Pain Sensitivity In Humans Research Articles

Morphine-induced hyperalgesia impacts small extracellular vesicle miRNA composition and function.

Morphine and other synthetic opioids are widely prescribed to treat pain. Prolonged morphine exposure can paradoxically enhance pain sensitivity in humans and nociceptive behavior in rodents. To better understand the molecular mechanisms underlying opioid-induced hyperalgesia, we investigated changes in miRNA composition of small extracellular vesicles (sEVs) from the serum of mice after a morphine treatment paradigm that induces hyperalgesia. We observed significant differential expression of 18 miRNAs in sEVs from morphine-treated mice of both sexes compared to controls. Several of these miRNAs were bioinformatically predicted to regulate cyclic AMP response element binding protein (CREB), a well-characterized transcription factor implicated in pain and drug addiction. We confirmed the binding and repression of Creb mRNA by miR-155 and miR-10a. We tested if serum-derived sEVs from morphine-treated mice could elicit nociceptive behavior in naïve recipient mice. Intrathecal injection of 1 μg sEVs did not significantly impact basal mechanical and thermal threshold in naïve recipient mice. However, prophylactic 1 μg sEV administration in recipient mice resulted in faster resolution of complete Freund's adjuvant-induced mechanical and thermal inflammatory hypersensitivity. Other behaviors assayed following administration of these sEVs were not impacted including sEV conditioned place preference and locomotor sensitization. These results indicate that morphine regulation of serum sEV composition can contribute to analgesia and suggest a potential for sEVs to be a non-opioid therapeutic intervention strategy to treat pain.

Functional Changes of White Matter Are Related to Human Pain Sensitivity during Sustained Nociception.

Pain is considered an unpleasant perceptual experience associated with actual or potential somatic and visceral harm. Human subjects have different sensitivity to painful stimulation, which may be related to different painful response pattern. Excellent studies using functional magnetic resonance imaging (fMRI) have found the effect of the functional organization of white matter (WM) on the descending pain modulatory system, which suggests that WM function is feasible during pain modulation. In this study, 26 pain sensitive (PS) subjects and 27 pain insensitive (PIS) subjects were recruited based on cold pressor test. Then, all subjects underwent the cold bottle test (CBT) in normal (26 degrees temperature stimulating) and cold (8 degrees temperature stimulating) conditions during fMRI scan, respectively. WM functional networks were obtained using K-means clustering, and the functional connectivity (FC) was assessed among WM networks, as well as gray matter (GM)-WM networks. Through repeated measures ANOVA, decreased FC was observed between the GM-cerebellum network and the WM-superior temporal network, as well as the WM-sensorimotor network in the PS group under the cold condition, while this difference was not found in PIS group. Importantly, the changed FC was positively correlated with the state and trait anxiety scores, respectively. This study highlighted that the WM functional network might play an integral part in pain processing, and an altered FC may be related to the descending pain modulatory system.

Modeling homeostatic and circadian modulation of human pain sensitivity.

Mathematical modeling has played a significant role in understanding how homeostatic sleep pressure and the circadian rhythm interact to influence sleep-wake behavior. Pain sensitivity is also affected by these processes, and recent experimental results have measured the circadian and homeostatic components of the 24 h rhythm of thermal pain sensitivity in humans. To analyze how rhythms in pain sensitivity are affected by disruptions in sleep behavior and shifts in circadian rhythms, we introduce a dynamic mathematical model for circadian and homeostatic regulation of sleep-wake states and pain intensity. The model consists of a biophysically based, sleep-wake regulation network model coupled to data-driven functions for the circadian and homeostatic modulation of pain sensitivity. This coupled sleep-wake-pain sensitivity model is validated by comparison to thermal pain intensities in adult humans measured across a 34 h sleep deprivation protocol. We use the model to predict dysregulation of pain sensitivity rhythms across different scenarios of sleep deprivation and circadian rhythm shifts, including entrainment to new environmental light and activity timing as occurs with jet lag and chronic sleep restriction. Model results show that increases in pain sensitivity occur under conditions of increased homeostatic sleep drive with nonlinear modulation by the circadian rhythm, leading to unexpected decreased pain sensitivity in some scenarios. This model provides a useful tool for pain management by predicting alterations in pain sensitivity due to varying or disrupted sleep schedules.

Disentangling the roles of circadian rhythms and sleep drive in experimental pain sensitivity

Differentiating between circadian rhythm and sleep's effect on pain is challenging, as these two systems can be tightly coupled. A recent study by Daguet et al. found that circadian rhythm, rather than sleep drive, significantly contributed to the variability of experimental heat pain sensitivity in humans. These results support chrono-pharmacological approaches to pain management.

Circadian rhythmicity of pain sensitivity in humans.

Pain intensity has been reported to fluctuate during the day in some experimental and clinical conditions, but the mechanisms underlying these fluctuations are unknown. Although the circadian timing system is known to regulate a wide range of physiological functions, its implication in pain regulation is largely unknown. Using highly controlled laboratory constant-routine conditions, we show that pain sensitivity is rhythmic over the 24 h and strongly controlled by the endogenous circadian timing system. We found that the circadian component of pain sensitivity can be modelled with a sinusoidal function, with a maximum in the middle of the night and a minimum in the afternoon. We also found a weak homeostatic control of pain sensitivity, with a linear increase over the 34 h of prolonged wakefulness, which slowly builds up with sleep pressure. Using mathematical modelling, we describe that the circadian system accounts for ∼80% of the full magnitude of pain sensitivity over the 24 h, and that sleep-related processes account for only ∼20%. Overall, our data reveal the neurobiological mechanisms involved in driving the rhythmicity of pain perception in humans. We show that pain sensitivity is controlled by two superimposed processes: a strong circadian component and a modest homeostatic sleep-related component. Our findings highlight the need to consider time of day in pain assessment, and indicate that personalized circadian medicine may be a promising approach to pain management.

The Diurnal Profile of Human Basal Pain Sensitivity and Skin Sympathetic Nerve Activity: A Healthy Volunteer Study.

ObjectiveThe diurnal rhythm profile of human basal pain sensitivity and its association with sympathetic nerve activity are not fully understood. This study aimed to examine rhythmic changes in experimental pain sensitivity and skin sympathetic nerve activity in healthy volunteers.MethodsThirty healthy volunteers were included in the study. Experimental pain sensitivity, including pressure pain threshold and tolerance, cold pain threshold (CPT) and tolerance, skin sympathetic nerve activity, and cardiovascular parameters (including heart rate, cardiac output, and peripheral vascular resistance) at six time points throughout the day (08:00, 12:00, 16:00, 20:00, 00:00, and 04:00) were sequentially measured. Circadian rhythm analysis was performed on the mean values of the different measurements and individual subjects.ResultsSignificant differences were found in experimental pain sensitivity, skin sympathetic nerve activity, and non-invasive cardiovascular parameters at different time points (P < 0.05). The minimum measured values of all four types of experimental pain sensitivity were consistently observed at 04:00. Rhythmical analysis showed that the mean values of pressure pain threshold (meta2d P = 0.016) and skin sympathetic nerve activity (meta2d P = 0.039) were significant. Significant diurnal rhythms in pain sensitivity and skin sympathetic nerve activity existed in some individuals but not in others. No significant correlation between experimental pain sensitivity and skin sympathetic nerve activity was found at any time point (P > 0.05).ConclusionSignificant diurnal fluctuations were observed in different pain sensitivities and skin sympathetic nerve activity. No significant correlation between experimental pain sensitivity and sympathetic excitability at different times was found; the reasons for these phenomena remain to be further studied.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [ChiCTR2000039709].

Pain and executive function: no association between remote exercise-induced hypoalgesia and cognitive inhibition in pain-free participants.

Cognitive inhibition, which denotes the ability to suppress predominant or automatic responses, has been associated with lower pain sensitivity and larger conditioned pain modulation in humans. Studies exploring the association between cognitive inhibition and other pain inhibitory phenomena, like exercise-induced hypoalgesia (EIH), are scarce. The primary aim was to explore the association between cognitive inhibition and EIH at exercising (local) and non-exercising (remote) muscles after isometric exercise. The secondary aim was to explore the association between cognitive inhibition and pressure pain sensitivity. Sixty-six pain-free participants (28.3±8.9 years old, 34 women) completed two cognitive inhibition tasks (stop-signal task and Stroop Colour-Word task), a 3-min isometric wall squat exercise, and a quiet rest control condition with pre- and post-assessments of manual pressure pain thresholds at a local (thigh) and a remote site (shoulder). In addition, cuff pressure pain thresholds, pain tolerance and temporal summation of pain were assessed at baseline. No association was found between remote EIH and cognitive inhibition (Stroop interference score: r=0.12, [-0.15; 0.37], p=0.405, BF01=6.70; stop-signal reaction time: r=-0.08, [-0.32; 0.17], p=0.524, BF01=8.32). Unexpectedly, individuals with worse performance on the Stroop task, as indicated by a higher Stroop interference score, showed higher local EIH (r=0.33; [0.10; 0.53], p=0.007, BF01=0.29). No associations were observed between pain sensitivity and any of the cognitive inhibition performance parameters. The present findings do not support previous evidence on positive associations between exercise-induced hypoalgesia and cognitive inhibition, as well as baseline pain sensitivity and cognitive inhibition.

Comprehensive analysis of GTP cyclohydrolase I activity in Mycobacterium tuberculosis H37 Rv via in silico studies.

GTP cyclohydrolase I enzyme (GTPCH-I) is a rate limiting enzyme in the biosynthesis pathway of tetrahydrobiopterin (BH4) and tetrahydrofolate (THF) compounds; latter being are an essential compounds involved in many biological functions. This enzyme has been evaluated structurally and functionally in many organisms to understand its putative role in cell processes, kinetics, regulations, drug targeting in infectious diseases, pain sensitivity in humans, and so on. In Mycobacterium tuberculosis (a human pathogen causing tuberculosis), this GTPCH-I activity has been predicted to be present in Rv3609c gene (folE) of H37 Rv strain, which till date has not been studied in detail. In order to understand in depth, the structure and function of folE protein in M. tuberculosis H37 Rv, in silico study was designed by using many different bioinformatics tools. Comparative and structural analysis predicts that Rv3609c gene is similar to folE protein ortholog of Listeria monocytogenes (cause food born disease), and uses zinc ion as a cofactor for its catalysis. Result shows that mutation of folE protein at 52th residue from tyrosine to glycine or variation in pH and temperature can lead to high destability in protein structure. Studies here have also predicted about the functional regions and interacting partners involved with folE protein. This study has provided clues to carry out experimentally the analysis of folE protein in mycobacteria and if found suitable will be used for drug targeting.

A Neanderthal Sodium Channel Increases Pain Sensitivity in Present-Day Humans

The sodium channel Nav1.7 is crucial for impulse generation and conduction in peripheral pain pathways [1]. In Neanderthals, the Nav1.7 protein carried three amino acid substitutions (M932L, V991L, and D1908G) relative to modern humans. We expressed Nav1.7 proteins carrying all combinations of these substitutions and studied their electrophysiological effects. Whereas the single amino acid substitutions do not affect the function of the ion channel, the full Neanderthal variant carrying all three substitutions, as well as the combination of V991L with D1908G, shows reduced inactivation, suggesting that peripheral nerves were more sensitive to painful stimuli in Neanderthals than in modern humans. We show that, due to gene flow from Neanderthals, the three Neanderthal substitutions are found in ∼0.4% of present-day Britons, where they are associated with heightened pain sensitivity.

Anodal transcranial direct current stimulation over the primary motor cortex attenuates capsaicin-induced dynamic mechanical allodynia and mechanical pain sensitivity in humans.

Anodal transcranial direct current stimulation over the primary cortex has been shown to activate regions of the brain involved in the descending modulation of pain sensitivity. However, more research is required to dissect the spinal cord analgesic mechanisms associated with the development of central sensitization. In this randomized, double blind, crossover study 12 healthy participants had baseline mechanical stimulus response (S/R) functions measured before and after the development of capsaicin-induced ongoing pain sensitivity. The effects of 20min of either real or sham transcranial direct current stimulation (tDCS, 2mA) over the primary motor cortex on dynamic mechanical allodynia (DMA) and mechanical pain sensitivity (MPS) were then investigated. Topical application of capsaicin resulted in an increase in area under the pain ratings curve for both DMA (p<.01) and MPS (p<.01). The effects of tDCS on the area under the curve ratio (i.e. post-/pre-treatment) revealed significant analgesic effects over DMA (p<.05) and MPS (p<.05) when compared with sham. This study demonstrates that anodal tDCS over the primary motor cortex can reduce both dynamic and static forms of mechanical pain sensitivity associated with the development of DMA and MPS, respectively. The use of tDCS may provide a novel mechanism-driven therapy in chronic pain patients with altered mechanical S/R functions. This research shows new evidence that anodal tDCS over the primary motor cortex can reduce dynamic and static forms of mechanical pain sensitivity in the capsaicin model of ongoing pain. By using this approach, it may be possible to provide mechanism-driven analgesia in chronic pain patients who have dynamic mechanical allodynia and/or secondary mechanical hyperalgesia.

Стресс-вызванная анальгезия: роль гормонов гипоталамо-гипофизарно-адренокортикальной системы

One of adaptive consequences of the stress response is a short-term decrease in pain sensitivity in humans and animals known as “stress-induced analgesia” (SIA). The HPA axis is a key system that activates during stress and provides organism adaptation. One of the mechanisms of SIA may be associated with the HPA hormones, in particular with corticotropin-releasing factor (CRF), the major hormone of the HPA axis, and glucocorticoids, whose analgesic properties are well known and used in medical practice. Based on the results of our research and literature review, the aim of the paper was to analyze SIA mechanisms related to CRF and glucocorticoid hormones mediated by CRF receptors 1 and 2 as well as glucocorticoid and opioid receptors.

Effects of Spicy Stimulation and Spicy-Food Consumption on Human Pain Sensitivity: A Healthy Volunteer Study

Spicy-food intake has been shown to affect various human physiological systems and diseases. This study tested the analgesia effect caused by stimulation of a spicy sensation (spicy stimulation) and explored the effect of spicy-food consumption on human basal pain sensitivity. A total of 60 healthy undergraduates were included in the primary study. Placebo and sweet stimulation were used as reference interventions. Pressure and cold-pain thresholds were measured before and after taste stimulation. The frequency of spicy-food intake was also evaluated. An additional 100 subjects were recruited to validate the results. Compared to placebo stimulation, both pressure and cold-pain thresholds increased during spicy stimulation (P < .05). The increased thresholds remained, even when the taste stimulation residue was nearly eliminated (P < .05). The pressure (10.0 [2.1] vs 12.7 [3.0] kg/cm2, P < .001) and cold-pain (4.4 [1.6] vs 6.2 [2.7] seconds, P = .003) thresholds in subjects who consume spicy food ≥3 days/week were significantly lower than in those who consume it <3 days/week. In the validation population, the frequency of spicy-food intake was negatively associated with subjects’ pressure (β = −.218, P = .013) and cold-pain (β = −.205, P = .035) thresholds. Spicy stimulation has an analgesia effect on adults that persists even after the taste stimulation stops. Conversely, a long-term spicy diet can reduce the human basal pain threshold. Trial RegistrationThe study protocol was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Army Medical University, People's Liberation Army (identification No., 2017-023-01), and it was registered on the Chinese Clinical Trial Registry at www.chictr.org.cn (No. ChiCTR1800015053). PerspectiveThis study directly examined the effects of stimulation of a spicy sensation on adult pain sensitivity and was the first to explore the relationship between long-term spicy-food intake and human pain sensitivity. The results provide evidence for future clinical pain intervention and individualized pain treatment.

Variation in the μ-opioid receptor gene (OPRM1) and experiences of felt security in response to a romantic partner's quarrelsome behavior.

Research suggests that endogenous opioids play a key role in the creation and maintenance of attachment bonds. Opioids acting at the μ-opioid receptor mediate reward and analgesia and are thus thought to underlie feelings of comfort and warmth experienced in the presence of close others. Disruption of μ-opioidergic activity increases separation distress in animals, suggesting that low opioid states may contribute to social pain. Accordingly, a functional μ-opioid receptor (OPRM1) polymorphism (C77G in primates, A118G in humans) affecting opioidergic signaling has been associated with separation distress and attachment behavior in nonhuman primates, and social pain sensitivity in humans. However, no research has examined the effects of this polymorphism on socioemotional experience, and specifically felt security, in daily interactions between romantic partners. Using an event-contingent recording method, members of 92 cohabiting romantic couples reported their felt security and quarrelsome behavior in daily interactions with each other for 20 days. Consistent with prior work, findings suggested that, relative to AA homozygotes, G allele carriers were more sensitive to their partners' self-reported quarrelsome behaviors (e.g., criticism), showing a greater decline in felt security when their partners reported higher quarrelsome behavior than usual. This is the first study to link variation in OPRM1 with felt security toward romantic partners in everyday social interactions. More generally, this research supports the theory that the attachment system incorporated evolutionarily primitive pain-regulating opioidergic pathways. We also discuss implications of this work for understanding of differential vulnerability to health risks posed by social stress.

Modeling the daily rhythm of human pain processing in the dorsal horn.

Experimental studies show that human pain sensitivity varies across the 24-hour day, with the lowest sensitivity usually occurring during the afternoon. Patients suffering from neuropathic pain, or nerve damage, experience an inversion in the daily modulation of pain sensitivity, with the highest sensitivity usually occurring during the early afternoon. Processing of painful stimulation occurs in the dorsal horn (DH), an area of the spinal cord that receives input from peripheral tissues via several types of primary afferent nerve fibers. The DH circuit is composed of different populations of neurons, including excitatory and inhibitory interneurons, and projection neurons, which constitute the majority of the output from the DH to the brain. In this work, we develop a mathematical model of the dorsal horn neural circuit to investigate mechanisms for the daily modulation of pain sensitivity. The model describes average firing rates of excitatory and inhibitory interneuron populations and projection neurons, whose activity is directly correlated with experienced pain. Response in afferent fibers to peripheral stimulation is simulated by a Poisson process generating nerve fiber spike trains at variable firing rates. Model parameters for fiber response to stimulation and the excitability properties of neuronal populations are constrained by experimental results found in the literature, leading to qualitative agreement between modeled responses to pain and experimental observations. We validate our model by reproducing the wind-up of pain response to repeated stimulation. We apply the model to investigate daily modulatory effects on pain inhibition, in which response to painful stimuli is reduced by subsequent non-painful stimuli. Finally, we use the model to propose a mechanism for the observed inversion of the daily rhythmicity of pain sensation under neuropathic pain conditions. Underlying mechanisms for the shift in rhythmicity have not been identified experimentally, but our model results predict that experimentally-observed dysregulation of inhibition within the DH neural circuit may be responsible. The model provides an accessible, biophysical framework that will be valuable for experimental and clinical investigations of diverse physiological processes modulating pain processing in humans.

Rapid eye movement sleep time in dairy cows changes during the lactation cycle

The importance of rest and sleep is well established; we know, for example, that lack of sleep impairs immune function in rats and increases pain sensitivity in humans. However, little is known about sleep in dairy cows, but a lack of rest and sleep is discussed as a possible welfare problem in cattle. A first step toward a better understanding of sleep in dairy cows is to quantify the time cows spend awake and asleep in different stages of lactation. Using electrophysiological recordings on 7 occasions in wk -2, 2, 7, 13, 22, 37, and 45 in relation to calving, we investigated changes in rapid eye movement (REM) sleep time as well as non-rapid eye movement (NREM) sleep, drowsing, awake, and rumination in 19 dairy cows of the Swedish Red breed kept in single pens with ad libitum access to feed and water. The recordings on wk -2 and 45 were conducted during the dry period, and all others during lactation. The PROC MIXED procedure in SAS (SAS Institute Inc., Cary, NC) was used to test for significant differences in REM, NREM, drowsing, awake, and rumination between the different stages of lactation cycle. Pairwise comparisons between all recording occasions showed that total REM sleep duration was shorter for cows in wk 2 relative to calving compared with wk -2, and the number of REM sleep bouts were fewer in wk 2 compared with wk -2. The REM sleep was recorded during both the day (0500-2100 h) and night (2100-0500 h), but predominantly performed at night compared with daytime, and the bout duration was longer during nighttime compared with daytime. A tendency was observed for time spent in NREM sleep to be shorter in wk 2 relative to calving compared with wk -2. The duration spent drowsing was shorter for cows in wk 2 and 13 relative to calving compared with wk -2. We found no effect of stage of lactation cycle on the duration of awake or ruminating. Our study is the first to assess sleep distribution during a lactation cycle, and our results show that stage of lactation is important to consider when moving forward with sleep investigations in dairy cows. The shortest REM sleep duration was found for cows 2 wk after calving and longest 2 wk before calving, and the difference was due a higher number of REM sleep bouts in the recording 2 wk before calving. The REM sleep and rumination predominantly occurred at night but were recorded during both day and night.

Genetic components of human pain sensitivity: a protocol for a genome-wide association study of experimental pain in healthy volunteers

IntroductionPain constitutes a major component of the global burden of diseases. Recent studies suggest a strong genetic contribution to pain susceptibility and severity. Whereas most of the available evidence relies...

MEMS sensors to assess pain sensitivity of human

This paper considers the possibility of creation of microelectronic systems to assess human pain sensitivity. The focus is devoted to the description of the known methods of pain sensitivity evaluation, the structure of the system to assess human pain sensitivity, as well as the description of the concept of the individual parts of the system with the use of MEMS sensors. A substantiation is presented of the use of the selected field type to create the impact of pain, as well as increased ease of use when using MEMS sensors for removal of photoplethysmogram, which is used in the evaluation of human pain sensitivity. The model of the device for readout photoplethysmogram data with the use of MEMS sensors is presented.

Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity.

Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.

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).

MEMS Sensors to Assess Pain Sensitivity of Human

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