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Background: Transcutaneous electrical nerve stimulation (TENS) is a non-invasive modality that utilizes electrical currents to modulate pain in populations with acute and chronic pain. TENS has been demonstrated to produce hypoalgesic effects in postoperative pain, fibromyalgia, knee osteoarthritis, and healthy subjects. Transcutaneous auricular vagus nerve stimulation (TaVNS) is a non-invasive modality that modulates the vagus nerve by stimulating its auricular branches. The effects of the combination of TENS and TaVNS on producing an analgesic response have not been studied. Considering that TENS and TaVNS both stimulate similar analgesic pathways but through different means of activation, we can hypothesize that a combination of both methods can produce a more pronounced analgesic response. Therefore, the objective of this study is to assess the hypoalgesic effect of a combination of TENS and TaVNS in pain-free subjects. Methods/design: The study will be a simple crossover design conducted at the University of Hartford. Subjects will be recruited from the University of Hartford population via oral communication, digital flyers, and posters on campus. Thirty participants will undergo two sessions in a crossover manner with one week in between. During one session, the participants will receive TENS with active TaVNS and the other session will be a placebo procedure (TENS with placebo TaVNS). The order of these sessions will be randomized. Importantly, the pressure pain threshold (PPT) and heat pain threshold (HPT) assessors will be blinded to the treatment category. For active TaVNS, a frequency of 25 Hz will be applied with a pulse duration of 200 µs. For placebo TaVNS, the intensity will be increased to a sensory level and then decreased to 0 mA. High-frequency TENS of 100 Hz will be applied in both sessions, with a pulse duration of 200 µsec, asymmetrical biphasic square waveform, and intensity of maximal tolerance without pain. TENS and TaVNS will be turned on for 30 min after a baseline measurement of outcomes. TENS and TaVNS will then be turned off, but the electrodes will remain on until completion of post-treatment assessment. Pressure pain threshold, heat pain threshold, blood pressure, oxygen saturation, and heart rate will be tested 4 times: Once pre-intervention, once during intervention, once immediately after the intervention, and once 15 min post-intervention. Statistical analysis of the data obtained will consider a significance level of p < 0.05. Discussion: This study will provide evidence concerning the combined effects of TENS and TaVNS on pain threshold in pain-free participants. Based on the outcomes, a greater understanding of how TENS and TaVNS, when used in conjunction, can modulate pain pathways. Trial registration: ClinicalTrials.gov NCT06361381. Registered on 09 April 2024. [ABSTRACT FROM AUTHOR]

Hojjat Daniali,1 Mollie A Ruben,2 Per M Aslaksen,3 Charlotte Fiskum,1 Ted J Kaptchuk,4 Magne A Flaten1 1Department of Psychology, Norwegian University of Science and Technology, Trondheim, Norway; 2Department of Psychology, University of Rhode Island, Kingston, RI, USA; 3Department of Psychology, UiT The Arctic University of Norway, Tromsø, Norway; 4Program in Placebo Studies, Beth Israel Deaconess Medical Center/ Harvard Medical School, Boston, MA, USACorrespondence: Hojjat Daniali, Department of Psychology, Norwegian University of Science and Technology, Trondheim, NO-7491, Norway, Email hojjat.daniali@ntnu.noIntroduction: Studies suggest facial expressions of caregivers may be important in placebo effects; however, this has not been systematically tested. This experiment investigated the effects of caregivers’ singular positive nonverbal behaviours (NBs) on pain reports.Methods: Fifty-one males and 53 females (total of 104) participants were randomized to four groups that were displayed positive facial expressions, tone of voice, body movement, or neutral NBs of videotaped experimenters. Subjective reports of pain, stress, arousal, and cardiac activity were obtained in a pre-test, a conditioning phase, and at a post-test. Four minutes of heat pain was induced in each test, and a placebo cream was administered before the conditioning and post-test in all groups.Results: There were no differences between the NB groups in the reduced pain. Males had larger reduction in pain in the post-test, and females had lower arousal than the opposite sex. During the conditioning, females had larger reduction in pain ie, unconditioned pain response (UPR). In females, the UPR predicted the reinforced expectation ie, increase in expectations from conditioning to post-test, and fear of minor pain negatively predicted both the UPR and reinforced expectation.Discussion: Singular NBs of caregiver were weak to enhance placebo effects. Females had lower pain during conditioning, and the UPR amplitude in females was associated with positive expectations. Moreover, for females, fear of minor pain weakened the UPR and expectations of cream.Conclusion: No NB of caregivers is more effective in reducing pain. Caregivers’ NBs are less effective when displayed individually. Males and females may be different in underlying mechanisms of placebo effects.Keywords: placebo effects, subtle factors, nonverbal behaviours, heat pain, experimenter effects, pain report

Parker A Kell,1 Claudia N Vore,1 Burkhart J Hahn,1,2 Michael F Payne,1,3 Jamie L Rhudy1 1Department of Psychology, The University of Tulsa, Tulsa, OK, USA; 2Department of Psychology, Oklahoma State University, Stillwater, OK, USA; 3Department of Pediatrics, Division of Child & Adolescent Psychiatry, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USACorrespondence: Jamie L Rhudy, University of Oklahoma Health Sciences Center, TSET Health Promotion Research Center, Department of Health Promotion Sciences, 4502 E. 41st Street, Tulsa, OK, 74104, USA, Tel +1 918-660-3050, Email jamie-rhudy@ouhsc.eduPurpose: Temporal summation (TS) of pain occurs when pain increases over repeated presentations of identical noxious stimuli. TS paradigms can model central sensitization, a state of hyperexcitability in nociceptive pathways that promotes chronic pain onset and maintenance. Many experimenters use painful heat stimuli to measure TS (TS-heat); yet, TS-heat research faces unresolved challenges, including difficulty evoking summation in up to 30– 50% of participants. Moreover, substantial variability exists between laboratories regarding the methods for evoking and calculating TS-heat.Patients and Methods: To address these limitations, this study sought to identify optimal parameters for evoking TS-heat in healthy participants with a commercially available constant contact heat stimulator, the Medoc TSA-II. Working within constraints of the TSA-II, stimulus trains with varying parameters (eg, stimulus frequency, baseline temp, peak temp, peak duration, testing site) were tested in a sample of 32 healthy, chronic pain-free participants to determine which combination best evoked TS-heat. To determine whether TS scoring method altered results, TS-heat was scored using three common methods.Results: Across all methods, only two trains successfully evoked group-level TS-heat. These trains shared the following parameters: site (palmar hand), baseline and peak temperatures (44°C and 50°C, respectively), and peak duration (0.5 s). Both produced summation that peaked at moderate pain (~50 out of 100 rating).Conclusion: Future TS-heat investigations using constant contact thermodes and fixed protocols may benefit from adopting stimulus parameters that include testing on the palmar hand, using 44°C baseline and 50°C peak temperatures, at ≥ 0.33 Hz stimulus frequency, and peak pulse durations of at least 0.5 seconds.Keywords: temporal summation, heat pain, second pain, wind-up, Medoc TSA-II

The persistence of inflammatory and neuropathic pain is poorly understood. We investigated a novel therapeutic paradigm by targeting gene networks that sustain or reverse persistent pain states. Our prior observations found that Sp1-like transcription factors drive the expression of TRPV1, a pain receptor, that is blocked in vitro by mithramycin A (MTM), an inhibitor of Sp1-like factors. Here, we investigate the ability of MTM to reverse in vivo models of inflammatory and chemotherapy-induced peripheral neuropathy (CIPN) pain and explore MTM's underlying mechanisms. Mithramycin reversed inflammatory heat hyperalgesia induced by complete Freund adjuvant and cisplatin-induced heat and mechanical hypersensitivity. In addition, MTM reversed both short-term and long-term (1 month) oxaliplatin-induced mechanical and cold hypersensitivity, without the rescue of intraepidermal nerve fiber loss. Mithramycin reversed oxaliplatin-induced cold hypersensitivity and oxaliplatin-induced TRPM8 overexpression in dorsal root ganglion (DRG). Evidence across multiple transcriptomic profiling approaches suggest that MTM reverses inflammatory and neuropathic pain through broad transcriptional and alternative splicing regulatory actions. Mithramycin-dependent changes in gene expression following oxaliplatin treatment were largely opposite to and rarely overlapped with changes in gene expression induced by oxaliplatin alone. Notably, RNAseq analysis revealed MTM rescue of oxaliplatin-induced dysregulation of mitochondrial electron transport chain genes that correlated with in vivo reversal of excess reactive oxygen species in DRG neurons. This finding suggests that the mechanism(s) driving persistent pain states such as CIPN are not fixed but are sustained by ongoing modifiable transcription-dependent processes. [ABSTRACT FROM AUTHOR]

TRPV3 is a non-selective cation channel that is highly expressed in keratinocytes in the skin. Traditionally, keratinocytes-expressed TRPV3 is involved in multiple physiological and pathological functions of the skin, such as itching, heat pain, and hair development. Although the underlying mechanisms by which TRPV3 functions in vivo remain obscure, recent research studies suggest that several cytokines and EGFR signaling pathways may be involved. However, there have also been other studies with opposite results that question the role of TRPV3 in heat pain. In addition, an increasing number of studies have suggested a novel role of TRPV3 in promoting skin regeneration, indicating that TRPV3 may become a new potential target for regulating skin regeneration. This paper not only reviews the role of keratinocytes-expressed TRPV3 in the physiological and pathological processes of itching, heat pain, hair development, and skin regeneration, but also reviews the relationship between TRPV3 gene mutations and skin diseases such as atopic dermatitis (AD) and Olmsted syndrome (OS). This review will lay a foundation for further developing our understanding of the mechanisms by which TRPV3 is involved in itching, heat pain, and hair development, as well as the treatments for TRPV3-related skin diseases. [ABSTRACT FROM AUTHOR]

Objectives: The thalamus plays an important role in the mediation and integration of various stimuli (e.g., somatosensory, pain, and vestibular). Whether a stimulus-specific and topographic organization of the thalamic nuclei exists is still unknown. The aim of our study was to define a functional, in vivo map of multimodal sensory processing within the human thalamus. Methods: Twenty healthy individuals (10 women, 21–34 years old) participated. Defined sensory stimuli were applied to both hands (innocuous touch, mechanical pain, and heat pain) and the vestibular organ (galvanic stimulation) during 3 T functional MRI. Results: Bilateral thalamic activations could be detected for touch, mechanical pain, and vestibular stimulation within the left medio-dorsal and right anterior thalamus. Heat pain did not lead to thalamic activation at all. Stimuli applied to the left body side resulted in stronger activation patterns. Comparing an early with a late stimulation interval, the mentioned activation patterns were far more pronounced within the early stimulation interval. Conclusions: The right anterior and ventral-anterior nucleus and the left medio-dorsal nucleus appear to be important for the processing of multimodal sensory information. In addition, galvanic stimulation is processed more laterally compared to mechanical pain. The observed changes in activity within the thalamic nuclei depending on the stimulation interval suggest that the stimuli are processed in a thalamic network rather than a distinct nucleus. In particular, the vestibular network within the thalamus recruits bilateral nuclei, rendering the thalamus an important integrative structure for vestibular function. [ABSTRACT FROM AUTHOR]

We studied the efficacy of a near-infrared laser (1475 nm) to activate rat dorsal root ganglion (DRG) neurons with short punctate radiant heat pulses (55 µm diameter) and investigated temporal and spatial summation properties for the transduction process for noxious heat at a subcellular level. Strength-duration curves (10–80 ms range) indicated a minimum power of 30.2mW for the induction of laser-induced calcium transients and a chronaxia of 13.9 ms. However, threshold energy increased with increasing stimulus duration suggesting substantial radial cooling of the laser spot. Increasing stimulus duration demonstrated suprathreshold intensity coding of calcium transients with less than linear gains (Stevens exponents 0.29/35mW, 0.38/60mW, 0.46/70mW). The competitive TRPV1 antagonist capsazepine blocked responses to short near-threshold stimuli and significantly reduced responses to longer duration suprathreshold heat. Heating 1/3 of the soma of a neuron was sufficient to induce calcium transients significantly above baseline (p < 0.05), but maximum amplitude was only achieved by centering the laser over the entire neuron. Heat-induced calcium increase was highest in heated cell parts but rapidly reached unstimulated areas reminiscent of spreading depolarization and opening of voltage-gated calcium channels. Full intracellular equilibrium took about 3 s, consistent with a diffusion process. In summary, we investigated transduction mechanisms for noxious laser heat pulses in native sensory neurons at milliseconds temporal and subcellular spatial resolution and characterized strength duration properties, intensity coding, and spatial summation within single neurons. Thermal excitation of parts of a nociceptor spread via both membrane depolarization and intracellular calcium diffusion. [ABSTRACT FROM AUTHOR]

Background: Rhodiola rosea L. (Crassulaceae) is one of the better known plant adaptogens possessing unique protective properties against various harmful environmental factors. Among the numerous pharmacological effects of R. rosea extracts (RRE) and their active compounds, antinociceptive activity has previously been demonstrated in experimental studies. Purpose: The study was aimed to evaluate the effect of a single, high dose of RRE on pain perception induced by diverse nociceptive stimuli in healthy volunteers. Material and methods: The study was designed as a double blind, placebo-controlled trial. Each participant underwent the trial after both placebo and RRE administration. The order of trials was randomly assigned to the participants. The threshold and tolerance to heat and pressure stimulus and cold water tolerance (cold pressor test) were assessed in a group of 142 volunteers aged 19–27 years. The subjects were tested in three subsequent trials in one-week intervals. Baseline measurements were followed by tests after a single, oral intake of hydroethanolic RRE capsules (50 mg/kg) or placebo (PL). Measurement results were analyzed for the entire study group and subgroups characterized by high and low pain sensitivity (≤ 25 and ≥ 75 percentile, respectively). Results: After intake of a single dose of RRE, both pain threshold (RRE 350.5 ± 115.4 kPa vs. PL 329.4 ± 117.4 kPa; p

Visceral pain is regarded as more salient than somatic pain. It has greater affective and emotional components, i.e., it elicits higher levels of pain-related fear and is perceived as more unpleasant than somatic pain. In this fMRI study, we examined the neural effects of painful visceral as compared to painful somatic stimulation on visual processing and memory encoding in a visual categorization and surprise recognition task in healthy volunteers. During the categorization task, participants received either rectal distensions or heat stimuli applied to the forearm, with stimuli being individually matched for unpleasantness. Behaviorally, visceral pain reduced memory encoding as compared to somatic pain (Kleine-Borgmann et al., 2021). Imaging analyses now revealed that visceral pain was associated with reduced activity (i.e., greater pain-related interruption) in neural areas typically involved in visual processing and memory encoding. These include the parahippocampal gyrus, fusiform gyrus, striatum, occipital cortex, insula, and the amygdala. Moreover, reduced engagement of the lateral occipital complex during visual categorization under visceral pain was associated with higher visceral pain-related fear. These findings obtained in healthy volunteers shed light on the neural circuitry underlying the interruptive effect of visceral pain and pave the way for future studies in patient samples.

Offset analgesia is defined by a dramatic drop in perceived pain intensity with a relatively small decrease in noxious input. Although functional magnetic resonance imaging studies implicate subcortical descending inhibitory circuits during offset analgesia, the role of cortical areas remains unclear. The current study identifies cortical correlates of offset analgesia using functional near infrared spectroscopy (fNIRS). Twenty-four healthy volunteers underwent fNIRS scanning during offset (OS) and control (Con) heat stimuli applied to the forearm. After controlling for non-neural hemodynamic responses in superficial tissues, widespread increases in cortical oxygenated hemoglobin concentration were observed, reflecting cortical activation during heat pain. OS–Con contrasts revealed deactivations in bilateral medial prefrontal cortex (mPFC) and bilateral somatosensory cortex (SSC) associated with offset analgesia. Right dorsolateral prefrontal cortex (dlPFC) showed activation only during OS. These data demonstrate opposing cortical activation patterns during offset analgesia and support a model in which right dlPFC underlies ongoing evaluation of pain intensity change. With predictions of decreasing pain intensity, right dlPFC activation likely inhibits ascending noxious input via subcortical pathways resulting in SSC and mPFC deactivation. This study identifies cortical circuitry underlying offset analgesia and introduces the use of fNIRS to study pain modulation in an outpatient clinical environment. [ABSTRACT FROM AUTHOR]

Purpose Exercise-induced hypoalgesia is frequently documented in the literature. However, the underlying neural mechanism of this phenomenon remains unclear. Here, we explored the effects of different intensities of isometric exercise on pain perception with a randomized controlled design and investigated its neural mechanisms through tracing the dynamic changes of heat-evoked brain responses. Methods Forty-eight participants were randomly assigned to one of the three groups with different exercise intensities (i.e. high, low, and control). Their subjective pain reports and brain responses elicited by heat stimuli before and after exercise were assessed. Results We observed 1) the increased pressure pain thresholds and heat pain thresholds on the dorsal surface of the hand and the biceps brachii muscle of the exercised limb (closed to the contracting muscle), and the decreased pressure pain ratings at the indexed finger of the unexercised limb; 2) more reduction of pain sensitivity on both the biceps brachii muscle and the dorsal surface of the hand induced by the high-intensity isometric exercise than the low-intensity isometric exercise; and 3) both the high-intensity and the low-intensity isometric exercise induced the reduction of N2 amplitudes and N2–P2 peak-to-peak amplitudes, as well as the reduction of event-related potential magnitudes elicited by the heat stimuli on the exercised limb. Conclusions The hypoalgesic effects induced by the isometric exercise were not only localized to the moving part of the body but also can be extended to the distal part of the body. The exercise intensities play a vital role in modulating these effects. Exercise-induced hypoalgesia could be related to the modulation of nociceptive information transmission via a spinal gating mechanism and also rely on a top-down descending pain inhibitory mechanism. [ABSTRACT FROM AUTHOR]

Abstract Background Pain is the vital sense preventing tissue damage by harmful noxious stimuli. The capsaicin receptor TRPV1 is activated by noxious temperatures, however, acute heat pain is only marginally affected in mice after TRPV1 knockout but completely eliminated in mice lacking TRPV1 positive fibers. Exploring contribution of candidate signal transduction mechanisms to heat pain in humans needs translational models. Methods We used focused, non-damaging, short near-infrared laser heat stimuli (wavelength 1470/1475 nm) to study the involvement of TRPV1-expressing nerve fibers in the encoding of heat pain intensity. Human psychophysics (both sexes) were compared to calcium transients in native rat DRG neurons and heterologously expressing HEK293 cells. Results Heating of dermal and epidermal nerve fibers in humans with laser stimuli of ≥ 2.5 mJ (≥ 25 ms, 100 mW) induced pain that increased linearly as a function of stimulus intensity in double logarithmic space across two orders of magnitude and was completely abolished by desensitization using topical capsaicin. In DRG neurons and TRPV1-expressing HEK cells, heat sensitivity was restricted to capsaicin sensitive cells. Strength duration curves (2–10 ms range) and thresholds (DRGs 0.56 mJ, HEK cells 0.52 mJ) were nearly identical. Tachyphylaxis upon repetitive stimulation occurred in HEK cells (54%), DRGs (59%), and humans (25%). Conclusion TRPV1-expressing nociceptors encode transient non-damaging heat pain in humans, thermal gating of TRPV1 is similar in HEK cells and DRG neurons, and TRPV1 tachyphylaxis is an important modulator of heat pain sensitivity. These findings suggest that TRPV1 expressed in dermal and epidermal populations of nociceptors serves as first line defense against heat injury.

TRPV3 is a non-selective cation channel that is highly expressed in keratinocytes in the skin. Traditionally, keratinocytes-expressed TRPV3 is involved in multiple physiological and pathological functions of the skin, such as itching, heat pain, and hair development. Although the underlying mechanisms by which TRPV3 functions in vivo remain obscure, recent research studies suggest that several cytokines and EGFR signaling pathways may be involved. However, there have also been other studies with opposite results that question the role of TRPV3 in heat pain. In addition, an increasing number of studies have suggested a novel role of TRPV3 in promoting skin regeneration, indicating that TRPV3 may become a new potential target for regulating skin regeneration. This paper not only reviews the role of keratinocytes-expressed TRPV3 in the physiological and pathological processes of itching, heat pain, hair development, and skin regeneration, but also reviews the relationship between TRPV3 gene mutations and skin diseases such as atopic dermatitis (AD) and Olmsted syndrome (OS). This review will lay a foundation for further developing our understanding of the mechanisms by which TRPV3 is involved in itching, heat pain, and hair development, as well as the treatments for TRPV3-related skin diseases.

This study investigated the sex-specific associations between pain perception and testosterone levels in healthy controls (HCs) and patients with migraine. Male and female HCs and migraine patients were recruited. A series of questionnaires were completed by the participants to evaluate their psychosocial profiles, which included data on mood, stress, and sleep quality. Heat pain thresholds and suprathreshold pain ratings at 45 °C (referred to as the pain perception score [PPS]) were assessed using the Thermode system. Salivary testosterone levels were analyzed using a commercial enzyme-linked immunosorbent assay kit. A total of 88 HCs (men/women: 41/47, age: 29.9 ± 7.7 years) and 75 migraine patients (men/women: 30/45, age: 31.1 ± 7.7 years) completed all assessments. No significant differences were observed in either the psychosocial profiles or heat pain thresholds and PPSs between the sexes in the control and migraine groups. A positive correlation between testosterone levels and PPSs was identified in the male controls (r = .341, P = .029), whereas a negative correlation was identified in the female controls (r = -.407, P = .005). No such correlations were identified in the migraine group. This study confirms that a negative association is present between PPSs and testosterone levels in female controls, which is in line with the findings that testosterone is associated with reduced pain perception. Our study is the first to demonstrate a sex-specific association between PPSs and testosterone levels in HCs. Moreover, this study also revealed that the presence of migraine appears to disrupt this association. PERSPECTIVE: This study revealed that testosterone levels demonstrate opposite associations with pain perception in healthy men and women. However, the presence of migraine appears to disrupt this sex-specific association., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Oxytocin (OT) is a neuropeptide broadly implicated in social relationships and behavior. OT also exerts antinociceptive and pain-reducing effects in both humans and rodents. Recent research in rodents demonstrates that these effects can be peripheral and local. In human studies, intravenous OT has reduced visceral pain, and subcutaneous injection of OT has reduced postsurgical pain. However, the local effects of subcutaneous OT on experimental pain have not been studied. We conducted a 2-session crossover study during which healthy adults received a subcutaneous injection of synthetic OT (4 mcg/2 mL) or saline placebo (isotonic saline 2 mL), in a randomized and double-blinded manner. Eighteen participants completed full study procedures. We hypothesized that 10 minutes after injection, OT would reduce measures of acute mechanical pain, pressure pain, and heat pain perception. Subcutaneous OT significantly reduced ratings of heat pain intensity and unpleasantness (both P < .01), but did not alter mechanical pain, pressure pain, or heat pain threshold (all P > .05). Changes in heat pain were observed only on the injected arm and not on the contralateral arm, confirming a localized mechanism. These findings confirm the ability of OT in or near the skin to modulate nociceptive processes in cutaneous tissues in human adults, opening exciting avenues for further mechanistic research as well as potential clinical applications for acute pain. PERSPECTIVE: This randomized-controlled trial showed that a subcutaneous injection of OT could reduce perception of heat pain tested with a thermode. OT did not alter mechanical or pressure pain or thresholds for perceiving heat pain. These findings are relevant to scientists and clinicians seeking nonaddictive local drug treatments for pain., (Published by Elsevier Inc.)

Pain perception and the ability to modulate arising pain vary tremendously between individuals. It has been shown that endurance athletes possess higher pain tolerance thresholds and a greater effect of conditioned pain modulation than nonathletes, both indicating a more efficient system of endogenous pain inhibition. The aim of the present study was to focus on the neural mechanisms of pain processing in endurance athletes that have not been investigated yet. Therefore, we analyzed the pain processing of 18 male athletes and 19 healthy male nonathletes using functional magnetic resonance imaging. We found lower pain ratings in endurance athletes compared to nonathletes to physically identical painful stimulation. Furthermore, brain activations of athletes versus nonathletes during painful heat stimulation revealed reduced activation in several brain regions that are typically activated by nociceptive stimulation. This included the thalamus, primary and secondary somatosensory cortex, insula, anterior cingulate cortex, midcingulate cortex, dorsolateral prefrontal cortex, and brain stem (BS). Functional connectivity analyses revealed stronger network during painful heat stimulation in athletes between the analyzed brain regions except for connections with the BS that showed reduced functional connectivity in athletes. Post hoc correlation analyses revealed associations of the subject's fitness level and the brain activation strengths, subject's fitness level and functional connectivity, and brain activation strengths and functional connectivity. Together, our results demonstrate for the first time that endurance athletes do not only differ in behavioral variables compared to nonathletes, but also in the neural processing of pain elicited by noxious heat. [ABSTRACT FROM AUTHOR]

Abstract: Human functional magnetic resonance imaging (fMRI) and behavioral studies have established the roles of cortical areas along the Sylvian fissure in sensing subjective pain. Yet, little is known about how sensory aspects of painful information are represented and processed by neurons in these regions and how their electrophysiological activities are related to fMRI signals. The current study aims to partially address this critical knowledge gap by performing fMRI-guided microelectrode mapping and recording studies in the homologous region of the parietal operculum in squirrel monkeys under light anesthesia. In each animal studied (n = 8), we detected mesoscale mini-networks for heat nociception in cortical regions around the lateral sulcus. Within the network, we discovered a ∼1.5 × 1.5-mm2-sized cortical patch that solely contained heat nociceptive neurons that aligned with the heat fMRI activation locus. These neurons responded slowly to thermal (heat and cold) nociceptive stimuli exclusively, continued firing for several seconds after the succession of stimulation, and exhibited multidigit receptive fields and high spontaneous firing rates. Similar to the fMRI responses, increasing temperatures in the nociceptive range led to a nonlinear increase in firing rates. The finding of a clustering of heat nociceptive neurons provides novel insights into the unique functional organization of thermal nociception in the S2 subregion of the primate brain. With fMRI, it supports the existence of a modality-preferred heat nociceptive patch that is spatially separated and intermingled with touch patches containing neurons with comparable receptive fields and the presence of functionally distinct mini-networks in primate opercular cortex. [ABSTRACT FROM AUTHOR]

Eugenol and carvacrol from clove and oregano, respectively, are agonists of the warmth-sensitive transient receptor potential channel TRPV3 and the irritant-sensitive transient receptor potential ankyrin (TRPA)-1. Eugenol and carvacrol induce oral irritation that rapidly desensitizes, accompanied by brief enhancement of innocuous warmth and heat pain in humans. We presently investigated if eugenol and carvacrol activate nociceptive primary afferent and higher order trigeminal neurons and enhance their heat-evoked responses, using calcium imaging of cultured trigeminal ganglion (TG) and dorsal root ganglion (DRG) neurons, and in vivo single-unit recordings in trigeminal subnucleus caudalis (Vc) of rats. Eugenol and carvacrol activated 20-30% of TG and 7-20% of DRG cells, the majority of which additionally responded to menthol, mustard oil and/or capsaicin. TG cell responses to innocuous (39°) and noxious (42 °C) heating were enhanced by eugenol and carvacrol. We identified dorsomedial Vc neurons responsive to noxious heating of the tongue in pentobarbital-anesthetized rats. Eugenol and carvacrol dose-dependently elicited desensitizing responses in 55% and 73% of heat-sensitive units, respectively. Responses to noxious heat were briefly enhanced by eugenol and carvacrol. Many eugenol- and carvacrol-responsive units also responded to menthol, cinnamaldehyde and capsaicin. These data support a peripheral site for eugenol and carvacrol to enhance warmth- and noxious heat-evoked responses of trigeminal neurons, and are consistent with the observation that these agonists briefly enhance warmth and heat pain on the human tongue.

Adaptation to the context in which we experience pain requires cognitive flexibility (CF) and affective flexibility (AF). Deficits in both flexibility types may be precursors of more intense and prolonged pain. This study aimed to examine the relation between CF and AF, and the experience of experimentally induced pain. Furthermore, correlations between behavioral and self-report measures of flexibility were explored. CF and AF were assessed with task-switching paradigms, using neutral (numbers ranging from 1 to 9, excluding 5) or affective stimuli (positive and negative pictures), respectively. Pain sensitivity measures, such as pain threshold (°C), pain tolerance (°C), and retrospective pain experience ratings (Visual Analog Scale) were assessed for an experimentally induced heat pain stimulus. Self-reported CF was measured with a questionnaire. Results demonstrated no associations between the flexibility constructs and any of the pain outcome measures. Correlations between the behavioral and self-report measures of CF were absent or weak at best. Current results are discussed against the background of methodological considerations and prior empirical research findings, suggesting the contribution of AF in especially the recovery from pain. [ABSTRACT FROM AUTHOR]

The application of functional magnetic resonance imaging (fMRI) to the human spinal cord is still a relatively small field of research and faces many challenges. Here we aimed to probe the limitations of task-based spinal fMRI at 3T by investigating the reliability of spinal cord blood oxygen level dependent (BOLD) responses to repeated nociceptive stimulation across two consecutive days in 40 healthy volunteers. We assessed the test-retest reliability of subjective ratings, autonomic responses, and spinal cord BOLD responses to short heat pain stimuli (1s duration) using the intraclass correlation coefficient (ICC). At the group level, we observed robust autonomic responses as well as spatially specific spinal cord BOLD responses at the expected location, but no spatial overlap in BOLD response patterns across days. While autonomic indicators of pain processing showed good-to-excellent reliability, both β -estimates and z-scores of task-related BOLD responses showed poor reliability across days in the target region (gray matter of the ipsilateral dorsal horn). When taking into account the sensitivity of gradient-echo echo planar imaging (GE-EPI) to draining vein signals by including the venous plexus in the analysis, we observed BOLD responses with fair reliability across days. Taken together, these results demonstrate that heat pain stimuli as short as one second are able to evoke a robust and spatially specific BOLD response, which is however strongly variable within participants across time, resulting in low reliability in the dorsal horn gray matter. Further improvements in data acquisition and analysis techniques are thus necessary before event-related spinal cord fMRI as used here can be reliably employed in longitudinal designs or clinical settings., Competing Interests: Competing interest: The Max Planck Institute for Human Cognitive and Brain Sciences has an institutional research agreement with Siemens Healthcare. Nikolaus Weiskopf holds a patent on acquisition of MRI data during spoiler gradients (US 10,401,453 B2). Nikolaus Weiskopf was a speaker at an event organized by Siemens Healthcare and was reimbursed for the travel expenses.

The thermal grill illusion (TGI) describes a peculiar or even painful percept caused by non-noxious, interlaced warm and cold stimuli. It involves the glutamatergic system and is affected in putatively nociplastic syndromes such as fibromyalgia. The glutamatergic system is also involved in wind-up, that is, the increased activation of spinal neurons following repeated noxious stimulation leading to a temporal summation of perceived stimulus intensity. Here we combined both stimulation methods to further investigate whether non-noxious stimuli as employed in the TGI can lead to a similar summation of perceived stimulus intensity. In an experiment using a full crossover within-subjects design, 35 healthy volunteers received repeated stimuli, either in a thermal grill configuration or simply noxious heat. Both modalities were presented as sequences of 1 lead-in contact, followed by 11 consecutive contacts (each between 1.5 and 3 seconds), with either fast repetition ("wind-up" condition), or 2 slow-repeating control conditions. The main analyses concerned the relative pre-to-post sequence changes to quantify putatively wind-up-related effects. Pain ratings and skin conductance level (SCL) increased more strongly in "wind-up" than in control conditions. Interestingly, wind-up-related effects were of the same magnitude in TGI as compared to the pain control modality. Further, contact-by-contact SCL tracked how the effect emerged over time. These results indicate that although TGI does not involve noxious stimuli it is amenable to temporal summation and wind-up-like processes. Since both phenomena involve the glutamatergic system, the combination of wind-up with the TGI could yield a promising tool for the investigation of chronic pain conditions. PERSPECTIVE: Using thermal stimuli in an experimental protocol to combine 1) the TGI (painful or peculiar percept from simultaneous cold/warm stimulation) and 2) wind-up (increase in stimulus intensity after repeated exposure) holds promise to investigate pain and thermoceptive mechanisms, and chronic pain conditions., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

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Background and aims: Evidence for analgesic effects of oral alcohol consumption on heat pain has recently been documented in a placebo-controlled, randomized and double-blind design. We aimed at further investigating these effects and now set the focus on pain threshold and the ratings of supra-threshold pain to cover most of the pain range. Moreover, we now firstly evaluated sex differences in these effects. Methods: We investigated 41 healthy participants (22 females) in a randomized, double-blind and placebo-controlled design and targeted two different moderate breath-alcohol levels of 0.06% and 0.08%. Before and after an alcoholic or placebo drink, contact heat was applied at the forearm. Subjects evaluated pain threshold (method of adjustment) and rated pain intensity and pain unpleasantness of supra-threshold stimuli (intensity: threshold +3 °C; duration: 5 s). Results: Analgesic effects taking the form of increased pain thresholds were found after both alcohol doses, surprisingly with more pronounced effects for the lower dose. While the high alcohol dose exerted small analgesic effects on pain intensity ratings (i.e. decrease), slightly increased ratings of pain intensity and pain unpleasantness after the low alcohol dose rather suggest pain enhancement. Alcohol did not affect intensity vs. unpleasantness ratings differentially. We found no evidence for sex differences in any of these effects. Conclusions: Overall, acute alcohol effects on pain were subtle. Our findings suggest that while low alcohol doses already exert analgesic effects on pain threshold, stronger doses are required for pain reduction on supra-threshold pain levels. Furthermore, sex differences could not be detected within our experimental paradigm but should be further explored in future research. Implications: Analgesic effects of sub-toxic alcohol doses – as normally occurring during social drinking – might be weak; however, susceptibility to pain relieving effects of alcohol might be a risk factor for the use of alcohol as self-medication in acute pain states. [ABSTRACT FROM AUTHOR]

Aims: To investigate associations between experimental pain sensitivity and five chronic pain conditions among 655 participants in the OPPERA study. Methods: Quantitative sensory tests were used to measure sensitivity to three modalities of nociception: blunt pressure pain, mechanical pinprick pain, and thermal heat pain. Participants were also classified according to the presence or absence of five chronic pain conditions: temporomandibular disorders, headache, low back pain, irritable bowel syndrome, and fibromyalgia. Results: Univariate analyses found each modality to be significantly associated with at least one pain condition, most consistently for pressure pain sensitivity (8 of 15 instances) and least consistently for heat pain sensitivity (5 of 35 instances). Yet, multivariable analyses that evaluated the independent contributions of all five pain conditions found few significant associations (12 of 75 instances). Instead, pain sensitivity consistently varied according to the total number of pain conditions a person experienced, implying that the combination of pain conditions influences each nociceptive modality. Conclusion: When evaluating nociceptive sensitivity in a chronic pain patient, comorbid pain conditions should be considered, as the more salient feature underlying sensitivity is likely the number rather than the type(s) of pain conditions. [ABSTRACT FROM AUTHOR]

Objective This study aims to assess whether acupuncture analgesia's effects are local or systemic and whether there is a dose response for these effects. Methods Twenty-eight healthy volunteers aged 18–45 were randomized to two doses of acupuncture using points closely associated with peripheral nerves in the legs. The lower-dose group involved acupoints overlying the deep peroneal nerve (DP), and the higher-dose involved acupoints overlying the deep peroneal and posterior tibial nerves (DPTN). Baseline and acupuncture quantitative sensory testing (QST) assessments were obtained locally in the calf and great toe and systemically in the hand. Results were analyzed using factorial repeated-measures analysis of variance for each of the QST variables—cold detection threshold (CDT), vibration detection threshold (VDT), heat pain threshold (HP0.5), and heat pain perception of 5/10 (HP5.0). Location (leg/hand) and time (baseline/acupuncture) were within-subject factors. Intervention (DP/DPTN) was a between-subject factor. Results CDT was increased in the calf (P  < 0.001) and in the hand (P  < 0.001). VDT was increased in the toe (P  < 0.001) but not in the hand. HP0.5 was increased in the calf (P  < 0.001) and in the hand (P  < 0.001). HP5.0 was increased in the calf (P  = 0.002) and in the hand (P  < 0.001), with the local effect being significantly greater than the systemic (P  = 0.004). In all of the above QST modalities, there was no difference between the low-dose (DP) and high-dose (DPTN) acupuncture groups. Conclusions Acupuncture caused comparable local and systemic analgesic effects in cold detection and heat pain perception and only local effects in vibration perception. There was no clear acupuncture dose response to these effects. [ABSTRACT FROM AUTHOR]

Background: Pain is the vital sense preventing tissue damage by harmful noxious stimuli. The capsaicin receptor TRPV1 is activated by noxious temperatures, however, acute heat pain is only marginally affected in mice after TRPV1 knockout but completely eliminated in mice lacking TRPV1 positive fibers. Exploring contribution of candidate signal transduction mechanisms to heat pain in humans needs translational models.Methods: We used focused, non-damaging, short near-infrared laser heat stimuli (wavelength 1470/1475 nm) to study the involvement of TRPV1-expressing nerve fibers in the encoding of heat pain intensity. Human psychophysics (both sexes) were compared to calcium transients in native rat DRG neurons and heterologously expressing HEK293 cells.Results: Heating of dermal and epidermal nerve fibers in humans with laser stimuli of ≥ 2.5 mJ (≥ 25 ms, 100 mW) induced pain that increased linearly as a function of stimulus intensity in double logarithmic space across two orders of magnitude and was completely abolished by desensitization using topical capsaicin. In DRG neurons and TRPV1-expressing HEK cells, heat sensitivity was restricted to capsaicin sensitive cells. Strength duration curves (2-10 ms range) and thresholds (DRGs 0.56 mJ, HEK cells 0.52 mJ) were nearly identical. Tachyphylaxis upon repetitive stimulation occurred in HEK cells (54%), DRGs (59%), and humans (25%).Conclusion: TRPV1-expressing nociceptors encode transient non-damaging heat pain in humans, thermal gating of TRPV1 is similar in HEK cells and DRG neurons, and TRPV1 tachyphylaxis is an important modulator of heat pain sensitivity. These findings suggest that TRPV1 expressed in dermal and epidermal populations of nociceptors serves as first line defense against heat injury. [ABSTRACT FROM AUTHOR]

This study investigates the comparative analysis of resting-state functional magnetic imaging (rs-fMRI) markers in heat and mechanical pain sensitivity among healthy adults. Using quantitative sensory testing (QST) in the orofacial area and rs-fMRI, we explored the relationship between pain sensitivities and resting-state functional connectivity (rsFC) across whole brain areas. Brain regions were spatially divided using group independent component analysis (gICA), and additional masked gICA was performed for brainstem regions. Our findings revealed that a significant number of rsFCs were correlated with either heat or mechanical pain sensitivity, with a substantial portion originating from the Sensorimotor Network (SMN). Furthermore, multivariable regression models incorporating rsFC features demonstrated predictive capabilities for pain sensitivities, with the inclusion of brainstem gICA components significantly enhancing model accuracy. Finally, a composite critical rsFC value was introduced to simplify and describe overall abnormal communication in the brain network, which could also be used in univariable regression models to predict heat and mechanical pain sensitivity., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

In pattern recognition, the selection of appropriate features is paramount to both the performance and the robustness of the system. Over-reliance on machine learning-based feature selection methods can, therefore, be problematic; especially when conducted using small snapshots of data. The results of these methods, if adopted without proper interpretation, can lead to sub-optimal system design or worse, the abandonment of otherwise viable and important features. In this work, a deep exploration of pain-based emotion classification was conducted to better understand differences in the results of the related literature. In total, 155 different time domain and frequency domain features were explored, derived from electromyogram (EMG), skin conductance levels (SCL), and electrocardiogram (ECG) readings taken from the 85 subjects in response to heat-induced pain. To address the inconsistency in the optimal feature sets found in related works, an exhaustive and interpretable feature selection protocol was followed to obtain a generalizable feature set. Associations between features were then visualized using a topologically-informed chart, called Mapper, of this physiological feature space, including synthesis and comparison of results from previous literature. This topological feature chart was able to identify key sources of information that led to the formation of five main functional feature groups: signal amplitude and power, frequency information, nonlinear complexity, unique, and connecting. These functional groupings were used to extract further insight into observable autonomic responses to pain through a complementary statistical interaction analysis. From this chart, it was observed that EMG and SCL derived features could functionally replace those obtained from ECG. These insights motivate future work on novel sensing modalities, feature design, deep learning approaches, and dimensionality reduction techniques. [ABSTRACT FROM AUTHOR]

Optimism is associated with lower pain sensitivity, positive adjustment to chronic pain, and greater reduction of pain thresholds in a conditioned pain modulation (CPM) paradigm. We hypothesized that participants with higher levels of optimism would experience greater inhibition of suprathreshold pain during CPM. Seventy-seven healthy adults completed a test of optimism, the Life Orientation Test-Revised, as well as measures of depression, pain catastrophizing, and neuroticism. Participants also underwent psychophysical tests of heat pain tolerance, heat pain threshold, and CPM. CPM magnitude was calculated as the change in heat pain ratings when applied alone and simultaneously with painful pressure. Greater optimism was significantly correlated with reduced CPM magnitude (P = .013). Regression analysis was performed using optimism as a predictor of CPM magnitude while controlling for pain catastrophizing, neuroticism, depression, and age. The overall model was significant (P = .003). Significant positive coefficients were found for depression (P = .014) and optimism (P < .001) scores. These results suggest that greater optimism predicts less inhibition of suprathreshold pain, the opposite of our hypothesis. This unexpected finding may be due to factors such as perceived stress and coping differences, and suggests that modulation of threshold-level and suprathreshold pain involves different underlying mechanisms. PERSPECTIVE: This article reports that greater optimism predicts less inhibition of suprathreshold pain, in contrast with previous work showing that optimism correlates positively with pain threshold reductions. These findings suggest that the association between optimism and the function of endogenous pain modulatory systems is complex and differs for threshold-level and suprathreshold pain. [ABSTRACT FROM AUTHOR]

Different paradigms can assess the effect of conditioned pain modulation (CPM). The aim of the present study was to compare heat pain, as an often used test stimulus (TS), to painful cutaneous electrical stimulation (PCES), having the advantage of the additional recording of PCES-related evoked potentials. In 28 healthy subjects we applied heat and PCES at the dominant hand as test stimulus (TS) to compare the CPM-effect elicited by hand immersion into cold water (10 °C) as conditioning stimulus (CS). Subjects rated the pain intensity of TS at baseline, during and 5 min after CS application and additionally of CS, on a numerical rating scale (NRS) (0–100). The ‘early’ (during CS–before CS) and ‘late’ (after CS–before CS) CPM-effects were analyzed. Parallel to the PCES, the related evoked potentials were recorded via Cz to evaluate any changes in PCES-amplitudes. CS reduced significantly the pain intensity of both PCES and heat pain as TS. On a group level, the CPM-effect did not differ significantly between both paradigms. Both early and late CPM-effect based on PCES correlated significantly with the CS pain intensity (r = −0.630 and −0.503, respectively), whereas using heat pain the correlation was not significant. We found a significant reduction of PCES-amplitudes during CS, but this did not correlate with the PCES-induced pain intensity. Correlation with the CS painfulness (r = −0.464) did not achieve the significance level after Bonferroni correction. The extent of the CPM effects was similar in both testing paradigms at group level, despite intraindividual differences. Future studies should further elicit the exact mechanisms explaining the modality of these specific differences.

Conditioned pain modulation (CPM) and temporal summation of pain (TSP) are 2 experimental paradigms capturing endogenous pain modulation, which have repeatedly demonstrated clinical relevance. Conditioned pain modulation describes the inhibition of the pain response to a test stimulus (Ts) when a second noxious stimulus, the conditioning stimulus (CS), is concurrently applied. Temporal summation of pain describes the enhanced pain response to a series of stimuli compared with single stimuli. Temporal summation of pain-limiting effects of CPM are likely but may depend on the stimulus modality of the Ts. This study aimed at investigating these differential effects of stimulus modality. Thirty-five healthy volunteers completed 2 experimental blocks (Ts modality: pressure vs heat) in balanced order. Both blocks consisted of 3 conditions: baseline (no CS), CPM1 (nonpainful CS: 42[degrees]C water bath), and CPM2 (painful CS: 46[degrees]C water bath). Single stimuli and series of stimuli were alternatingly applied to assess TSP by means of a Numerical Rating Scale. Both TSP and CPM were successfully induced with no difference between the 2 Ts modalities. We also detected a significant interaction between TSP and CPM, with higher pain reduction for a series of Ts compared with single Ts during the painful CS. Interestingly, this interaction was modality-dependent: TSP for heat Ts was completely abolished by CPM, whereas this was not the case for pressure Ts. Our findings suggest different forms of central sensitization induced by TSP using either heat or pressure stimuli, which differ in their susceptibility to CPM. Clinical implications and directions for future research are discussed. [ABSTRACT FROM AUTHOR]

Prior research indicates that older adults exhibit a deficient capacity to activate multiple pain inhibitory mechanisms, including pain inhibition after acute exercise termed exercise-induced hypoalgesia (EIH). The influence of physical activity levels and psychological processes on EIH in older adults remains unclear. Purpose: This study examined potential psychological and physical activity predictors of the magnitude of EIH after submaximal isometric exercise in healthy older adult men and women. Methods: Fifty-two healthy older adults completed a test of EIH, the Pain Catastrophizing Scale, the Tampa Scale of Kinesiophobia, and wore an accelerometer on the hip for 1 wk to assess physical activity levels. For the test of EIH, participants complete a 3-min isometric handgrip at 25% of maximum voluntary contraction. Pressure pain thresholds (PPT) and a 30-s continuous heat pain test were completed before and immediately after the exercise. Results: Mixed-model ANOVA revealed that older adults demonstrated significantly decreased PPT after isometric exercise (P = 0.030), and no changes on the heat pain trials from pretest to posttest (P > 0.05). A multiple regression revealed that accumulated moderate to vigorous physical activity (MVPA) per week significantly predicted the change in PPT after exercise (β = 0.35, P = 0.012). Participants who averaged greater MVPA experienced a greater increase in PPT after exercise. No relationships were found with EIH and the psychological variables. Conclusions: Older adults did not exhibit EIH after submaximal isometric exercise. However, those who did more MVPA per week experienced a greater magnitude of pain inhibition after acute exercise. [ABSTRACT FROM AUTHOR]

Fear-avoidance models propose that pain-related fear may spur avoidance behavior leading to chronic pain disability. Pain-related fear elicits avoidance behavior, which is typically aimed at reducing fear. We hypothesized that engaging in avoidance may (paradoxically) increase rather than decrease pain-related fear (ie, bidirectionality hypothesis). In a between-subject design, participants (n = 64) were randomly assigned to the avoidance group or the control group. Avoidance group participants were led to believe they could avoid full exposure to a painful heat stimulus by pressing the stop button, whereas control group participants believed they were exposed to the full painful heat stimulus at all times. In reality and unknown to the participants, the intensity and duration of the heat stimulus was independent of the avoidance response, and was identical in both groups. During the test, the avoidance response (ie, pressing the stop button) was no longer available. As expected, pain-related fear levels were higher after avoiding the painful heat stimulus. Interestingly, in the avoidance group, pain-related fear increased after receiving instructions that avoidance would be possible, even before actually engaging in avoidance behavior. In the control group, no significant change was observed in pain-related fear throughout the experiment. The eyeblink startle measures did not corroborate this data pattern.Perspective: These observations provide partial support for the bidirectionality hypothesis between avoidance behavior and fear. These findings may have clinical implications and suggest that allowing avoidance behaviors during treatment may thwart fear reduction. [ABSTRACT FROM AUTHOR]

Transient receptor potential (TRP) cation channels are the largest group of sensory detector proteins expressed in the nerve terminals of many receptors including nociceptors, and are activated by temperature and chemicals that elicit hot or cold sensations. Antagonists of these channels are likely promising targets for new analgesic drugs at the peripheral and central levels. Because some non-steroidal anti-inflammatory drugs (NSAIDs) are structural analogs of prostaglandins and NSAIDs attenuate heat nociception and mechanical allodynia in models of inflammatory and neuropathic pain, we investigated whether three widely used NSAIDs (diclofenac, ketorolac, and xefocam) affect thermal and mechanical hyperalgesia following the activation of TRPA1 and TRPV1 channels. We measured nociceptive thermal paw withdrawal latencies and mechanical thresholds bilaterally at various time points following intraplantar injection of the TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC) or the TRPV1 agonist capsaicin, or vehicle. When pretreated with vehicle, intraplantar injection of CA, AITC and capsaicin each resulted in significant decreases in thermal withdrawal latency and mechanical threshold in the ipsilateral hindpaw that did not return to baseline for more than 2 h. To test effects of NSAIDS either diclofenac, ketorolac or xefocam was pre-injected in the same hindpaw 35 min prior to CA, AITC or capsaicin. Pretreatment with each of the three NSAIDs produced strong antinociceptive and antihyperalgesic effects lasting approximately 60 min. Thus, we show for the first time that local administration of NSAIDs reduces thermal and mechanical hyperalgesia following TRPA1 or TRPV1 activation. [ABSTRACT FROM AUTHOR]

The comprehensive assessment of pain-related human phenotypes requires combinations of nociceptive measures that produce complex high-dimensional data, posing challenges to bioinformatic analysis. In this study, we assessed established experimental models of heat hyperalgesia of the skin, consisting of local ultraviolet-B (UV-B) irradiation or capsaicin application, in 82 healthy subjects using a variety of noxious stimuli. We extended the original heat stimulation by applying cold and mechanical stimuli and assessing the hypersensitization effects with a clinically established quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain). This study provided a 246 × 10-sized data matrix (82 subjects assessed at baseline, following UV-B application, and following capsaicin application) with respect to 10 QST parameters, which we analyzed using machine-learning techniques. We observed statistically significant effects of the hypersensitization treatments in 9 different QST parameters. Supervised machine-learned analysis implemented as random forests followed by ABC analysis pointed to heat pain thresholds as the most relevantly affected QST parameter. However, decision tree analysis indicated that UV-B additionally modulated sensitivity to cold. Unsupervised machine-learning techniques, implemented as emergent self-organizing maps, hinted at subgroups responding to topical application of capsaicin. The distinction among subgroups was based on sensitivity to pressure pain, which could be attributed to sex differences, with women being more sensitive than men. Thus, while UV-B and capsaicin share a major component of heat pain sensitization, they differ in their effects on QST parameter patterns in healthy subjects, suggesting a lack of redundancy between these models. [ABSTRACT FROM AUTHOR]

Pain is one of the most prominent symptoms of osteoarthritis (OA). However, there is often discordance between the pain experienced by individuals with OA and the degree of articular pathology. This suggests that individual differences, including genetic variability in the central processing of nociceptive stimuli, may impact the presentation of OA. Here we show that the SNP rs16868943 in the collagen gene COL11A2 is significantly associated with lowered heat pain tolerance on the arm in participants with knee OA (P=1.21x10-6, P=0.0053 after Bonferroni correction, beta= -3.42). A total of 161 knee OA participants were included and evaluated for heat, punctate and pressure pain sensitivity of the affected knee and the ipsilateral arm. Each participant was genotyped for 4392 SNPs in genes implicated in pain perception, inflammation and mood and tested for association with pain sensitivity. The minor A allele of SNP rs16868943 was significantly associated with lower arm heat pain tolerance after correction for age, gender, race and study site. This SNP was also nominally associated with other measures of heat pain sensitivity, including lowered knee heat pain tolerance (P=1.14x10-5, P=0.05 after Bonferroni correction), lowered arm heat pain threshold (P=0.0039, uncorrected) and lowered knee heat pain threshold (P=0.003, uncorrected). Addition of genotypes from 91 participants without knee pain produced a significant interaction between knee OA status and the rs16868943 SNP in heat pain tolerance (P=1.71x10-5), such that rs16868943 was not associated with heat pain tolerance in participants without knee pain (P=0.12, beta=1.3). This is the first study to show genetic association with heat pain tolerance in individuals with OA. The association is specific to participants who have already developed knee OA, suggesting that the COL11A2 gene, which has previously been associated with familial OA, may play a role in pain sensitization after the development of OA. [ABSTRACT FROM AUTHOR]

Key points Voltage-gated sodium channels play a fundamental role in determining neuronal excitability., Specifically, voltage-gated sodium channel subtype NaV1.7 is required for sensing acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown., Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for NaV1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling., These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality-specific manner and help to direct drug discovery efforts towards novel visceral analgesics., Abstract Voltage-gated sodium channel NaV1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of NaV1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific NaV1.7 knockout mouse (NaV1.7Nav1.8) and selective small-molecule NaV1.7 antagonist PF-5198007. NaV1.7Nav1.8 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both NaV1.7Nav1.8 and littermate controls. Loss, or blockade, of NaV1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of NaV1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed NaV1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of NaV1.7 (in NaV1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective NaV1.7 antagonist PF-5198007. Our data demonstrate that NaV1.7 (in NaV1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of NaV1.7 alone in the viscera may be insufficient in targeting chronic visceral pain. [ABSTRACT FROM AUTHOR]

The demographic factors of sex, age, and race/ethnicity are well recognized as relevant to pain sensitivity and clinical pain expression. Of these, sex differences have been the most frequently studied, and most of the literature describes greater pain sensitivity for women. The other 2 factors have been less frequently evaluated, and current literature is not definitive. Taking advantage of the large Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study cohort, we evaluated the association of sex, age, and self-reported race with 34 measures of pressure, mechanical, and thermal pain sensitivity encompassing threshold and suprathreshold perception. Women were significantly more pain-sensitive than men for 29 of 34 measures. Age effects were small, and only significant for 7 of 34 measures, however, the age range was limited (18-44 years of age). Race/ethnicity differences varied across groups and pain assessment type. Non-Hispanic white individuals were less pain-sensitive than African-American (for 21 of 34 measures), Hispanic (19 of 34), and Asian (6 of 34) individuals. No pain threshold measure showed significant racial differences, whereas several suprathreshold pain measures did. This suggests that racial differences are not related to tissue characteristics or inherent nociceptor sensitivity. Rather, the differences observed for suprathreshold pain ratings or tolerance are more likely related to differences in central nociceptive processing, including modulation imposed by cognitive, psychological, and/or affective factors.Perspective: The influence of sex, age, and race/ethnicity on various aspects of pain sensitivity, encompassing threshold and suprathreshold measures and multiple stimulus modalities, allows for a more complete evaluation of the relevance of these demographic factors to acute pain perception. [ABSTRACT FROM AUTHOR]

Objective : Assessment of the analgesic effect of an agent in an experimental pain model permits a level of control not possible in a clinical pain setting and is an ideal approach for evaluation of analgesic drugs. The aim of the present study was to establish a simple and reliable method of producing experimental pain, which can be used for screening of various analgesic agents. Materials and Methods: The standardized method was followed in all cases, by recording thermal pain threshold in seconds in 24 healthy volunteers using hot air source at two different speeds, which is equipped in an acrylic-made chamber adjustable to three different levels. Reproducibility of the test procedure was evaluated by recording the thermal threshold parameter by a single observer on two sessions (interday reproducibility) and second observer on one session (interobserver reproducibility) separately. Validity of model was further tested by evaluating the analgesic effect of tramadol on 12 healthy volunteers. Results: Thermal pain model was found to produce low variability with coefficient of variation (CV) less than 10%. Interobserver and interday reproducibility were very good, as shown by Bland-Altman plot, with most of the values within ± 2SD. There was a significant increase in pain threshold time with use of tramadol as compared to placebo which was statistically significant (P < 0.05). Conclusion: The newly developed pain model offers a stable and sensitive method for the early assessment of analgesic activity.