasts (HPBFs) express TRPV1 and whether inflammatory mediators can induce TRPV1 expression. The authors show that fibroblasts are predominantly TRPV1 negative; however, following stimulation with 3 common inflammatory mediators, tumor necrosis factor α (TNF-α), lipopolysaccharide (LPS), and interleukin-1α (IL-1α), TRPV1 mRNA was observed at 24 and 48 hours post treatment with all 3 mediators. Using Western blotting an increase in TRPV1 expression with all 3 inflammatory mediators was detected with significant increases seen at 72 hours post LPS and IL-1α treatment. In stark contrast to the untreated fibroblasts, significant calcium signaling in response to capsaicin and resiniferatoxin in HPBFs treated for 24 and 48 hours with TNF-α, LPS, or IL-1α was also observed. These results indicate that TRPV1 can be expressed on bronchial fibroblasts in situations where an underlying inflammatory stimulus exists, as is the case in airway diseases such as asthma and COPD.

Tonic pain and continuous EEG: Prediction of subjective pain perception by alpha-1 power during stimulation and at rest

ObjectivePain neurophysiology has been chiefly characterized via event-related potentials (ERPs), which are exerted using brief, phase-locked noxious stimuli. Striving for objectively characterizing clinical pain states using more natural, prolonged stimuli, tonic pain has been recently associated with the individual peak frequency of alpha oscillations. This finding encouraged us to explore whether alpha power, reflecting the magnitude of the synchronized activity within this frequency range, will demonstrate a corresponding relationship with subjective perception of tonic pain. MethodsFive-minute-long continuous EEG was recorded in 18 healthy volunteers under: (i) resting-state; (ii) innocuous temperature; and (iii) psychophysically-anchored noxious temperature. Numerical pain scores (NPSs) collected during the application of tonic noxious stimuli were tested for correlation with alpha-1 and alpha-2 power. ResultsNPSs and alpha power remained stable throughout the recording conditions (Ps⩾0.381). In the noxious condition, alpha-1 power obtained at the bilateral temporal scalp was negatively correlated with NPSs (Ps⩽0.04). Additionally, resting-state alpha-1 power recorded at the bilateral temporal scalp was negatively correlated with NPSs reported during the noxious condition (Ps⩽0.038). ConclusionsCurrent findings suggest alpha-1 power may serve as a direct, objective and experimentally stable measure of subjective perception of tonic pain. Furthermore, resting-state alpha-1 power might reflect individuals’ inherent tonic pain responsiveness. SignificanceThe relevance of alpha-1 power to tonic pain perception may deepen the understanding of the mechanisms underlying the processing of prolonged noxious stimulation.

The interrealtionship between locally applied heat, ageing and skin blood flow on heat transfer into and from the skin

In response to a thermal stress, skin blood flow (BF) increases to protect the skin from damage. When a very warm, noxious, heat source (44°C) is applied to the skin, the BF increases disproportionately faster than the heat stress that was applied, creating a safety mechanism for protecting the skin. In the present investigation, the rate of rise of BF in response to applied heat at temperatures between 32°C and 40°C was examined as well as the thermal transfer to and from the skin with and without BF in younger and older subjects to see how the skin responds to a non-noxious heat source. Twenty male and female subjects (10 – 20–35 years, 10 – 40–70 years) were examined. The arms of the subjects were passively heated for 6 min with and without vascular occlusion by a thermode at temperatures of 32, 36, 38 or 40°C. When occlusion was not used during the 6 min exposure to heat, there was an exponential rise in skin temperature and BF in both groups of subjects over the 6-min period. However, the older subjects achieved similar skin temperatures but with the expenditure of fewer calories from the thermode than was seen for the younger subjects (p < 0.05). BF was significantly less in the older group than the younger group at rest and after exposure to each of the three warmest thermode temperatures (p < 0.05). As was seen for noxious temperatures, after a delay, the rate of rise of BF at the three warmest thermode temperatures was faster than the rise in skin temperature in the younger group but less in the older group of subjects. Thus, a consequence of ageing is reduced excess BF in response to thermal stress increasing susceptibility to thermal damage. This must be considered in modelling of BF.