Differences In Pain Sensitivity Research Articles

Sex differences in osteoarthritis prevalence, pain perception, physical function and therapeutics

ObjectiveWomen have a higher prevalence of osteoarthritis (OA) and worse clinical courses than men. However, the underlying factors and therapeutic outcomes of these sex-specific differences are incompletely researched. This review examines the current state of knowledge regarding sex differences in OA prevalence, risk factors, pain severity, functional outcomes, and use and response to therapeutics. MethodsPubMed database was used with the title keyword combinations “{gender OR sex} AND osteoarthritis” plus additional manual search of the included papers for pertinent references, yielding 212 references. Additional references were added and 343 that were reviewed for appropriateness. ResultsGlobally, women account for 60% of people with osteoarthritis with a greater difference after age 40. The higher risk for women may be due to differences in joint anatomy, alignment, muscle strength, hormonal influences, obesity, and/or genetics. At the same radiographic severity, women have greater pain severity than men, which may be explained by biologically distinct pain pathways, differential activation of central pain pathways, differences in pain sensitivity, perception, reporting, and coping strategies. Women have greater limitations of physical function and performance than men independent of BMI, OA severity, injury history, amount of weekly exercise. Women also have greater use of analgesic medications than men but less use of arthroplasty and poorer prognosis after surgical interventions. ConclusionsThe recognition of sex differences in OA manifestations and management could guide tailoring of sex-specific treatment protocols, and analysis of sex as a biological variable in future research would enhance development of precision medicine.

Preliminary Characterization of Age and Chronic Low Back Pain Effects on Multimodal Pain Sensitivity: A Comparison Study in Older Adults with and Without Chronic Low Back Pain

Though pain sensitivity impairments contribute to chronic pain in younger adults, it is unclear if pain hypersensitivity manifests with aging and is heightened in the geriatric chronic low back pain population. The cross-sectional study preliminarily addressed this gap by measuring pain sensitivity in older adults with chronic low back pain (n = 25) as well as pain-free sex-matched older (n = 25) and younger adults (n = 25). Pain sensitivity was quantified by 8 distinct measures that were subdivided as static (ie, pressure pain thresholds, heat pain thresholds, fixed mechanical pain, and fixed cold pain) and dynamic pain sensitivity (ie, mechanical temporal summation, thermal ramp and hold, heat pain aftersensations, and conditioned pain modulation). Test-retest reliability values for pain sensitivity ranged from moderate to excellent (intraclass correlation coefficients ≥ .500; p’s < .05). The main effect for the group was significant (partial η2 = .413, P < .001), revealing between-group differences in pain sensitivity on 5 out of 8 tests (p’s ≤ .043). Predominantly, both older adult groups demonstrated increased pain facilitation and decreased pain inhibition during dynamic pain sensitivity testing compared to pain-free younger adults (p’s ≤ .044). Despite qualitative differences, static and dynamic pain sensitivity responses were statistically similar between older adults with and without chronic LBP (p’s > .05). Findings suggest pain sensitivity can be reliably measured in older adults and that pain hypersensitivity develops with chronological aging, providing partial support for the theory that pain hypersensitivity may impact geriatric chronic pain populations. Further study is needed to more definitively parse out whether pain hypersensitivity is comparatively heightened in older adults with chronic LBP beyond the influence of chronological aging. PerspectiveThis article establishes that surrogate measures of centrally mediated pain sensitization are heightened with aging. Impaired endogenous pain modulation may influence chronic pain development, maintenance, treatment efficacy, and/or ensuing disability, necessitating research to comprehensively characterize how pain hypersensitivity contributes to geriatric chronic pain conditions.

A study protocol testing pre-exposure dose and compound pre-exposure on the mechanisms of latent inhibition of dental fear

BackgroundDental stimuli can evoke fear after being paired - or conditioned - with aversive outcomes (e.g., pain). Pre-exposing the stimuli before conditioning can impair dental fear learning via a phenomenon known as latent inhibition. Theory suggests changes in expected relevance and attention are two mechanisms responsible for latent inhibition. In the proposed research, we test whether pre-exposure dose and degree of pre-exposure novelty potentiate changes in expected relevance and attention to a pre-exposed stimulus. We also assess if the manipulations alter latent inhibition and explore the possible moderating role of individual differences in pain sensitivity.MethodsParticipants will be healthy individuals across a wide range of ages (6 to 35 years), from two study sites. Participants will undergo pre-exposure and conditioning followed by both a short-term and long-term test of learning, all in a novel virtual reality environment. The unconditioned stimulus will be a brief pressurized puff of air to a maxillary anterior tooth. Pre-exposure dose (low vs. high) and pre-exposure novelty (element stimulus vs. compound stimuli) will be between-subject factors, with stimulus type (pre-exposed to-be conditioned stimulus, a non-pre-exposed conditioned stimulus, and an unpaired control stimulus) and trial as within-subject factors. Pain sensitivity will be measured through self-report and a cold pressor test. It is hypothesized that a larger dose of pre-exposure and compound pre-exposure will potentiate the engagement of the target mechanisms and thereby result in greater latent inhibition in the form of reduced fear learning. Further, it is hypothesized that larger effects will be observed in participants with greater baseline pain sensitivity.DiscussionThe proposed study will test whether pre-exposure dose and compound stimulus presentation change expected relevance and attention to the pre-exposed stimulus, and thereby enhance latent inhibition of dental fear. If found, the results will add to our theoretical understanding of the latent inhibition of dental fear and inform future interventions for dental phobia prevention.

Age differences in pain sensitivity and effect of topical lidocaine on the tongue in healthy female subjects.

To assess the sensitivity and the effect of topical lidocaine on the tongue by quantitative sensory testing, comparing healthy middle-aged female subjects with healthy young female subjects. Sixteen healthy female subjects including eight in their fifties and eight in their twenties participated. They participated in two sessions at a 2-week interval in randomized order: lidocaine (experimental session) or placebo gel (placebo session) was applied on the tongue tip for 5min. The following parameters were taken on the tongue tip before and after application of the gel in each session: tactile detection threshold (TDT), filament-prick pain detection threshold (FPT), and numerical rating scale (NRS). An increase of both TDT and FPT and a decrease of NRS were found after lidocaine application in both middle-aged and young female subjects. In the elder females, an increase of TDT, FPT, and NRS was also found after placebo gel application. However, the changes were not statistically significant, except for FPT in middle-aged subjects. The reactions found after lidocaine application in middle-aged female subjects could be due to habituation as well as to the post-application effect of placebo gel. Placebo-induced changes appeared more pronounced in the elder females.

Combined transcranial magnetic stimulation and electroencephalography reveals alterations in cortical excitability during pain.

Transcranial magnetic stimulation (TMS) has been used to examine inhibitory and facilitatory circuits during experimental pain and in chronic pain populations. However, current applications of TMS to pain have been restricted to measurements of motor evoked potentials (MEPs) from peripheral muscles. Here, TMS was combined with electroencephalography (EEG) to determine whether experimental pain could induce alterations in cortical inhibitory/facilitatory activity observed in TMS-evoked potentials (TEPs). In Experiment 1 (n=29), multiple sustained thermal stimuli were administered to the forearm, with the first, second, and third block of thermal stimuli consisting of warm but non-painful (pre-pain block), painful (pain block) and warm but non-painful (post-pain block) temperatures, respectively. During each stimulus, TMS pulses were delivered while EEG (64 channels) was simultaneously recorded. Verbal pain ratings were collected between TMS pulses. Relative to pre-pain warm stimuli, painful stimuli led to an increase in the amplitude of the frontocentral negative peak ~45 ms post-TMS (N45), with a larger increase associated with higher pain ratings. Experiments 2 and 3 (n=10 in each) showed that the increase in the N45 in response to pain was not due to changes in sensory potentials associated with TMS, or a result of stronger reafferent muscle feedback during pain. This is the first study to use combined TMS-EEG to examine alterations in cortical excitability in response to pain. These results suggest that the N45 TEP peak, which indexes GABAergic neurotransmission, is implicated in pain perception and is a potential marker of individual differences in pain sensitivity.

Multimodal covarying brain patterns mediate genetic and psychological contributions to individual differences in pain sensitivity.

Individuals vary significantly in their pain sensitivity, with contributions from the brain, genes, and psychological factors. However, a multidimensional model integrating these factors is lacking due to their complex interactions. To address this, we measured pain sensitivity (ie, pain threshold and pain tolerance) using the cold pressor test, collected magnetic resonance imaging (MRI) data and genetic data, and evaluated psychological factors (ie, pain catastrophizing, pain-related fear, and pain-related anxiety) from 450 healthy participants with both sexes (160 male, 290 female). Using multimodal MRI fusion methods, we identified 2 pairs of covarying structural and functional brain patterns associated with pain threshold and tolerance, respectively. These patterns primarily involved regions related to self-awareness, sensory-discriminative, cognitive-evaluative, motion preparation and execution, and emotional aspects of pain. Notably, pain catastrophizing was negatively correlated with pain tolerance, and this relationship was mediated by the multimodal covarying brain patterns in male participants only. Furthermore, we identified an association between the single-nucleotide polymorphism rs4141964 within the fatty acid amide hydrolase gene and pain threshold, mediated by the identified multimodal covarying brain patterns across all participants. In summary, we suggested a model that integrates the brain, genes, and psychological factors to elucidate their role in shaping interindividual variations in pain sensitivity, highlighting the important contribution of the multimodal covarying brain patterns as important biological mediators in the associations between genes/psychological factors and pain sensitivity.

Relationship between individual differences in pain empathy and task- and resting-state EEG

Pain empathy is a complex form of psychological inference that enables us to understand how others feel in the context of pain. Since pain empathy may be grounded in our own pain experiences, it exhibits huge inter-individual variability. However, the neural mechanisms behind the individual differences in pain empathy and its association with pain perception are still poorly understood. In this study, we aimed to characterize brain mechanisms associated with individual differences in pain empathy in adult participants (n = 24). The 32-channel electroencephalography (EEG) was recorded at rest and during a pain empathy task, and participants viewed static visual stimuli of the limbs submitted to painful and nonpainful stimulation to solicit empathy. The pain sensitivity of each participant was measured using a series of direct current stimulations. In our results, the N2 of Fz and the LPP of P3 and P4 were affected by painful pictures. We found that both delta and alpha bands in the frontal and parietal cortex were involved in the regulation of pain empathy. For the delta band, a close relationship was found between average power, either in the resting or task state, and individual differences in pain empathy. It suggested that the spectral power in Fz's delta band may reflect subjective pain empathy across individuals. For the alpha band, the functional connectivity between Fz and P3 under painful picture stimulation was correlated to individuals' pain sensitivity. It indicated that the alpha band may reflect individual differences in pain sensitivity and be involved in pain empathy processing. Our results suggested the distinct role of the delta and alpha bands of EEG signals in pain empathy processing and may deepen our understanding of the neural mechanisms underpinning pain empathy.

Sexual dimorphic distribution of G protein-coupled receptor 30 in pain-related regions of the mouse brain.

Sex differences in pain sensitivity have contributed to the fact that medications for curing chronic pain are unsatisfactory. However, the underlying mechanism remains to be elucidated. Brain-derived estrogen participates in modulation of sex differences in pain and related emotion. G protein-coupled receptor 30 (GPR30), identified as a novel estrogen receptor with a different distribution than traditional receptors, has been proved to play a vital role in regulating pain affected by estrogen. However, the contribution of its distribution to sexually dimorphic pain-related behaviors has not been fully explored. In the current study, immunofluorescence assays were applied to mark the neurons expressing GPR30 in male and female mice (in metestrus and proestrus phase) in pain-related brain regions. The neurons that express CaMKIIα or VGAT were also labeled to observe overlap with GPR30. We found that females had more GPR30-positive (GPR30+ ) neurons in the primary somatosensory (S1) and insular cortex (IC) than males. In the lateral habenula (LHb) and the nucleus tractus solitarius (NTS), males had more GPR30+ neurons than females. Moreover, within the LHb, the expression of GPR30 varied with estrous cycle phase; females in metestrus had fewer GPR30+ neurons than those in proestrus. In addition, females had more GPR30+ neurons, which co-expressed CaMKIIα in the medial preoptic nucleus (mPOA) than males, while males had more than females in the basolateral complex of the amygdala (BLA). These findings may partly explain the different modulatory effects of GPR30 in pain and related emotional phenotypes between sexes and provide a basis for comprehension of sexual dimorphism in pain related to estrogen and GPR30, and finally provide new targets for exploiting new treatments of sex-specific pain.

Pain sensitivity differs between dog breeds but not in the way veterinarians believe.

Veterinarians hold distinct breed-specific pain sensitivity beliefs that differ from the general public but are highly consistent with one another. This is remarkable as there is no current scientific evidence for biological differences in pain sensitivity across dog breeds. Therefore, the present study evaluated whether pain sensitivity thresholds differ across a set of dog breeds and, if so, whether veterinarians' pain sensitivity ratings explain these differences or whether these ratings are attributed to behavioral characteristics. Pain sensitivity thresholds [using quantitative sensory testing (QST) methods] and canine behaviors (using owner questionnaires and emotional reactivity tests) were prospectively measured across selected dog breeds. Adult, healthy dogs from 10 dog breeds/breed types were recruited, representing breeds subjectively rated by veterinarians as high (chihuahua, German shepherd, Maltese, Siberian husky), average (border collie, Boston terrier, Jack Russell terrier), or low (golden retriever, pitbull, Labrador retriever) pain sensitivity. A final sample of 149 dogs was included in statistical analyses. Veterinarians' pain sensitivity ratings provided a minimal explanation for pain sensitivity thresholds measured using QST in dogs; however, dog breeds did differ in their pain sensitivity thresholds across the QST methods evaluated. Breed differences were observed for some aspects of emotional reactivity tests; however, these behavioral differences did not explain the differences in pain sensitivity thresholds found. Veterinarians' pain sensitivity ratings were positively associated with dog approach scores for the disgruntled stranger test suggesting that the way dogs greet strangers may be a factor influencing veterinarians' ratings of pain sensitivity across dog breeds. Overall, these findings highlight a need to investigate biological mechanisms that may explain breed differences in pain sensitivity because this may inform pain management recommendations. Further, future research should focus on when and how these breed-specific pain sensitivity beliefs developed in veterinarians, as veterinarians' beliefs could impact the recognition and treatment of pain for canine patients.

Pain sensitivity after Roux-en-Y gastric bypass- associations with chronic abdominal pain and psychosocial aspects.

The aims of this study were to investigate modifications in pain sensitivity after RYGB and to explore associations between pain sensitivity and weight loss, chronic abdominal pain, total body pain, anxiety, depression, and pain catastrophizing. In total, 163 patients with obesity were examined with a cold pressor test for pain sensitivity before and two years after RYGB. Two aspects of pain sensitivity were registered: Pain intensity (numeric rating scale, range 0-10) and pain tolerance (seconds). Associations between pain sensitivity and the explanatory variables were assessed with linear regression. Two years after RYGB the pain intensity increased (mean±SD 0.64±1.9 score units, p<0.001). Pain tolerance decreased (7.2±32.4 s, p=0.005). A larger reduction in body mass index was associated with increased pain intensity, β=-0.090 (95 % CI-0.15 to-0.031, p=0.003), and decreased pain tolerance β=1.1 (95 % CI 0.95 to 2.2, p=0.03). Before surgery, participants with chronic abdominal pain reported 1.2±0.5 higher pain intensity (p=0.02) and had 19.2±9.3 s lower pain tolerance (p=0.04) than those without abdominal pain. No differences in pain sensitivity were observed between participants who did or did not develop chronic abdominal pain after RYGB. Pain sensitivity was associated with symptoms of anxiety but not with pain catastrophizing, depression or bodily pain. The pain sensitivity increased after RYGB and was associated with larger weight loss and anxiety symptoms. Changes in pain sensitivity were not associated with development of chronic abdominal pain after RYGB in our study.

Diffusion tensor imaging reveals sex differences in pain sensitivity of rats.

Studies on differences in brain structure and function according to sex are reported to contribute to differences in behavior and cognition. However, few studies have investigated brain structures or used tractography to investigate gender differences in pain sensitivity. The identification of tracts involved in sex-based structural differences that show pain sensitivity has remained elusive to date. Here, we attempted to demonstrate the sex differences in pain sensitivity and to clarify its relationship with brain structural connectivity. In this study, pain behavior test and brain diffusion tensor imaging (DTI) were performed in male and female rats and tractography was performed on the whole brain using fiber tracking software. We selected eight brain regions related to pain and performed a tractography analysis of these regions. Fractional anisotropy (FA) measurements using automated tractography revealed sex differences in the anterior cingulate cortex (ACC)-, prefrontal cortex (PFC)-, and ventral posterior thalamus-related brain connections. In addition, the results of the correlation analysis of pain sensitivity and DTI tractography showed differences in mean, axial, and radial diffusivities, as well as FA. This study revealed the potential of DTI for exploring circuits involved in pain sensitivity. The behavioral and functional relevance's of measures derived from DTI tractography is demonstrated by their relationship with pain sensitivity.

Neuropathic pain as a trigger for histone modifications in limbic circuitry.

Chronic pain involves both central and peripheral neuronal plasticity that encompasses changes in the brain, spinal cord, and peripheral nociceptors. Within the forebrain, mesocorticolimbic regions associated with emotional regulation have recently been shown to exhibit lasting gene expression changes in models of chronic pain. To better understand how such enduring transcriptional changes might be regulated within brain structures associated with processing of pain or affect, we examined epigenetic modifications involved with active or permissive transcriptional states (histone H3 lysine 4 mono and trimethylation, and histone H3 lysine 27 acetylation) in periaqueductal gray (PAG), lateral hypothalamus (LH), nucleus accumbens (NAc), and ventral tegmental area (VTA) 5 weeks after sciatic nerve injury in mice to model chronic pain. For both male and female mice in chronic pain, we observed an overall trend for a reduction of these epigenetic markers in periaqueductal gray, LH, and NAc, but not VTA. Moreover, we discovered that some epigenetic modifications exhibited changes associated with pain history, while others were associated with individual differences in pain sensitivity. When taken together, these results suggest that nerve injury leads to chronic chromatin-mediated suppression of transcription in key limbic brain structures and circuits, which may underlie enduring changes in pain processing and sensitivity within these systems.

Linking interpretation bias to individual differences in pain sensitivity

Linking interpretation bias to individual differences in pain sensitivity

Acquisition learning is stronger for aversive than appetitive events

Appetitive and aversive learning are both key building blocks of adaptive behavior, yet knowledge regarding their differences is sparse. Using a capsaicin heat pain model in 36 healthy participants, this study directly compared the acquisition and extinction of conditioned stimuli (CS) predicting pain exacerbation and relief. Valence ratings show stronger acquisition during aversive compared to appetitive learning, but no differences in extinction. Skin conductance responses and contingency ratings confirmed these results. Findings were unrelated to individual differences in pain sensitivity or psychological factors. Our results support the notion of an evolutionarily hardwired preponderance to acquire aversive rather than appetitive cues as is protective for acute aversive states such as pain but may contribute to the development and maintenance of clinical conditions such as chronic pain, depression or anxiety disorders.

Inflammatory and Immune Protein Pathways Possible Mechanisms for Pain Following Walking in Knee Osteoarthritis.

Knee osteoarthritis affects nearly 30% of adults aged 60 years or older and causes significant pain and disability. Walking is considered a "gold standard" treatment option for reducing knee osteoarthritis pain and maintaining joint mobility but does not reduce pain for all adults with knee osteoarthritis pain and may induce pain-particularly when starting a walking routine. The mechanism by which walking is helpful for knee osteoarthritis pain is unclear. Quantitative sensory testing has revealed that knee osteoarthritis pain has both peripheral and central components, which vary by individual. The purpose of this study was to better understand the mechanisms underlying the value of walking for knee pain. We conducted a pretest/posttest study using quantitative sensory testing to measure neurophysiological parameters and examined systemic protein signatures. Adults with knee osteoarthritis and healthy controls underwent quantitative sensory testing and blood draw for platelet proteomics before and after a 30-minute walk at 100 steps per minute. A single 30-minute walk moderately increased pressure pain sensitivity at the affected knee among persons with knee osteoarthritis. Healthy adults showed no difference in pain sensitivity. Protein signatures among participants with knee osteoarthritis indicated changes in inflammatory and immune pathways, including the complement system and SAA1 protein that coincided with changes in pain with walking and differed from healthy participants. One goal of developing individualized interventions for knee osteoarthritis pain is to elucidate the mechanisms by which self-management interventions affect pain. The addition of therapies that target the complement system or SAA1 expression may improve the pain sensitivity after a moderate walk for adults with knee osteoarthritis.

Pain sensitivity is associated with general attitudes towards pain: Development and validation of a new instrument for pain research and clinical application.

With regard to attitudes towards pain, many questionnaires have been developed. Although undoubtedly useful, they were specifically designed for the use in chronic pain and are less suitable for the assessment in the general population. The purpose of the present paper was to develop a measure for the assessment of general attitudes towards pain applicable in the general population, regardless of clinical condition, and to test its psychometric properties. We developed the General Attitudes Towards Pain Inventory and conducted two studies in order to provide psychometric data: In a general population sample (N=362, study one), participants were asked to complete a questionnaire battery. To assess test-retest reliability, participants were contacted again after 4weeks (retest sample: N=101). For the evaluation of criterion validity (study two), a sample with sadomasochistic sexual preference (N=68) was additionally recruited. Statistical analyses revealed, overall, acceptable internal consistencies and test-retest reliabilities. A 10-factor model showed acceptable fit and was superior to alternative models. The inventory demonstrated convergent and divergent validity. In this context, we found pain sensitivity to be associated with pain attitudes. Finally, compared to the general population sample, individuals with sadomasochistic sexual preference showed significantly higher scores on fascination-pleasure and challengesubscales. In the present paper, we introduce a new and comprehensive instrument for pain research and provide evidence for its reliability and validity. In addition, we present new insights into how interindividual differences in pain sensitivity relate to pain attitudes. Acknowledging the lack of basic research on pain attitudes in the general population, we have developed and validated the first psychometric instrument to measure ten general attitudes towards pain. The inventory is based on the literature and clinical expertise and has been demonstrated to be useful in pain sensitivity research. In the clinical context, general pain attitudes could be pivotal when a person who has only known everyday pain suddenly becomes a patient confronted with prolonged states of intense pain.

Joint Damage and Neuropathic Pain in Rats Treated With Lysophosphatidic Acid.

Joint pain is a complex phenomenon that involves multiple endogenous mediators and pathophysiological events. In addition to nociceptive and inflammatory pain, some patients report neuropathic-like pain symptoms. Examination of arthritic joints from humans and preclinical animal models have revealed axonal damage which is likely the source of the neuropathic pain. The mediators responsible for joint peripheral neuropathy are obscure, but lysophosphatidic acid (LPA) has emerged as a leading candidate target. In the present study, male and female Wistar rats received an intra-articular injection of LPA into the right knee and allowed to recover for 28 days. Joint pain was measured by von Frey hair algesiometry, while joint pathology was determined by scoring of histological sections. Both male and female rats showed comparable degenerative changes to the LPA-treated knee including chondrocyte death, focal bone erosion, and synovitis. Mechanical withdrawal thresholds decreased by 20-30% indicative of secondary allodynia in the affected limb; however, there was no significant difference in pain sensitivity between the sexes. Treatment of LPA animals with the neuropathic pain drug amitriptyline reduced joint pain for over 2 hours with no sex differences being observed. In summary, intra-articular injection of LPA causes joint degeneration and neuropathic pain thereby mimicking some of the characteristics of neuropathic osteoarthritis.

Race-Related Differences Between and Within Sex to Experimental Thermal Pain in Middle and Older Adulthood: An Exploratory Pilot Analysis.

This brief report details a pilot analysis conducted to explore racial differences in pain sensitivity and unpleasantness between cognitively healthy Black and White adults, stratified by sex. A total of 24 cognitively healthy adults (12 Black and 12 White) from two completed studies were matched by age and sex, and divided into two groups based on race. Stratified analyses by sex demonstrated that Black females reported experiencing pain intensity ratings of all three intensity sensations at lower temperatures than White females. These findings will inform future research studies to determine if these results hold true in a fully-powered sample and should include mixed methodologies, incorporating neuroimaging data to further assess this phenomenon. Improving pain assessment and management across racial/ethnic groups will help healthcare providers such as nurses and physicians to ensure optimal quality of life for all.

The role of negative emotions in sex differences in pain sensitivity

Pain perception varies widely among individuals due to the varying degrees of biological, psychological, and social factors. Notably, sex differences in pain sensitivity have been consistently observed in various experimental and clinical investigations. However, the neuropsychological mechanism underlying sex differences in pain sensitivity remains unclear. To address this issue, we quantified pain sensitivity (i.e., pain threshold and tolerance) using the cold pressure test and negative emotions (i.e., pain-related fear, pain-related anxiety, trait anxiety, and depression) using well-established questionnaires and collected magnetic resonance imaging (MRI) data (i.e., high-resolution T1 structural images and resting-state functional images) from 450 healthy subjects. We observed that, as compared to males, females exhibited lower pain threshold and tolerance. Notably, sex differences in pain sensitivity were mediated by pain-related fear and anxiety. Specifically, pain-related fear and anxiety were the complementary mediators of the relationship between sex and pain threshold, and they were the indirect-only mediators of the relationship between sex and pain tolerance. Besides, structural MRI data revealed that the amygdala subnuclei (i.e., the lateral and basal nuclei in the left hemisphere) volumes were the complementary mediators of the relationship between sex and pain-related fear, which further influenced pain sensitivity. Altogether, our results provided a comprehensive picture of how negative emotions (especially pain-related negative emotions) and related brain structures (especially the amygdala) contribute to sex differences in pain sensitivity. These results deepen our understanding of the neuropsychological underpinnings of sex differences in pain sensitivity, which is important to tailor a personalized method for treating pain according to sex and the level of pain-related negative emotions for patients with painful conditions.

Mechanical Pain Sensitivity in Postamputation Pain.

Postamputation, clinical markers of pain-related peripheral and central nervous system hypersensitivity remain understudied. This study aimed to identify whether adults with postamputation pain demonstrate greater pain sensitivity in primary (ie, amputated region) and secondary (ie, nonamputated region) sites, as compared with pain-free peers and controls with intact limbs. Ninety-four participants postunilateral, transtibial amputation (59 with pain, 35 pain-free) and 39 controls underwent pain-pressure threshold (PPT) testing at 10 sites. Pain-pressure thresholds were normalized to sex-specific control data using Z score conversions. Normalized primary-site and secondary-site PPTs were compared between groups using multivariate analysis of variance (P<0.050). Compared with pain-free peers, adults with postamputation pain demonstrated reduced normalized PPTs across primary and secondary sites (mean difference=0.61-0.74, P=0.001 to 0.007). Compared with controls, adults with postamputation pain demonstrated reduced normalized PPTs (mean difference=0.52, P=0.026) only at primary sites. Adults with postamputation pain demonstrate greater amputated region pain sensitivity as compared with pain-free peers or controls with intact limbs, indicating peripheral sensitization persists even after limb healing. Secondary-site pain sensitivity was similar between controls and adults with postamputation pain, suggesting central nervous system hypersensitivity may not be ubiquitous with postamputation pain. Studies are needed to investigate mechanisms underlying pain sensitivity differences between adults with and without postamputation pain.