Cold Pain Perception Research Articles

TMC6 functions as a GPCR-like receptor to sense noxious heat via Gαq signaling

Thermosensation is vital for the survival, propagation, and adaption of all organisms, but its mechanism is not fully understood yet. Here, we find that TMC6, a membrane protein of unknown function, is highly expressed in dorsal root ganglion (DRG) neurons and functions as a Gαq-coupled G protein-coupled receptor (GPCR)-like receptor to sense noxious heat. TMC6-deficient mice display a substantial impairment in noxious heat sensation while maintaining normal perception of cold, warmth, touch, and mechanical pain. Further studies show that TMC6 interacts with Gαq via its intracellular C-terminal region spanning Ser780 to Pro810. Specifically disrupting such interaction using polypeptide in DRG neurons, genetically ablating Gαq, or pharmacologically blocking Gαq-coupled GPCR signaling can replicate the phenotype of TMC6 deficient mice regarding noxious heat sensation. Noxious heat stimulation triggers intracellular calcium release from the endoplasmic reticulum (ER) of TMC6- but not control vector-transfected HEK293T cell, which can be significantly inhibited by blocking PLC or IP3R. Consistently, noxious heat-induced intracellular Ca2+ release from ER and action potentials of DRG neurons largely reduced when ablating TMC6 or blocking Gαq/PLC/IP3R signaling pathway as well. In summary, our findings indicate that TMC6 can directly function as a Gαq-coupled GPCR-like receptor sensing noxious heat.

Virtual reality hypnosis diminishes experimental cold pain and alters autonomic responses.

Immersive virtual reality (VR) is a promising tool to reduce pain in clinical setting. Digital scripts displayed by VR disposals can be enriched by several analgesic interventions, which are widely used to reduce pain. One of these techniques is hypnosis induced through the VR script (VRH) which is facilitated by immersive environment and particularly efficient even for low hypnotizable patients. The aim of this study is to assess the efficacy of a VRH script on experimentally induced cold pain perception (intensity and unpleasantness) and physiological expression. 41 healthy volunteers had been recruited in this within-subjects study. They received 9 stimulations of 20 s (3 non-nociceptive cold; 3 low nociceptive cold and 3 highly nociceptive cold) during a VRH session of 20 min (VRH condition) or without VRH (noVRH condition). Physiological monitoring during the cold pain stimulation protocol consisted of recording heart rate, heart rate variability and respiratory frequency. Maximum cold pain intensity perception, measured through the visual analog scale (VAS) on 10, was of 3.66 ± 1.84 (VAS score/10) in noVRH condition and 2.46 ± 1.54 in VRH (Wilcoxon, p < 0.0001). Considering pain unpleasantness perception, 3.68 ± 2.06 in noVRH and 2.21 ± 1.63 in VRH (Wilcoxon, p < 0.0001). Hypnotizability negatively correlated with the decrease in VAS intensity from noVRH to VRH (Spearman r = -0.45; p = 0.0038). In our sample, we found that 31/41 volunteers (75.6%) displayed a reduction of more than 10% of their VAS pain intensity and unpleasantness scores. Trait anxiety was the best predictor of the VRH responders, as well as heart rate variability. In addition, respiratory rate was diminished under VRH in every subgroup. VRH is an effective tool to reduced pain intensity and unpleasantness in a vast majority of healthy subjects. We further indicate in this study that heart rate variability parameter RMSSD (root mean square of successive differences) is a good predictor of this effect, as well as anxiety as a personality trait (but not state anxiety). Further studies are expected to determine more precisely to whom it will be the most useful to offer tailored, non-pharmacological pain management solutions to patients.

A novel thermoelectric device integrated with a psychophysical paradigm to study pain processing in human subjects

IntroductionCerebral projections of nociceptive stimuli are of great interest as targets for neuromodulation in chronic pain. To study cerebral networks involved in processing noxious stimuli, researchers often rely on thermo-nociception to induce pain. However, various limitations exist in many pain-inducing techniques, such as not accounting for individual variations in pain and trial structure predictability. MethodsWe propose an improved and reliable psychometric experimental method to evaluate human nociceptive processing to overcome some of these limitations. The developed testing paradigm leverages a custom-built, open-source, thermoelectric device (TED). The device construction and hardware are described. A maximum-likelihood adaptive algorithm is integrated into the TED software, facilitating individual psychometric functions representative of both hot and cold pain perception. In addition to testing only hot or cold thresholds, the TED may also be used to induce the thermal grill illusion (TGI), where the bars are set to alternating warm and cool temperatures. ResultsHere, we validated the TED's capability to adjust between different temperatures and showed that the device quickly and automatically changes temperature without any experimenter input. We also validated the device and integrated psychometric pain task in 21 healthy human subjects. Hot and cold pain thresholds (HPT, CPT) were determined in human subjects with <1 °C of variation. Thresholds were anticorrelated, meaning a volunteer with a low CPT likely had a high HPT. We also showed how the TED can be used to induce the TGI. ConclusionThe TED can induce thermo-nociception and provide probabilistic measures of hot and cold pain thresholds. Based on the findings presented, we discuss how the TED could be used to study thermo-nociceptive cerebral projections if paired with intracranial electrode monitoring.

Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels

Thermosensitive transient receptor potential V3 (TRPV3) is a polymodal receptor implicated in nociceptive, thermoceptive, pruritoceptive, and inflammatory pathways. Reports focused on understanding the role of TRPV3 in thermoception or nociception are not conclusive. Previous studies also show that aberrant hyperactivity of TRPV3 channels results in spontaneous itch and dermatitis-like symptoms, but the resultant behavior is highly dependent on the background of the animal and the skin microbiome. To determine the function of hyperactive TRPV3 channels in somatosensory sensations, we tested different somatosensory behaviors using a genetic mouse model that carries a gain-of-function point mutation G573S in the Trpv3 gene (Trpv3G573S). Here we report that Trpv3G573S mutants show reduced perception of cold, acetone-induced cooling, punctate, and sharp mechanical pain. By contrast, locomotion, noxious heat, touch, and mechanical itch are unaffected in Trpv3G573S mice. We fail to observe any spontaneous itch responses and/or dermatitis in Trpv3G573S mutants under specific pathogen (Staphylococcus aureus)-free conditions. However, we find that the scratching events in response to various pruritogens are dramatically decreased in Trpv3G573S mice in comparison to wild-type littermates. Interestingly, we observe sensory hypoinnervation of the epidermis in Trpv3G573S mutants, which might contribute to the deficits in acute mechanical pain, cool, cold, and itch sensations.

Evaluation of Acute Tonic Cold Pain From Microwave Transcranial Transmission Signals Using Multi-Entropy Machine Learning Approach

This study aims to improve the accuracy of detecting acute tonic cold pain (CP) perception from microwave transcranial transmission (MTT) signals. Two different types of CP and no-pain (NP) MTT signals are obtained from 15 subjects. Four features, namely, power spectral exponential entropy, improved multiscale permutation entropy, refined composite multiscale dispersion entropy, and refined composite multiscale fuzzy entropy, are extracted in the variational modal decomposition domain. The feature datasets are divided into training datasets and test datasets in a 3:1 ratio. Random forest (RF) and support vector machine (SVM) are selected as classifiers. The training datasets are imported into the classifier, and the optimal training dataset is obtained with a 10-fold cross validation strategy. The feature dimension reduction algorithm of the principal component analysis is used to reduce the complexity of the feature datasets and select the most recognizable features. The classification performance of the test datasets is evaluated by the optimal classifiers. Results showed that the RF classifier performs better than the SVM classifier. The RF classifier provides high values of specificity (91.67%), sensitivity (95.83%), positive predictive value (92.00%), accuracy (93.75%), and area under curve (0.867). The combination of the microwave detection approach and machine learning algorithm can effectively detect brain activity induced by nociceptive stimulation. This approach is important in improving the accuracy of pain detection.

Epidermal expression of human TRPM8, but not of TRPA1 ion channels, is associated with sensory responses to local skin cooling.

Human cold perception and nociception play an important role in persisting pain. However, species differences in the target temperature of thermosensitive ion channels expressed in peripheral nerve endings have fueled discussions about the mechanism of cold nociception in humans. Most frequently implicated thermosensors are members of the transient receptor potential (TRP) ion channel family TRPM8 and TRPA1. Regularly observed, distinct cold pain phenotype groups suggested the existence of interindividually differing molecular bases. In 28 subjects displaying either high or medium sensitivity to local cooling of the skin, the density at epidermal nerve fibers of TRPM8, but not that of TRPA1 expression, correlated significantly with the cold pain threshold. Moreover, reproducible grouping of the subjects, based on high or medium sensitivity to cooling, was reflected in an analogous grouping based on high or low TRPM8 expression at epidermal nerve fibers. The distribution of TRPM8 expression in epidermal nerve fibers provided an explanation for the previously observed (bi)modal distribution of human cold pain thresholds which was reproduced in this study. In the light of current controversies on the role of human TRPA1 ion channels in cold pain perception, the present observations demonstrating a lack of association of TRPA1 channel expression with cold sensitivity-related measures reinforce doubts about involvement of this channel in cold pain in humans. Since TRP inhibitors targeting TRPM8 and TRPA1 are currently entering clinical phases of drug development, the existence of known species differences, in particular in the function of TRPA1, emphasizes the increasing importance of new methods to directly approach the roles of TRPs in humans.

Detection of Acute Tonic Cold Pain From Microwave Transcranial Transmission Signals Obtained via the Microwave Scattering Approach

To investigate the feasibility of detecting acute tonic cold pain (CP) perception from recordable microwave transcranial transmission (MTT) signals by using machine learning techniques. CP and no-pain (NP) MTT signals collected from 15 young subjects are analyzed in the wavelet packet transformation (WPT) and variational mode decomposition (VMD) domains. In addition, features such as relative energy change, refined composite multiscale dispersion entropy, refined composite multiscale fuzzy entropy, and autoregressive model coefficients are extracted in the WPD, VMD, VMD-WPD, and WPD-VMD domains. Simultaneously, support vector machine (SVM) is selected as the classifier, and feature indexes are input into the classifier by using the 10-fold cross validation method to obtain the best training and test datasets. Principal component analysis is used to reduce the feature dimensions of the training and test datasets and to improve classification accuracy. Then, the test dataset is imported into the trained classifier for the calculation and evaluation of the model's classification performance. In the validation of the SVM classifier, feature extraction in the WPD-VMD domain is the best pain detection algorithm. It provides high values of sensitivity (91.30%), specificity (90.47%), positive predictive value (91.30%), accuracy (90.90%), and area under curve (0.806). The microwave scattering technique can be used as a direct, objective, and experimentally stable method to detect acute CP perception, this approach has a high application prospect for clinical real-time diagnosis.

Changes of EEG band oscillations to tonic cold pain and the behavioral inhibition and fight-flight-freeze systems.

Using electroencephalography (EEG) power measures within conventional delta, theta, alpha, beta, and gamma bands, the aims of the current study were to highlight cortical correlates of subjective perception of cold pain (CP) and the associations of these measures with behavioral inhibition system (BIS), fight-flight-freeze system (FFFS), and behavioral approach system personality traits. EEG was recorded in 55 healthy right-handed women under (i) a white noise interruption detection condition (Baseline); (ii) enduring CP induced by the cold cup test. CP and Baseline EEG band power scores within conventional frequency bands served for covariance analyses. We found that: (1) higher Pain scorers had higher EEG beta power changes at left frontal, midline central, posterior temporal leads; (2) higher BIS was associated with greater EEG delta activity changes at parietal scalp regions; (3) higher FFFS was associated with higher EEG delta activity changes at temporal and left-parietal regions, and with lower EEG gamma activity changes at right parietal regions. High FFFS, compared to Low FFFS scorers, also showed a lower gamma power across the midline, posterior temporal, and parietal regions. Results suggest a functional role of higher EEG beta activity in the subjective perception of tonic pain. EEG delta activity underpins conflict resolution system responsible for passive avoidance control of pain, while higher EEG delta and lower EEG gamma activity changes, taken together, underpin active avoidance system responsible for pain escape behavior.

Epidermal Expression of TRPM8 But Not of TRPA1 Ion Channels is Associated with Human Cold Pain Sensitivity Patterns

Human cold perception and nociception play an important role in persisting pain. However, species differences in the target temperature of thermosensitive ion channels expressed at peripheral nerve endings have fueled discussions about the mechanism of cold nociception in humans. Most frequently implicated thermosensors are the members of the transient receptor potential (TRP) ion channel family TRPM8 and TRPA1. Reproducibly observed distinct cold pain phenotype groups hinted at inter individually differing molecular bases. In 28 subjects displaying either high or medium cold pain sensitivity, the density of TRPM8 but not that of TRPA1 expression at dermal nerve fibers correlated significantly with the cold pain threshold. Moreover, a reproducible grouping of the subjects based on high or medium cold pain sensitivity was reflected in an analogous grouping based on high or low TRPM8 expression at dermal nerve fibers. The distribution of TRPM8 expression in dermal nerve fibers provided a sufficient explanation of the previously observed and presently reproduced (bi)modal distribution of human cold pain thresholds. Considering current controversies about the role of human TRPA1 ion channels in cold pain perception, the present observations with a lack of association of TRPA1 channel expression with pain related measures fuels doubts about its involvement in cold pain in humans. Considering that TRP inhibitors targeting TRPM8 and TRPA1 are currently entering clinical phases of drug development, known species differences, in particular in the function of TRPA1, emphasize an increasing importance of research methods developed to approach TRPs directly in humans. Funding Statement: This work has been funded by the Else Kroner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation – Pharma (TRIP, JL) and by the Landesoffensive zur Entwicklung wissenschaftlich - okonomischer Exzellenz (LOEWE), LOEWE-Zentrum fur Translationale Medizin und Pharmakologie (JL). Declaration of Interests: The authors have declared that no competing interests exist. Ethics Approval Statement: The study followed the Declaration of Helsinki and was approved by the Ethics Committee of the Medical Faculty of the Goethe – University Frankfurt am Main, Germany (protocol number 110/16).

Longer Sleep Duration and Later Sleep Timing are Associated with Increased Cold-Pain Perception During the Day

Experimental studies on the associations between sleep and evoked pain in healthy individuals have generally demonstrated increased pain sensitivity following sleep deprivation, yet few have addressed the association between habitual sleep patterns and next-day pain sensitivity. This study aimed to assess relationships between habitual sleep quantity, quality, and timing based on objective measurement of sleep (actigraphy) and experimentally evoked cold-pain perception during the day in healthy young men. Forty-eight healthy, young male participants without pain or sleep disturbance were examined via cold pressor test to obtain measures of cold-pain threshold, tolerance, and intensity in the morning, afternoon, and evening, in a randomized-order repeated-measures design. Sleep characteristics were assessed by actigraphy for 7 days prior to testing. Correlations (Spearman) were computed between all sleep and pain measures. Sleep measures that significantly correlated with pain were entered as covariates in repeated-measures (RM) ANOVA. Longer sleep duration and later sleep timing were associated with increased sensitivity to evoked cold-pain tests at different times of the day (p < 0.05). After controlling for age, BMI, and weekday–weekend differences in sleep duration and bedtime, longer sleep duration, and later wake time were associated with lower pain threshold, and later bed- and wake times were associated with lower pain tolerance (p < 0.05). Sleep quality was not associated with any pain measures. Objectively measured habitual sleep duration and timing are associated with cold-pain perception in healthy young men. Further investigation is needed to elucidate the mechanism underlying the detrimental effects of long sleep duration and late sleep timing on pain perception.

Night-shift work increases cold pain perception

BackgroundAlthough night-shift work (NSW) is associated with a higher risk for several physical and mental disorders, the impact of NSW on pain perception is still unclear. This study investigates the impact of NSW on cold pain perception considering the impact of mood and sleepiness. MethodQuantitative sensory testing (QST) was performed in healthy night-shift workers. Cold pain threshold as well as tonic cold pain was assessed after one habitual night (T1), after a 12-hour NSW (T2) and after one recovery night (T3). Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI) before T1, sleepiness with the Stanford Sleepiness Scale (SSS) and mood with a German short-version of the Profile of Mood States (ASTS) at T1, T2 and T3. Depending on the distribution of the data, ANOVAs or Friedman tests as well as t- or Wilcoxon tests were performed. ResultsNineteen healthy shift-workers (13 females; 29.7 ± 7.5 years old; 8.1 ± 6.6 years in shift work, PSQI: 4.7 ± 2.2) were included. Tonic cold pain showed a significant difference between T1 (48.2 ± 27.5 mm), T2 (61.7 ± 26.6 mm; effect size: Cohen's d=.49; percent change 28%), and T3 (52.1 ± 28.7 mm) on a 0–100 mm Visual Analog Scale (p = 0.007). Cold pain threshold changed from 11.0 ± 7.9 °C (T1) to 14.5 ± 8.8 °C (T2) (p = 0.04), however, an ANOVA comparing T1, T2, and T3 was not significant (p = 0.095). Sleepiness (SSS) and mood (ASTS) changed significantly between T1, T2 and T3 (p-values < 0.01). The change of mood but not of sleepiness correlated with the difference in tonic cold pain from T1 to T2 (R: 0.53; R2: 0.29; p = 0.022). DiscussionNSW increases cold pain perception. The same tonic cold pain stimulus is rated 28% more painful after NSW and normalizes after a recovery night. Increases in cold pain perception due to NSW appear to be more strongly related to changes in mood as compared to changes in sleepiness.

Machine-learned analysis of quantitative sensory testing responses to noxious cold stimulation in healthy subjects.

Pain in response to noxious cold has a complex molecular background probably involving several types of sensors. A recent observation has been the multimodal distribution of human cold pain thresholds. This study aimed at analysing reproducibility and stability of this observation and further exploration of data patterns supporting a complex background. Pain thresholds to noxious cold stimuli (range 32-0°C, tonic: temperature decrease -1°C/s, phasic: temperature decrease -8°C/s) were acquired in 148 healthy volunteers. The probability density distribution was analysed using machine-learning derived methods implemented as Gaussian mixture modeling (GMM), emergent self-organizing maps and self-organizing swarms of data agents. The probability density function of pain responses was trimodal (mean thresholds at 25.9, 18.4 and 8.0°C for tonic and 24.5, 18.1 and 7.5°C for phasic stimuli). Subjects' association with Gaussian modes was consistent between both types of stimuli (weighted Cohen's κ=0.91). Patterns emerging in self-organizing neuronal maps and swarms could be associated with different trends towards decreasing cold pain sensitivity in different Gaussian modes. On self-organizing maps, the third Gaussian mode emerged as particularly distinct. Thresholds at, roughly, 25 and 18°C agree with known working temperatures of TRPM8 and TRPA1 ion channels, respectively, and hint at relative local dominance of either channel in respective subjects. Data patterns suggest involvement of further distinct mechanisms in cold pain perception at lower temperatures. Findings support data science approaches to identify biologically plausible hints at complex molecular mechanisms underlying human pain phenotypes. Sensitivity to pain is heterogeneous. Data-driven computational research approaches allow the identification of subgroups of subjects with a distinct pattern of sensitivity to cold stimuli. The subgroups are reproducible with different types of noxious cold stimuli. Subgroups show pattern that hints at distinct and inter-individually different types of the underlying molecular background.

Cutaneous microvascular response during local cold exposure - the effect of female sex hormones and cold perception

It is generally known that differences exist between males and females with regard to sensitivity to cold. Similar differences even among females in different hormonal balance might influence microvascular response during cold provocation testing.The aim of the present study was to measure sex hormone levels, cold and cold pain perception thresholds and compare them to cutaneous laser-Doppler flux response during local cooling in both the follicular and luteal phases of the menstrual cycle.In the luteal phase a more pronounced decrease in laser-Doppler flux was observed compared to follicular phase during local cooling at 15°C (significant difference by Dunnett's test, p<0.05). In addition, statistically significant correlations between progesterone level and laser-Doppler flux response to local cooling were observed during the follicular (R=−0.552, p=0.0174) and during the luteal phases (R=0.520, p=0.0271). In contrast, the correlation between estradiol level and laser-Doppler flux response was observed only in the follicular phase (R=−0.506, p=0.0324).Our results show that individual sensitivity to cold influences cutaneous microvascular response to local cooling; that microvascular reactivity is more pronounced during the luteal phase of the menstrual cycle; and that reactivity correlates with hormone levels. The effect of specific sex hormone levels is related to the cold-provocation temperature.

Impact of concurrent cognitive processing on cold pain perception: Implications for pain management and its neurobiological basis

ABSTRACTFindings for heat pain have shown consistent pain attenuation through concurrent cognitive task completion; but only a minimal amount of studies have explored that for cold pain. This study investigated the direct impact of two well-established cognitive tasks on cold pain tolerance. In a within-subject design, 36 female Hong Kong locals were required to complete a baseline pain tolerance measurement, induced by the well-established Cold Pressor Test. This was followed by the counterbalanced presentation of the Colour Stroop or the Judgment of Line Orientation task with and without concurrent pain administration. As suggested by the Limited Capacity, Multiple Resource, and Cognitive-Affective Models, participants were expected to tolerate pain for significantly longer durations when they perform either concurrent Colour Stroop or concurrent Judgment of Line Orientation tasks compared to baseline measures with no concurrent task. The findings clearly indicated increased pain tolerance times during task completion compared with baseline measures, providing support for the a-priori hypothesis. The results contribute to existing literature by confirming increased cold pain tolerance during selective attention to cognitive tasks and extending this finding to tasks previously established in heat pain but not for cold pain research.

PTU-019 Pain, perception and reality – comparison of comfort scores of south asian and white british patients undergoing bowel cancer screening colonoscopy:

<h3>Introduction</h3> There have been several studies suggesting South Asian patients have differing pain perception to White British patients.¹Watson <i><i>et al</i>.</i>compared hot and cold pain perception in 20 age-matched South Asian and White British volunteers, with significantly increased heat pain scores and reduced pain threshold.² Recently, Al-Hashimi <i><i>et al</i></i>showed no significant differences in post-operative pain scores and analgesia consumption in 60 South Asian patients undergoing total abdominal hysterectomy versus 60 age-matched White British controls.³ Sedation and analgesia administration is well regulated in colonoscopy practice and comparing comfort scores in similar aged South Asian and White British screening patients is of interest to bowel cancer screening programme (BCSP) centres in ethnically diverse areas. <h3>Method</h3> In 2014, colonoscopy screened individuals (BCSP) in Leicester and Kettering had their self-selected ethnic origin recorded. Comfort scores of 713 patients recorded in the Exeter online database was correlated to ethnic origin data and analysed. <h3>Results</h3> Total number of patients: 713 Difference between means: 0.26 (95% CI: 0.05–0.47) <h3>Conclusion</h3> This analysis shows mean comfort scores are significantly <i>lower</i>in South Asian patients (p = &lt;0.02). This is counter to what published literature might suggest. We reported in 2014 that South Asian patients undergoing BCSP colonoscopy have significantly lower adenoma detection rates when compared to White British patients (31.68% vs 48.09% p = &lt;0.02). ⁴Perhaps fewer adenomas requiring polypectomy lead to more straightforward colonoscopy and lower comfort scores. Whatever the explanation, this analysis shows that pain perception is complex. The interaction of patient ethnicity factors (behavioural, cultural, social and psychological) are not easily predicted and requires further study. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Edwards CL, Fillingim RB, Keefe F. Race, ethnicity and pain. Pain 2001; 94: 133–137 Watson PJ, Latif RK, Rowbotham DJ. Ethnic differences in thermal pain responses: a comparison of South Asian and White British healthy males. Pain 2005;118:194–200 Al-Hashimi M, Scott S, Griffin-Teall N, Thompson J. Influence of ethnicity on the perception and treatment of early post-operative pain. Pain 2014. doi: 10.1177/2049463714559254 Verma AM, Lewin V, Chilton AP, de Caestecker J, Dixon A, Jameson J, Wurm P, Robinson RJ. Variations in adenoma detection rate and cancer detection rate in individuals from different ethnic groups undergoing bowel cancer screening colonoscopy. Gut 2014;<b>63</b>(Suppl 1):A122

Multimodal distribution of human cold pain thresholds.

BackgroundIt is assumed that different pain phenotypes are based on varying molecular pathomechanisms. Distinct ion channels seem to be associated with the perception of cold pain, in particular TRPM8 and TRPA1 have been highlighted previously. The present study analyzed the distribution of cold pain thresholds with focus at describing the multimodality based on the hypothesis that it reflects a contribution of distinct ion channels.MethodsCold pain thresholds (CPT) were available from 329 healthy volunteers (aged 18 – 37 years; 159 men) enrolled in previous studies. The distribution of the pooled and log-transformed threshold data was described using a kernel density estimation (Pareto Density Estimation (PDE)) and subsequently, the log data was modeled as a mixture of Gaussian distributions using the expectation maximization (EM) algorithm to optimize the fit.ResultsCPTs were clearly multi-modally distributed. Fitting a Gaussian Mixture Model (GMM) to the log-transformed threshold data revealed that the best fit is obtained when applying a three-model distribution pattern. The modes of the identified three Gaussian distributions, retransformed from the log domain to the mean stimulation temperatures at which the subjects had indicated pain thresholds, were obtained at 23.7 °C, 13.2 °C and 1.5 °C for Gaussian #1, #2 and #3, respectively.ConclusionsThe localization of the first and second Gaussians was interpreted as reflecting the contribution of two different cold sensors. From the calculated localization of the modes of the first two Gaussians, the hypothesis of an involvement of TRPM8, sensing temperatures from 25 – 24 °C, and TRPA1, sensing cold from 17 °C can be derived. In that case, subjects belonging to either Gaussian would possess a dominance of the one or the other receptor at the skin area where the cold stimuli had been applied. The findings therefore support a suitability of complex analytical approaches to detect mechanistically determined patterns from pain phenotype data.

The Nav1.9 channel is a key determinant of cold pain sensation and cold allodynia.

Cold-triggered pain is essential to avoid prolonged exposure to harmfully low temperatures. However, the molecular basis of noxious cold sensing in mammals is still not completely understood. Here, we show that the voltage-gated Nav1.9 sodium channel is important for the perception of pain in response to noxious cold. Nav1.9 activity is upregulated in a subpopulation of damage-sensing sensory neurons responding to cooling, which allows the channel to amplify subthreshold depolarizations generated by the activation of cold transducers. Consequently, cold-triggered firing is impaired in Nav1.9(-/-) neurons, and Nav1.9 null mice and knockdown rats show increased cold pain thresholds. Disrupting Nav1.9 expression in rodents also alleviates cold pain hypersensitivity induced by the antineoplastic agent oxaliplatin. We conclude that Nav1.9 acts as a subthreshold amplifier in cold-sensitive nociceptive neurons and is required for the perception of cold pain under normal and pathological conditions.

Discriminative validity of sensory evaluation in a whiplash-associated disorder II population

Aim: Evidence suggests chronic whiplash is associated with sensory hypersensitivity. Understanding the degree of sensory impairment could enhance rehabilitation strategies. This preliminary study determined whether differences in sensory evaluation occur post whiplash injury. Methods: Single-blinded, case control observational study using a convenience sample of 20 participants (median age 28.5 years, low disability) with chronic grade II whiplash-associated disorder (CWADII) and 22 control participants (median age 26 years) with no history of whiplash/neck injury. Outcome measures included vibration and cold pain perception threshold, and joint position error. Results: Significant associations using Kendall's tau correlation coefficient were found between: vibration thresholds (thenar and hypothenar eminences) for the CWADII group (p&lt;0.01); cold pain thresholds (thenar, 5th metacarpophalangeal, mid cervical spine) in both groups (p&lt;0.01); joint positioning errors (global positioning following right/left rotations, left rotation/extension) (p&lt;0.01) in the CWADII group; and between vertical direction errors (following right/left rotation) in both groups (p&lt;0.01). Discrimination between groups was not identified using separate logistic regressions on vibration or cold pain thresholds (thenar eminence) or on global flexion/extension/right rotation position errors (p&gt;0.01). Conclusions: The findings do not support the use of vibration, cold pain threshold or joint position error to identify individuals with CWADII with low disability.

Insula and sensory insular cortex and somatosensory control in patients with insular stroke

In functional imaging studies, the insular cortex (IC) has been identified as an essential part of the processing of a whole spectrum of multimodal sensory input. However, there are no lesion studies including a sufficient number of patients, which would reinforce the functional imaging data obtained from healthy subjects. Such lesion studies should examine how damage to the IC affects sensory perception. We chose acute stroke patients with lesions affecting the IC in order to fill this gap. A comprehensive sensory profiling by applying a quantitative sensory testing protocol was performed and a voxel-lesion behaviour mapping analysis in 24 patients with acute unilateral cortical damage was applied. Our data demonstrate that patients with lesions of the posterior IC have deficits in temperature perception, but did not show other sensory deficits such as hot or cold pain perception associated with specific lesion locations. Our data allow the conclusion that the posterior IC may represent the major region responsible for encoding warm and cold perception in the brain. To what extent focal IC lesions may also impair pain processing or induce post-stroke pain has to be addressed in future studies including more patients.

Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L‐menthol and trans‐cinnamaldehyde in healthy volunteers

Activation of TRPM8 and TRPA1 receptors generates cold and cold pain sensations, respectively, and is presumably important in clinical pain manifestations, such as cold hyperalgesia. This study investigated the interaction between TRPM8 and TRPA1 receptors through stimulation of glabrous human skin (volar forearm) by topical administration of 40% L-menthol and 10% trans-cinnamaldehyde (CA), individually and in combination. Sensory manifestations were assessed in 10 healthy volunteers via a platform of 11 quantitative sensory (thermal and mechanical stimuli) and vasomotor tests (skin temperature, perfusion and axon-reflex-flare) in a double-blinded randomized crossover design. Cold pain threshold was increased (p < 0.01, cold allodynia) by L-menthol alone and L-menthol + CA in combination but unaffected by CA. Mechanical pain threshold was significantly decreased (mechanical hyperalgesia) by all three substances (p < 0.01), with a significant intergroup difference found between CA alone and the less decreased L-menthol + CA (p < 0.05). Application of CA alone and L-menthol + CA in combination showed an increase in skin temperature and perfusion significantly larger than that induced by L-menthol alone (p < 0.05). An axon-reflex-flare was present after CA administration, but was significantly reduced upon addition of L-menthol (p < 0.01). This study elucidates the potential of L-menthol as a counter-irritant to secondary neurogenic inflammation and provides evidence of an intricate interplay between cold receptors TRPA1 and TRPM8, warranting further investigation of the neural coding of cold pain perception.