How can the pain sensitivity to be affected by maximal progressive exercise test during pregnancy?

The multidimensional etiology of pain may explain the beneficial effects of regular physical activity, as evidenced by increased pain tolerance. Physically active people find it easier to exert themselves, which enables them to increase their physical activity, which in turn leads to a reduction in pain. However, no study investigated the physical activity and exercise tests as modulators of pain sensitivity in pregnant women. Therefore, this study aimed to investigate the changes in pain perception in pregnant women during pregnancy, with a particular interest in the effects of maximal progressive exercise test (CPET) and self-performed physical activity (PA). Thirty-one women with an uncomplicated singleton pregnancy (aged 23-41 years; M = 31.29, SD = 4.18) were invited to participate in pain sensitivity measurements before and after CPET twice during pregnancy (with an 8-week break). We found that pregnant women had a significantly lower pain threshold after a maximal exercise test than before, regardless of whether the test was performed in the second or third trimester of pregnancy. This effect was most pronounced in women with low levels of physical activity. Second, women with high physical activity had higher pain tolerance than women with moderate and low physical activity. In addition, physical activity levels predicted changes in pain tolerance over the course of pregnancy, with negative changes in women with low physical activity and positive changes in women with moderate physical activity. Finally, these associations were not reflected in differences in the subjective pain experience.

Comparison of Thermal and Mechanical Pain Testing Modalities in Sprague Dawley and Fischer 344 Rats (Rattus norvegicus).

While rodents are used extensively for studying pain, there is a lack of reported direct comparisons of thermal and mechanical pain testing methods in rats of different genetic backgrounds. Understanding the range of interindividual variability of withdrawal thresholds and thermal latencies based on these testing methods and/or genetic background is important for appropriate experimental design. Testing was performed in two common rat genetic backgrounds: outbred Sprague-Dawley (SD) and inbred Fischer 344 (F344). Male and female, 10- to 14-wk-old F344 and SD rats were used to assess withdrawal thresholds in 3 different modalities: the Randall-Selitto test (RST), Hargreaves test (HT), and tail flick test (TFT). The RST was performed by using an operator-controlled handheld instrument to generate a noxious pressure stimulus to the left hind paw. The HT and the TFT used an electronically controlled light source to deliver a noxious thermal stimulus to the left hind paw or tail tip, respectively. Rats of each sex and genetic background underwent one type of test on day 0 and day 7. Withdrawal thresholds and thermal latencies were compared among tests. No significant differences were observed. Our findings can serve as a guide for researchers considering these nociceptive tests for their experiments.

Meningeal lymphatic vessel dysfunction driven by CGRP signaling causes migraine-like pain in mice.

Migraines are a type of headache that occur with other neurological symptoms, but the pathophysiology remains unclear. In this issue of the JCI, Nelson-Maney and authors used constitutive and inducible knockouts of the CGRP receptor components, elegantly demonstrating an essential function of CGRP in modulating meningeal lymphatic vessels (MLVs) in migraine. CGRP was shown to induce rearrangement of membrane-bound gap junction proteins in MLVs, resulting in a reduced CSF flux into cervical lymph nodes. The authors also provided evidence of a primary role for CGRP in modulating neuro-immune function. Finally, by showing that blocking CGRP signaling in MLVs attenuated pain behavior associated with acute migraine in rodents, the authors provided a target for pharmacological blockade of CGRP in relation to primary headache disorders.

Mechanical pain sensitivity is associated with hippocampal structural integrity.

ABSTRACT: Rodents and human studies indicate that the hippocampus, a brain region necessary for memory processing, responds to noxious stimuli. However, the hippocampus has yet to be considered a key brain region directly involved in the human pain experience. One approach to answer this question is to perform quantitative sensory testing on patients with hippocampal damage-ie, medial temporal lobe epilepsy. Some case studies and case series have performed such tests in a handful of patients with various types of epilepsy and have reported mixed results. Here, we aimed to determine whether mechanical pain sensitivity was altered in patients diagnosed with temporal lobe epilepsy. We first investigated whether mechanical pain sensitivity in patients with temporal lobe epilepsy differs from that of healthy individuals. Next, in patients with temporal lobe epilepsy, we evaluated whether the degree of pain sensitivity is associated with the degree of hippocampal integrity. Structural integrity was based on hippocampal volume, and functional integrity was based on verbal and visuospatial memory scores. Our findings show that patients with temporal lobe epilepsy have lower mechanical pain sensitivity than healthy individuals. Only left hippocampal volume was positively associated with mechanical pain sensitivity-the greater the hippocampal damage, the lower the sensitivity to mechanical pain. Hippocampal measures of functional integrity were not significantly associated with mechanical pain sensitivity, suggesting that the mechanisms of hippocampal pain processing may be different than its memory functions. Future studies are necessary to determine the mechanisms of pain processing in the hippocampus.

Benefits of home-based foot neuromuscular electrical stimulation on self-reported function, leg pain and other leg symptoms among community-dwelling older adults: a sham-controlled randomised clinical trial.

INTRODUCTION: Lower leg pain and symptoms, and poor leg circulation are common in older adults. These can significantly affect their function and quality of life. Neuromuscular electrical stimulation (NMES) applied via the feet as 'foot NMES' activates the leg musculovenous pump. This study investigated the effects of foot NMES administered at home using Revitive® among community-dwelling older adults with lower leg pain and/or other lower leg symptoms such as cramps, or sensations of tired, aching, and heavy feeling legs. METHODS: A randomised placebo-controlled study with three groups (2 NMES, 1 Sham) and three assessments (baseline, week 8, week 12 follow-up) was carried out. Self-reported function using Canadian occupational performance measure (COPM), leg pain, overall leg symptoms score (heaviness, tiredness, aching, or cramps), and ankle blood flow were assessed. Analysis of covariance (ANCOVA) and logistic regression were used to compare the groups. Statistical significance was set at p < 0.05 (two-sided 5%). RESULTS: Out of 129 participants enrolled, 114 completed the study. The improvement in all outcomes were statistically significant for the NMES interventions compared to Sham at both week 8 (p < 0.01) and week 12 (p < 0.05). The improvement in COPM met the minimal clinically important difference (MCID) for the NMES interventions compared to Sham at both week 8 (p < 0.005) and week 12 (p < 0.05). Improvement in leg pain met MCID at week 8 compared to Sham (p < 0.05). Ankle blood flow increased approximately 3-fold during treatment compared to Sham. Compliance with the interventions was high and no device-related adverse events were reported. CONCLUSIONS: The home-based foot NMES is safe, and significantly improved self-reported function, leg pain and overall leg symptoms, and increased ankle blood flow compared to a Sham among older adults. TRIAL REGISTRATION: The trial was prospectively registered in ISRCTN on 17/06/2019 with registration number ISRCTN10576209. It can be accessed at https://www.isrctn.com/ISRCTN10576209 .

Females with hip pain walk with altered kinematics at peaks and throughout the gait cycle.

BACKGROUND: Females with acetabular dysplasia and/or labral tears (hip pain) exhibit altered walking kinematics, with studies reporting mixed results in sagittal and frontal planes compared to pain-free controls, often conducting only discrete analyses and warranting further investigation. The objective of this study was to investigate discrete and continuous hip and pelvic kinematics between females with and without hip pain in two walking conditions. METHODS: We collected kinematic walking data from 69 females (35 with hip pain, 34 controls) using motion capture and an instrumented treadmill in two conditions: preferred and fast (125% preferred). We used a general linear model and one-dimensional statistical parametric mapping to conduct discrete and continuous analyses comparing kinematics between groups, with and without adjustment for gait speed. FINDINGS: The hip pain group walked with reduced peak hip extension (Preferred: P = .046, Cohen's d = 0.41; Fast: P = .028, d = 0.48) and greater peak anterior pelvic tilt (Preferred: P = .011, d = 0.57; Fast: P = .012, d = 0.58) compared to controls. From continuous analyses, the hip pain group walked with reduced hip extension during terminal stance (Fast: P = .040), greater anterior pelvic tilt throughout (Preferred: P = .007; Fast: P = .004), and greater contralateral pelvic drop (Preferred: P = .045) during midstance. Adjusting for speed slightly affected p-values, but significance was retained for all prior variables except pelvic drop. INTERPRETATION: Kinematic differences between individuals with and without hip pain may provide insight into potential predisposing factors for hip pathology and/or compensations for pain or pathological processes. This work furthers understanding of altered movement patterns in individuals with hip pain and may inform physical therapy treatments.

Experimental nerve block study on painful withdrawal reflex responses in humans.

The nociceptive withdrawal reflex (NWR) is a protective limb withdrawal response triggered by painful stimuli, used to assess spinal nociceptive excitability. Conventionally, the NWR is understood as having two reflex responses: a short-latency Aß-mediated response, considered tactile, and a longer-latency Aδ-mediated response, considered nociceptive. However, nociceptors with conduction velocities similar to Aß tactile afferents have been identified in human skin. In this study, we investigated the effect of a preferential conduction block of Aß fibers on pain perception and NWR signaling evoked by intradermal electrical stimulation in healthy participants. We recorded a total of 198 NWR responses in the intact condition, and no dual reflex responses occurred within our latency bandwidth (50-150 ms). The current required to elicit the NWR was higher than the perceptual pain threshold, indicating that NWR did not occur before pain was felt. In the block condition, when the Aß-mediated tuning fork sensation was lost while Aδ-mediated nonpainful cooling was still detectable (albeit reduced), we observed that the reflex was abolished. Further, short-latency electrical pain intensity at pre-block thresholds was greatly reduced, with any residual pain sensation having a longer latency. Although electrical pain was unaffected at suprathreshold current, the reflex could not be evoked despite a two-fold increase in the pre-block current and a five-fold increase in the pre-block pulse duration. These observations lend support to the possible involvement of Aß-fiber inputs in pain and reflex signaling.

Posttraumatic headache: pain related evoked potentials (PREP) and conditioned pain modulation (CPM) to assess the pain modulatory function.

Posttraumatic headache (PTH) is common following traumatic brain injury and impacts quality of life. We investigated descending pain modulation as one possible mechanism for PTH and correlated it to clinical measures. Pain-related evoked potentials (PREP) were recorded in 26 PTH-patients and 20 controls after electrical stimulation at the right hand and forehead with concentric surface electrodes. Conditioned pain modulation (CPM) was assessed using painful cutaneous electric stimulation (PCES) on the right hand as test stimulus and immersion of the left hand into 10 °C-cold water bath as conditioning stimulus based on changes in pain intensity and in amplitudes of PCES-evoked potentials. All participants completed questionnaires assessing depression, anxiety, and pain catastrophising. PTH-patients reported significantly higher pain ratings during PREP-recording in both areas despite similar stimulus intensity at pain threshold. N1P1-amplitudes during PREP and CPM-assessment were lower in patients in both areas, but statistically significant only on the hand. Both, PREP-N1-latencies and CPM-effects (based on the N1P1-amplitudes and pain ratings) were similar in both groups. Patients showed significantly higher ratings for anxiety and depression, which did not correlate with the CPM-effect. Our results indicate generalized hyperalgesia for electrical stimuli in both hand and face in PTH. The lacking correlation between pain ratings and EEG parameters indicates different mechanisms of pain perception and nociception.

An externally validated resting-state brain connectivity signature of pain-related learning.

Pain can be conceptualized as a precision signal for reinforcement learning in the brain and alterations in these processes are a hallmark of chronic pain conditions. Investigating individual differences in pain-related learning therefore holds important clinical and translational relevance. Here, we developed and externally validated a novel resting-state brain connectivity-based predictive model of pain-related learning. The pre-registered external validation indicates that the proposed model explains 8-12% of the inter-individual variance in pain-related learning. Model predictions are driven by connections of the amygdala, posterior insula, sensorimotor, frontoparietal, and cerebellar regions, outlining a network commonly described in aversive learning and pain. We propose the resulting model as a robust and highly accessible biomarker candidate for clinical and translational pain research, with promising implications for personalized treatment approaches and with a high potential to advance our understanding of the neural mechanisms of pain-related learning.

Reliability and minimal detectable change of dynamic temporal summation and conditioned pain modulation using a single experimental paradigm.

BACKGROUND: Quantitative sensory tests (QST) are frequently used to explore alterations in somatosensory systems. Static and dynamic QST like pain threshold and temporal summation (TS) and conditioned pain modulation (CPM) are commonly used to evaluate excitatory and inhibitory mechanisms involved in pain processing. The aim of the present study was to document the reliability and the minimal detectable change (MDC) of these dynamic QST measurements using a standardized experimental paradigm. MATERIAL AND METHODS: Forty-six (46) pain-free participants took part in 2 identical sessions to collect TS and CPM outcomes. Mechanical (pressure pain threshold [PPT]) and thermal (constant 2-minute heat pain stimulation [HPS]) nociceptive stimuli were applied as test stimuli, before and after a cold-water bath (conditioning stimulus). TS was interpreted as the change in pain perception scores during HPS. CPM were determined by calculating the difference in pain perception between pre- and post- water bath for both PPT and HPS. Relative and absolute reliability were analyzed with intra-class correlation coefficient (ICC2, k), standard error of the measurements (SEMeas) and MDC. RESULTS: Results revealed a good to excellent relative reliability for static QST (ICC ≥ 0.73). For TS, a poor to moderate relative reliability depending on the calculation methods (ICC = 0.25 ≤ ICC ≤ 0.59), and a poor relative reliability for CPM (ICC = 0.16 ≤ ICC ≤ 0.37), both when measured with mechanical stimulation (PPT) and thermal stimulation (HPS). Absolute reliability varied from 0.73 to 7.74 for static QST, 11 to 22 points for TS and corresponded to 11.42 points and 1.56 points for thermal and mechanical-induced CPM, respectively. MDC analyses revealed that a change of 1.58 to 21.46 point for static QST, 31 to 52 points for TS and 4 to 31 points for CPM is necessary to be interpreted as a real change. CONCLUSION: Our approach seems well-suited to clinical use. Although our method shows equivalent relative and absolute reliability compared to other protocols, we found that the reliability of endogenous pain modulation mechanisms is vulnerable, probably due to its dynamic nature.

Data-driven dynamic profiles of tonic heat pain perception in pain-free volunteers are associated with differences in anandamide levels.

Our laboratory previously developed a method for assessing experimentally induced pain perception through a 2-min constant heat pain stimulation. However, the traditional analysis relying on group means struggles to interpret the considerable inter-individual variability due to the dynamic nature of the response. Recently, trajectory analysis techniques based on extended mixed models have emerged, providing insights into distinct response profiles. Notably, these methods have never been applied to pain paradigms before. Furthermore, various socio-demographic and neurobiological factors, including endocannabinoids, may account for these inter-individual differences. This study aims to apply the novel analysis to dynamic pain responses and investigate variations in response profiles concerning socio-demographic, psychological, and blood endocannabinoid concentrations. 346 pain-free participants were enrolled in a psychophysical test involving a continuous painful heat stimulation lasting for 2 min at a moderate intensity. Pain perception was continuously recorded using a computerized visual scale. Dynamic pain response analyses were conducted using the innovative extended mixed model approach. In contrast to the traditional group-mean analysis, the extended mixed model revealed three pain response trajectories. Trajectory 1 is characterized by a delay peak pain. Trajectory 2 is equivalent to the classic approach (peak pain follow by a constant and moderate increase of pain perception). Trajectory 3 is characterized by extreme responses (steep peak pain, decrease, and increase of pain perception), Furthermore, age and blood anandamide levels exhibited significant variations among these three trajectories. Using an innovative statistical approach, we found that a large proportion of our sample had a response significantly different from the average expected response. Endocannabinoid system seems to play a role in pain response profile.

The influence of pain catastrophizing on pain and function after knee arthroplasty in knee osteoarthritis.

Pain catastrophizing is an exaggerated focus on pain sensations. It may be an independent factor influencing pain and functional outcomes of knee arthroplasty. We aimed to evaluate the association between pre-operative pain catastrophizing with pain and function outcomes up to one year after knee arthroplasty. We used data from a cohort study of patients undergoing primary knee arthroplasty (either total or unicompartmental arthroplasty) for knee osteoarthritis. Pain catastrophizing was assessed pre-operatively using the Pain Catastrophizing scale (PCS). Other baseline variables included demographics, body mass index, radiographic severity, anxiety, depression, and knee pain and function assessed using the Western Ontario and McMaster University Index (WOMAC). Patients completed the WOMAC at 6- and 12-months after arthroplasty. WOMAC pain and function scores were converted to interval scale and the association of PCS and changes of WOMAC pain and function were evaluated in generalized linear regression models with adjustment with confounding variables. Of the 1136 patients who underwent arthroplasty (70% female, 84% Chinese, 92% total knee arthroplasty), 1102 and 1089 provided data at 6- and 12-months post-operatively. Mean (± SD) age of patients was 65.9 (± 7.0) years. PCS was associated with a change in WOMAC pain at both 6-months and 12-months (ß = - 0.04, 95% confidence interval: - 0.06, - 0.02; P < 0.001) post-operatively after adjustment in multivariable models; as well as change in WOMAC function at 6-months and 12-months. In this large cohort study, pre-operative pain catastrophizing was associated with lower improvements in pain and function at 6-months and 12-months after arthroplasty.

A novel methodology utilizing microchip implants to monitor individual activity and body temperature for assessing knee pain in group-housed rats.

The pain assessment in animals is challenging as they cannot verbally express the site and severity of pain. In this study, we tried a small implantable actimeter, "Nanotag", to monitor spontaneous locomotor activity and body temperature in animals suffering from a chemical-induced rat knee arthritis as compared to naïve and steroid-treated rats. Nanotag could detect the decrease in locomotor activity quickly after the arthritis induction and anti-inflammation analgesic treatment by intra-articular injection of steroid significantly improved locomotor activity. These changes were in the same line with those of a conventional knee pain evaluation method (incapacitance test). Nanotag can be utilized as the non-interventional, continuous, and completely objective monitoring the amount of pain in rat knee arthritis model. This traditional yet innovative method may be universally applicable to various pain models and species, making it a worthwhile device for research across diverse fields.

Unpacking the relationship between Big Five personality traits and experimental pain: A systematic review and meta-analysis.

Pain is essential for survival, but individual responses to painful stimuli vary, representing a complex interplay between sensory, cognitive, and affective factors. Individual differences in personality traits and in pain perception covary but it is unclear which traits play the most significant role in understanding the pain experience and whether this depends on pain modality. A systematic search identified 1534 records (CINAHL, MEDLINE, PsycInfo, PubMed and Web of Science), of which 22 were retained and included in a systematic review. Only studies from the pressure pain domain (n=6) could be compared in a formal meta-analysis to evaluate the relationship between Big Five traits and experimental pain. Pressure pain tolerance correlated positively with Extraversion and negatively with Neuroticism with a trivial effect size (<0.1). While these findings suggest personality might be only weakly related to pain in healthy individuals, we emphasize the need to consider standardization, biases, and adequate sample sizes in future research, as well as additional factors that might affect experimental pain sensitivity.

Itch and Pain Behaviors in Irritant Contact Dermatitis Produced by Sodium Lauryl Sulfate in Mice.

Irritant contact dermatitis (ICD) is a nonspecific skin inflammation caused by irritants, leading to itch and pain. We tested whether differential responses to histamine-dependent and -independent pruritogens can be evoked in ICD induced by sodium lauryl sulfate (SLS). An ICD mouse model was established with 5% SLS in acetone versus a vehicle topically applied for 24 h to the cheek. Site-directed itch- and pain-like behaviors, occurring spontaneously and in response to mechanical, thermal, and chemical stimuli (histamine, ß-alanine, BAM8-22, and bradykinin) applied to the cheek, were recorded before (day 0) and after irritant removal (days 1, 2, 3, and 4). Skin inflammation was assessed through visual scoring, ultrasound, and measurements of skin thickness. SLS-treated mice exhibited hyperalgesia-like behavior in response to mechanical and heat stimuli on day 1 compared to the controls. SLS mice exhibited more spontaneous wipes (pain) but not scratching bouts (itch) on day 1. Pruritogen injections caused more scratching but not wiping in SLS-treated mice compared to the controls. Only bradykinin increased wiping behavior compared to saline. SLS-treated mice developed noticeable erythema, scaling, and increased skin thickness on days 1 and 2. SLS induced cutaneous inflammation and behavioral signs of spontaneous pain and itching, hyperalgesia to mechanical and heat stimuli and a chemical algogen, and enhanced itch response to pruritogens. These sensory reactions preceded the inflammation peak and lasted up to two days.

Neural pathways that compel us to scratch an itch.

Itch is a unique sensory experience that is responded to by scratching. How pruritogens, which are mechanical and chemical stimuli with the potential to cause itch, engage specific pathways in the peripheral and central nervous system has been a topic of intense investigation over the last few years. Studies employing recently developed molecular, physiological, and behavioral techniques have delineated the dedicated mechanisms that transmit itch information to the brain. This review outlines the genetically defined and evolutionary conserved circuits for itch ranging from the skin-innervating peripheral neurons to the cortical neurons that drive scratching. Moreover, scratch suppression of itch is attributed to the concurrent activation of pain and itch pathways. Hence, we discuss the similarities between circuits driving pain and itch.

Psychopathy, pain, and pain empathy: A psychophysiological study.

The present study examined whether people higher in psychopathy experienced less self-reported and psychophysiological nociceptive pressure than people lower in psychopathy. We also examined whether psychopathy affects empathy for others' pain via self-reported and psychophysiological measures. Three hundred and sixty-nine students (18-78 years; M = 26, SD = 9.34) were screened for psychopathic traits using the Youth Psychopathy Inventory (YPI). Stratified sampling was used to recruit 49 adults residing in the highest (n = 23) and lowest (n = 26) 20% of the psychopathy spectrum. Using skin conductance response (SCR) and self-report responses, participants responded to individually adjusted intensities of pneumatic pressure and others' pain images and completed self-reported psychopathy and empathy measures (Triarchic Psychopathy Measure, TriPm; Interpersonal Reactivity Index, IRI). People higher in psychopathy self-reported feeling less nociceptive pressure compared to people lower in psychopathy, yet we did not find any differences in SCR to nociceptive pressure. However, when viewing other people in pain, the high psychopathy group displayed lower SCR and lower self-reported empathy compared to those lower in psychopathy. Our results suggest psychopathic traits relate to problems empathising with others' pain, as well as the perception of nociceptive pressure. We also show support for the theory of dual harm which has been receiving increasing attention. Consequently, psychopathy interventions should focus both on recognising and empathising with the pain of others.

Empathy incites a stable prosocial decision bias.

Empathy toward suffering individuals serves as potent driver for prosocial behavior. However, it remains unclear whether prosociality induced by empathy for another person's pain persists once that person's suffering diminishes. To test this, participants underwent functional magnetic resonance imaging while performing a binary social decision task that involved allocation of points to themselves and another person. In block one, participants completed the task after witnessing frequent painful stimulation of the other person, and in block two, after observing low frequency of painful stimulation. Drift-diffusion modeling revealed an increased initial bias toward making prosocial decisions in the first block compared with baseline that persisted in the second block. These results were replicated in an independent behavioral study. An additional control study showed that this effect may be specific to empathy as stability was not evident when prosocial decisions were driven by a social norm such as reciprocity. Increased neural activation in dorsomedial prefrontal cortex was linked to empathic concern after witnessing frequent pain and to a general prosocial decision bias after witnessing rare pain. Altogether, our findings show that empathy for pain elicits a stable inclination toward making prosocial decisions even as their suffering diminishes.