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Pain sensitivity of healthy subjects in the cold-pressor (CP) test was proposed to be dichotomously distributed and to represent a pain sensitivity trait. Still, it has not been systematically explored which factors influence this pain sensitivity readout. The aim of this study was to distinguish potential contributions of local tissue-related factors such as perfusion and thermoregulation or gain settings in nociceptive systems. Cold-pressor–sensitive and CP-insensitive students screened from a medical student laboratory course were recruited for a CP retest with additional cardiovascular and bilateral local vascular monitoring. In addition, comprehensive quantitative sensory testing according to Deutscher Forschungsverbund Neuropathischer Schmerz standards and a sustained pinch test were performed. Cold pressor was reproducible across sessions (Cohen kappa 0.61 ± 0.14, P < 0.005). At 30 seconds in ice water, CP-sensitive subjects exhibited not only more pain (78.6 ± 26.3 vs 29.5 ± 17.5, P < 0.0001) but also significantly stronger increases in mean arterial blood pressure (12.6 ± 9.3 vs 5.6 ± 8.1 mm Hg, P < 0.05) and heart rate (15.0 ± 8.2 vs 7.1 ± 6.2 bpm, P < 0.005), and lower baroreflex sensitivity, but not local or vasoconstrictor reflex–mediated microcirculatory responses. Cold-pressor–sensitive subjects exhibited significantly lower pain thresholds also for cold, heat, and blunt pressure, and enhanced pain summation, but no significant differences in Aδ-nociceptor–mediated punctate mechanical pain. In conclusion, differences in nociceptive signal processing drove systemic cardiovascular responses. Baroreceptor activation suppressed pain and cardiovascular responses more efficiently in CP-insensitive subjects. Cold-pressor sensitivity generalized to a pain trait of C-fiber–mediated nociceptive channels, which was independent of local thermal and vascular changes in the ice-water–exposed hand. Thus, the C-fiber pain trait reflects gain setting of the nociceptive system. [ABSTRACT FROM AUTHOR]

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]

OBJECTIVE: The study aimed to evaluate the applicability and repeatability of cold stimulation in dogs. ANIMALS: 10 healthy Beagle dogs were used in a blinded cross-over experiment. METHODS: Measurements were performed in triplicate at 4 skin locations. The probe was manually placed, and temperature decreased (32 to 10 °C) at different cooling rates (0.5, 1, and 5 °C second-1) and latency was measured (11 °C for 60 seconds). Stimulations were discontinued when avoidance reactions were detected. Thermal threshold or time-to-reaction were recorded. Experiments were performed 3 times per animal in weeks 1 (Exp1), 2 (Exp2), and 5 (Exp3). Feasibility of cold stimulation was scored (0-5). Data were analyzed with mixed logistic regression. RESULTS: No significant differences in number of avoidance reactions between cooling-rates were detected. Significantly more reactions (P < .001) were observed during Exp1 compared to Exp2 and Exp3. Thermal thresholds were 13 ± 2.6 °C, 17.7 ± 4 °C and 16.3 ± 4.6 °C for 5, 0.5 and 1 °C second-1, respectively. Latency to the reaction was determinable in 37% of measurements. The mean time-to-reaction was 13 ± 11 seconds. In 85% of measurements, a feasibility score of 0 (best feasibility) was assigned. CLINICAL RELEVANCE: The method is easily applicable and well tolerated, but habituation could not be excluded. Overall, the aversiveness of cold stimulation in healthy dogs is limited and it is not possible to recommend a specific protocol. In future studies, it needs to be determined if the aversiveness of cold stimulation is increased in diseased dogs. [ABSTRACT FROM AUTHOR]

The influence of repeated exposures to cold pain stimulus, a surrogate of clinical pain, has remained largely unexplored. The study was planned to test the effect of repeated exposures to cold pain through cold pressor task on pain sensitivity and vascular reactivity. Single-group experimental study. Thirty-seven healthy male volunteers (18–25 years) were exposed to cold pressor tasks for seven consecutive days and on the 14th day on the nondominant hand. The same was repeated on dominant hand on first and seventh days; 31 completed the protocol. Pain threshold and tolerance in the nondominant hand increased from day 1 to day 7 (p < 0.001) and were positively correlated on day 1 (ρ =0.45, p = 0.011) and day 7 (ρ =0.38, p = 0.036). Diastolic blood pressure response was found to increase by day 7 (p < 0.0024) and positively correlated with tolerance. On the dominant hand, the threshold reduced from day 1 to day 7, while tolerance increased. Both threshold and tolerance remained lower than that of nondominant hand. Day 14 values of threshold and tolerance were in between day 1 and day 7 values but not significantly different from both. Habituation in pain threshold and tolerance was observed on repeated exposure to cold pain, which was not significantly retained till the 14th day. The same was not observed with subjective feeling of pain perception. The increased diastolic blood pressure response is suggestive of peripheral vasoconstriction. Increased tolerance in the dominant hand by day 7 demonstrates a systemic effect in habituation. [ABSTRACT FROM AUTHOR]

Effective treatments for patients experiencing temperature-related symptoms are limited. The hot and cold effects of traditional herbal medicines have been utilized to treat and manage these symptoms, but their molecular mechanisms are not fully understood. Previous studies with arbitrarily selected herbs and ingredients may have produced biased results. Here, we aim to systematically elucidate the molecular mechanisms of the hot and cold properties of herbal medicines through an unbiased large-scale investigation of herbal ingredients, their target genes, and the transcriptome signatures induced by them. Using data regarding 243 herbs retrieved from two herbal medicine databases, we statistically identify (R)-Linalool, (-)-alpha-pinene, peruviol, (L)-alpha-terpineol, and cymol as five new hot-specific ingredients that share a common target, a norepinephrine transporter. However, no significant ingredients are cold-specific. We also statistically identify 14 hot- and 8 cold-specific new target genes. Pathway enrichment analysis of hot-specific target genes reveals the associated pathways including neurotransmitter reuptake, cold-induced thermogenesis, blood pressure regulation, adrenergic receptor signaling, and cation symporter activity. Cold-specific target genes are associated with the steroid pathway. Transcriptome analysis also shows that hot herbs are more strongly associated with coagulation and synaptic transmission than cold herbs. Our results, obtained from novel connections between herbal ingredients, target genes, and pathways, may contribute to the development of pharmacological treatment strategies for temperature-related pain using medicinal plants. [ABSTRACT FROM AUTHOR]

Objective: The 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. Methods: Thirty 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. Results: Significant 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). Conclusion: Significant 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]. [ABSTRACT FROM AUTHOR]

Objective: Pain assessment is of great importance in both clinical research and patient care. Facial expression analysis is becoming a key part of pain detection because it is convenient, automatic, and real-time. The aim of this study is to present a cold pain intensity estimation experiment, investigate the importance of the spatial-temporal information on facial expression based cold pain, and study the performance of the personalized model as well as the generalized model. Methods: A cold pain experiment was carried out and facial expressions from 29 subjects were extracted. Three different architectures (Inception V3, VGG-LSTM, and Convolutional LSTM) were used to estimate three intensities of cold pain: No pain, Moderate pain, and Severe Pain. Architectures with Sequential information were compared with single-frame architecture, showing the importance of spatial-temporal information on pain estimation. The performances of the personalized model and the generalized model were also compared. Results: A mean F1 score of 79.48% was achieved using Convolutional LSTM based on the personalized model. Conclusion: This study demonstrates the potential for the estimation of cold pain intensity from facial expression analysis and shows that the personalized spatial-temporal framework has better performance in cold pain intensity estimation. Significance: This cold pain intensity estimator could allow convenient, automatic, and real-time use to provide continuous objective pain intensity estimations of subjects and patients.

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].

Effective treatments for patients experiencing temperature-related symptoms are limited. The hot and cold effects of traditional herbal medicines have been utilized to treat and manage these symptoms, but their molecular mechanisms are not fully understood. Previous studies with arbitrarily selected herbs and ingredients may have produced biased results. Here, we aim to systematically elucidate the molecular mechanisms of the hot and cold properties of herbal medicines through an unbiased large-scale investigation of herbal ingredients, their target genes, and the transcriptome signatures induced by them. Using data regarding 243 herbs retrieved from two herbal medicine databases, we statistically identify (R)-Linalool, (-)-alpha-pinene, peruviol, (L)-alpha-terpineol, and cymol as five new hot-specific ingredients that share a common target, a norepinephrine transporter. However, no significant ingredients are cold-specific. We also statistically identify 14 hot- and 8 cold-specific new target genes. Pathway enrichment analysis of hot-specific target genes reveals the associated pathways including neurotransmitter reuptake, cold-induced thermogenesis, blood pressure regulation, adrenergic receptor signaling, and cation symporter activity. Cold-specific target genes are associated with the steroid pathway. Transcriptome analysis also shows that hot herbs are more strongly associated with coagulation and synaptic transmission than cold herbs. Our results, obtained from novel connections between herbal ingredients, target genes, and pathways, may contribute to the development of pharmacological treatment strategies for temperature-related pain using medicinal plants.

Abstract: The proper detection and behavioral response to painfully cold temperatures is critical for avoiding potentially harmful tissue damage. Cold allodynia and hyperalgesia, pain associated with innocuous cooling and exaggerated pain with noxious cold, respectively, are common in patients with chronic pain. In peripheral somatosensory afferents, the ion channels transient receptor potential melastatin 8 (TRPM8) and transient receptor potential ankyrin 1 (TRPA1) are candidate receptors for innocuous and noxious cold temperatures, respectively. However, the role of TRPA1 as a cold sensor has remained controversial, and recent evidence suggests that TRPM8 channels and afferents mediate the detection of both pleasant and painful cold. To determine the role of TRPA1 afferents in cold-induced mouse behaviors in vivo, we used functional phenotyping by targeted nerve conduction block with the cell-impermeant lidocaine derivative QX-314. Surprisingly, we find that injection of QX-314 with TRPA1 agonists reduces cold-induced behaviors in mice, but does so in a TRPM8-dependent manner. Moreover, this effect is sexually dimorphic and requires the glial cell line-derived neurotrophic factor receptor GFRα3, as does cold hypersensitivity produced by the activation of TRPA1 channels. Taken together, these results suggest that under conditions of neurogenic inflammation, TRPA1 works upstream of GFRα3 and TRPM8 to produce cold hypersensitivity, providing novel insights into the role of TRPA1 channels in cold pain. [ABSTRACT FROM AUTHOR]

Abstract Background Activating transcription factor 2 (ATF2) is a member of the leucine zipper family of DNA binding proteins and is widely distributed in tissues. Several recent studies have demonstrated that this protein is involved in mechanisms that are related to pain and inflammation. However, unclear is whether polymorphisms of the ATF2 gene, which encodes the human ATF2 protein, influence pain or analgesic sensitivity. This study examined associations between the analgesic effect of fentanyl in the cold pressor‐induced pain test and polymorphisms in the ATF2 gene in 355 Japanese subjects. Results In this study, 33 single nucleotide polymorphisms (SNPs) were selected, and a total of 2 linkage disequilibrium blocks with 6 Tag SNPs (rs1153702, rs7583431, rs2302663, rs3845744, rs268214, and rs1982235) were observed in the region within and around the ATF2 gene. We further analyzed associations between these Tag SNPs and clinical data. Even after multiple testing with Bonferroni adjustments, an increase in the analgesic effect of fentanyl in the cold pressor‐induced pain test was significantly associated with a greater number of the A allele of the rs7583431 SNP (linear regression, P = .001). Conclusions The present findings may contribute to adequate pain relief in individual patients. Although more research on the genetic factors that influence opioid sensitivity is needed, analgesic requirements may be predicted by analyzing ATF2SNPs, together with other polymorphisms of genes that are reportedly associated with opioid sensitivity, such as CREB1, OPRM1, and GIRK2.

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• Innocuous cold and noxious cold elicits activation in distinct brain areas. • Innocuous cold activates secondary somatosensory and insula cortices. • Noxious and innocuous cold activates anterior and posterior insula, respectively. Humans have a sophisticated set of neural structures for cutaneous thermoception. Sufficiently cold temperatures are thought to evoke pain and motivation to resolve disturbed homeostasis, while cool but not painful temperatures are evaluated as cold but do not cause thermoregulatory behaviour. Brain networks for innocuous and noxious cold temperature have been proposed but a quantitative meta-analysis comparing the two has never been conducted. As a result, we sought to perform activation likelihood estimation analysis of the brain activity associated with innocuous and noxious cold exposure. Combining data from 33 data sets revealed that innocuous cold exposure activates the posterior insular, middle/orbital and posterior parietal cortices while noxious cold activates the thalamus, putamen, and right anterior insula cortex. Both conditions respectively show greater activation in these areas and no areas are common between conditions. Our results confirm the long-standing hypothesis that noxious cold is encoded in the right anterior insula, but contradicts the selective importance of the posterior insula for cool somatosensory processing. [ABSTRACT FROM AUTHOR]

Conditioned pain modulation (CPM) is an endogenous pain inhibition phenomenon that can be summarized simply as one type of pain being able to inhibit another, which must be in a remote area in relation to the first pain. We aimed to compare the effectiveness of four CPM test paradigms as well as the association of the CPM effect with potential predictors in 72 healthy volunteers. Pressure pain from an algometer was used as the test stimulus, and pain provoked by cold water or ischemic pressure was used as the conditioning stimulus, applied either sequentially or in parallel. No significant differences were found between the test paradigms, although the cold-parallel test showed the most significant effect size (ηP2 = 0.614). No association was found between the CPM effect and sociodemographic variables (age or sex), nor anxiety, depression, catastrophizing, previous history of pain or self-perceived pain tolerance. Nevertheless, a strong association was found between the CPM effect and individual affinity for the stimulus in participants who underwent the cold water test paradigm; this explained around 45% of the total CPM effect when the paradigm (cold water) coincided with personal affinity for the stimulus (“I prefer cold to heat”, “cold is not unpleasant”).

Objective: The study aimed to evaluate the applicability and repeatability of cold stimulation in dogs., Animals: 10 healthy Beagle dogs were used in a blinded cross-over experiment., Methods: Measurements were performed in triplicate at 4 skin locations. The probe was manually placed, and temperature decreased (32 to 10 °C) at different cooling rates (0.5, 1, and 5 °C second-1) and latency was measured (11 °C for 60 seconds). Stimulations were discontinued when avoidance reactions were detected. Thermal threshold or time-to-reaction were recorded. Experiments were performed 3 times per animal in weeks 1 (Exp1), 2 (Exp2), and 5 (Exp3). Feasibility of cold stimulation was scored (0-5). Data were analyzed with mixed logistic regression., Results: No significant differences in number of avoidance reactions between cooling-rates were detected. Significantly more reactions (P < .001) were observed during Exp1 compared to Exp2 and Exp3. Thermal thresholds were 13 ± 2.6 °C, 17.7 ± 4 °C and 16.3 ± 4.6 °C for 5, 0.5 and 1 °C second-1, respectively. Latency to the reaction was determinable in 37% of measurements. The mean time-to-reaction was 13 ± 11 seconds. In 85% of measurements, a feasibility score of 0 (best feasibility) was assigned., Clinical Relevance: The method is easily applicable and well tolerated, but habituation could not be excluded. Overall, the aversiveness of cold stimulation in healthy dogs is limited and it is not possible to recommend a specific protocol. In future studies, it needs to be determined if the aversiveness of cold stimulation is increased in diseased dogs.

Approximately one-third of individuals with sickle cell disease (SCD) develop chronic pain. This debilitating pain is inadequately treated because the underlying mechanisms driving the pain are poorly understood. In addition to persistent pain, patients with SCD are also in a tonically proinflammatory state. Previous studies have revealed that there are elevated plasma levels of many inflammatory mediators including chemokine (c-c motif) ligand 2 (CCL2) in individuals with SCD. Using a transgenic mouse model of SCD, we investigated the contributions of CCL2 signaling to SCD-related pain. Inhibition of chemokine receptor 2 (CCR2), but not CCR4, alleviated the behavioral mechanical and cold hypersensitivity in SCD. Furthermore, acute CCR2 blockade reversed both the behavioral and the in vitro responsiveness of sensory neurons to an agonist of TRPV1, a neuronal ion channel previously implicated in SCD pain. These results provide insight into the immune-mediated regulation of hypersensitivity in SCD and could inform future development of analgesics or therapeutic measures to prevent chronic pain. [ABSTRACT FROM AUTHOR]

Transient receptor potential ankyrin 1 (TRPA1), a cold receptor in sensory neurons activated by a variety of stimuli, is implicated in nociception and mechanotransduction. To help understand the vesicular glutamate transporter (VGLUT)-mediated glutamate signaling in TRPA1-immunopositive (+) neurons, we examined the expression of VGLUT1 and VGLUT2 in the TRPA1+ neurons in the male rat trigeminal ganglion (n = 19) under normal conditions and following experimental inflammation in the vibrissal pad by light microscopic immunohistochemistry (n = 11), western blot (n = 8), and quantitative analysis. One half (50.8%, 250/492) of the TRPA1+ neurons expressed VGLUT2, and a small fraction (8.3%, 57/683) also expressed VGLUT1. The majority of the VGLUT2-expressing TRPA1+ (VGLUT2+/TRPA1+) neurons coexpressed the markers of peptidergic and non-peptidergic neurons, CGRP, IB4, and TRPV1 but not the markers of neurons with myelinated fibers, NF200 and parvalbumin. In contrast, most VGLUT1+/TRPA1+ neurons coexpressed NF200 and parvalbumin but rarely expressed CGRP, IB4, or TRPV1. Following experimental inflammation, the fraction of VGLUT2+ (experimental vs. control: 34.7% vs. 22.3%), TRPA1+ (39.3% vs. 25.3%), and VGLUT2+/TRPA1+ (60.7% vs. 49.7%) neurons and the protein levels for TRPA1 and VGLUT2 increased significantly, compared to control, whereas the fraction of VGLUT1+ and VGLUT1+/TRPA1+ neurons and the protein level for VGLUT1 remained unchanged. These findings suggest that both VGLUT1 and VGLUT2 are involved in the glutamate signaling in TRPA1+ neurons under normal conditions in the male rats, and raise a possibility that VGLUT2 may play a role in the TRPA1-induced hypersensitivity following inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Activating transcription factor 2 (ATF2) is a member of the leucine zipper family of DNA binding proteins and is widely distributed in tissues. Several recent studies have demonstrated that this protein is involved in mechanisms that are related to pain and inflammation. However, unclear is whether polymorphisms of the ATF2 gene, which encodes the human ATF2 protein, influence pain or analgesic sensitivity. This study examined associations between the analgesic effect of fentanyl in the cold pressor‐induced pain test and polymorphisms in the ATF2 gene in 355 Japanese subjects. Results: In this study, 33 single nucleotide polymorphisms (SNPs) were selected, and a total of 2 linkage disequilibrium blocks with 6 Tag SNPs (rs1153702, rs7583431, rs2302663, rs3845744, rs268214, and rs1982235) were observed in the region within and around the ATF2 gene. We further analyzed associations between these Tag SNPs and clinical data. Even after multiple testing with Bonferroni adjustments, an increase in the analgesic effect of fentanyl in the cold pressor‐induced pain test was significantly associated with a greater number of the A allele of the rs7583431 SNP (linear regression, P = .001). Conclusions: The present findings may contribute to adequate pain relief in individual patients. Although more research on the genetic factors that influence opioid sensitivity is needed, analgesic requirements may be predicted by analyzing ATF2SNPs, together with other polymorphisms of genes that are reportedly associated with opioid sensitivity, such as CREB1, OPRM1, and GIRK2. [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]

The molecular sensor of innocuous (painless) cold sensation is well-established to be transient receptor potential cation channel, subfamily M, member 8 (TRPM8). However, the role of transient receptor potential cation channel, subfamily A, member 1 (TRPA1) in noxious (painful) cold sensation has been controversial. We find that TRPA1 channels contribute to the noxious cold sensitivity of mouse somatosensory neurons, independent of TRPM8 channels, and that TRPA1-expressing neurons are largely non-overlapping with TRPM8-expressing neurons in mouse dorsal-root ganglia (DRG). However, relatively few TRPA1-expressing neurons (e.g., responsive to allyl isothiocyanate or AITC, a selective TRPA1 agonist) respond overtly to cold temperature in vitro , unlike TRPM8-expressing neurons, which almost all respond to cold. Using somatosensory neurons from TRPM8−/− mice and subtype-selective blockers of TRPM8 and TRPA1 channels, we demonstrate that responses to cold temperatures from TRPA1-expressing neurons are mediated by TRPA1 channels. We also identify two factors that affect the cold-sensitivity of TRPA1-expressing neurons: (1) cold-sensitive AITC-sensitive neurons express relatively more TRPA1 transcripts than cold-insensitive AITC-sensitive neurons and (2) voltage-gated potassium (K V ) channels attenuate the cold-sensitivity of some TRPA1-expressing neurons. The combination of these two factors, combined with the relatively weak agonist-like activity of cold temperature on TRPA1 channels, partially explains why few TRPA1-expressing neurons respond to cold. Blocking K V channels also reveals another subclass of noxious cold-sensitive DRG neurons that do not express TRPM8 or TRPA1 channels. Altogether, the results of this study provide novel insights into the cold-sensitivity of different subclasses of somatosensory neurons. [ABSTRACT FROM AUTHOR]

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

Neuropathic pain can be debilitating and drastically affects the quality of life of those patients suffering from this condition. The Chinese herb Notopterygium incisum Ting ex H.T. Chang has long been used to disperse "cold". One under examined clinical feature of neuropathic pain is sensitivity to cold. Patients with neuropathic pain or arthritis usually describe a worsening of symptoms during the winter. We proposed to test the hypothesis that Notopterygium incisum has a positive effect on the cold sensitivity found in neuropathic pain. In this study, we established chronic constriction injury (CCI) and cisplatin induced neuropathic pain mice models. Behavioral experiments and physiological examination methods were employed to investigate the effect of water extract of Notopterygium incisum (WN) on cold pain. We found WN reduced cold pain and allyl isothiocyanate (AITC, Transient Receptor Potential A1 (TRPA1 agonist)) induced pain. WN inhibited AITC induced calcium response in HEK 293 cells transfected with TRPA1 and dorsal root ganglion (DRG) neurons. Moreover, we found that oral administration of WN reduced cold allodynia and mechanical allodynia caused by (CCI) and cisplatin induced neuropathic pain. We also observed that oral administration of WN decreased responses to AITC in DRG neurons as well as expression of TRPA1 in the WN treated neuropathic pain model. The present study provide evidence that Notopterygium incisum alleviates cold allodynia in CCI and cisplatin induced neuropathic pain mouse models. WN alleviated neuropathic pain induced cold allodynia via directly modulating TRPA1. Our findings identify WN as a promising candidate for treating neuropathic pain that highlights a new mechanism of Notopterygium incisum on 'disperse cold'. • WN reduced cold pain and allyl isothiocyanate (AITC, Transient Receptor Potential A1 (TRPA1 agonist)) induced pain by inhibiting TRPA1 directly. • WN reduced chronic constriction injury (CCI) and cisplatin induced cold allodynia in neuropathic pain by inhibiting TRPA1. [ABSTRACT FROM AUTHOR]

Cold temperature detection involves the process of sensory transduction in cutaneous primary sensory nerve terminals, which converts thermal stimuli into depolarizations of the membrane. This transformation into electrical signals is followed by the subsequent propagation of action potentials in cold-sensitive afferent nerve fibers. A large array of ion channels shapes this process; however, the precise contribution of specific ion channel subtypes to cold perception and cold pain remains elusive. This review aims at giving an update on our current understanding of the role played by TRPs, leak K+ and voltage-gated Na+ and K+ channels in the transduction of cold by nociceptors and in cold-induced pain. [ABSTRACT FROM AUTHOR]

Transient receptor potential melastatin 8 (TRPM8) is activated by innocuous cool and noxious cold and plays a crucial role in cold-induced acute pain and pain hypersensitivity. To help understand the mechanism of TRPM8-mediated cold perception under normal and pathologic conditions, we used light microscopic immunohistochemistry and Western blot analysis in mice expressing a genetically encoded axonal tracer in TRPM8-positive (+) neurons. We investigated the coexpression of TRPM8 and vesicular glutamate transporter 1 (VGLUT1) and VGLUT2 in the trigeminal ganglion (TG) and the dental pulp before and after inducing pulpal inflammation. Many TRPM8+ neurons in the TG and axons in the dental pulp expressed VGLUT2, while none expressed VGLUT1. TRPM8+ axons were dense in the pulp horn and peripheral pulp and also frequently observed in the dentinal tubules. Following pulpal inflammation, the proportion of VGLUT2+ and of VGLUT2+/TRPM8+ neurons increased significantly, whereas that of TRPM8+ neurons remained unchanged. Our findings suggest the existence of VGLUT2 (but not VGLUT1)-mediated glutamate signaling in TRPM8+ neurons possibly underlying the cold-induced acute pain and hypersensitivity to cold following pulpal inflammation. [ABSTRACT FROM AUTHOR]

Background The P2X7 receptor is a member of the P2X family of adenosine 5'-triphosphate-gated cation channels. Several recent studies have demonstrated that this receptor is involved in mechanisms related to pain and inflammation. However, unknown is whether polymorphisms of the P2RX7 gene that encodes the human P2X7 receptor influence pain sensitivity and analgesic effects of opioids. The P2RX7 gene is known to be highly polymorphic. Thus, the present study examined associations between fentanyl sensitivity and polymorphisms in the P2RX7 gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery. Results We first conducted linkage disequilibrium (LD) analyses for 55 reported single-nucleotide polymorphisms (SNPs) in the region within and around the P2RX7 gene using genomic samples from 100 patients. In our samples, 42 SNPs were polymorphic, and a total of five LD blocks with six Tag SNPs (rs2708092, rs1180012, rs1718125, rs208293, rs1718136, and rs7132846) were observed. Thus, we further analyzed associations between genotypes/haplotypes of these Tag SNPs and clinical data using a total of 355 samples. In the genotype-based association study, only the rs1718125 G > A SNP tended to be associated with higher pain scores on a visual analog scale 24 h after surgery (VAS24). The haplotypebased association study showed that subjects with homozygous haplotype No.3 (GTAAAC; estimated frequency: 15.0%) exhibited significantly higher cold pain sensitivity and lower analgesic effects of fentanyl for acute cold pain in the cold pressor test. Conversely, subjects who carried haplotype No.1 (ACGGAC; estimated frequency: 24.5%) tended to exhibit lower cold pain sensitivity and higher analgesic effects of fentanyl. Furthermore, subjects with homozygous haplotype No.2 (GCGGAC; estimated frequency: 22.9%) exhibited significantly lower VAS24 scores. Conclusions Cold pain sensitivity and analgesic effects of fentanyl were related to the SNP and haplotypes of the P2RX7 gene. The patients with the rs1718125 G>A SNP tended to show higher VAS24 scores. Moreover, the combination of polymorphisms from the 5'-flanking region to exon 5 recessively affected cold pain sensitivity and analgesic effects of opioids for acute cold pain. The present findings shed light on the involvement of P2RX7 gene polymorphisms in naive cold pain sensitivity and analgesic effects of fentanyl. [ABSTRACT FROM AUTHOR]

Nordihydroguaiaretic acid (NDGA) is a major biologically active component of the creosote bush, Larrea tridentate, widely used in unregulated therapies. NDGA is a lipoxygenase inhibitor while a derivative, terameprocol, has been trialed as a chemotherapeutic agent. When investigating fatty acid activation of the human transient receptor potential cation channel subfamily A, member 1 ( hTRPA1), we found that NDGA activated the channel. Here we investigate the actions of NDGA and terameprocol at hTRPA1 and the consequences of this for noxious cold sensitivity in mice. hTRPA1 was stably expressed in HEK 293 cells (HEK 293-TRPA1) and channel activity examined by measuring changes in intracellular calcium ([Ca]i) using a fluorescent dye and activation of membrane currents using patch clamp electrophysiology. The effects of local NDGA and terameprocol application on acetone-induced paw flinching were examined in mice. NDGA ( pEC50 of 5.4 ± 0.1, maximum change in fluorescence of 385 ± 30%) and terameprocol ( pEC50 4.5 ± 0.2, maximum 550 ± 75%) increased [Ca]i in HEK 293- hTRPA1 cells. NDGA also induced an increase in membrane conductance in HEK 293- hTRPA1 cells. These effects were prevented by the TRPA1 antagonist HC-030031, and were dependent on the presence of Cys621, Cys 641, and Cys 665 in hTRPA1. Neither NDGA nor terameprocol alone produced spontaneous pain behaviors in mice after hind paw injection, but both enhanced responses to acetone. NDGA and terameprocol are efficacious activators of TRPA1. NDGA should be used with care to probe lipoxygenase involvement in nociception while TRPA1 activity should be considered when considering use of these drugs in humans. [ABSTRACT FROM AUTHOR]