Journal of Pain最新文献

{"title":"Response to Nufi. letter to the editor, \"From fragmented services to whole-person care: Rethinking young people's pain-mental health management\".","authors":"Nardia-Rose Klem, Andrew M Briggs, Helen Slater","doi":"10.1016/j.jpain.2025.105574","DOIUrl":"10.1016/j.jpain.2025.105574","url":null,"abstract":"","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":" ","pages":"105574"},"PeriodicalIF":4.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shifting the distribution of risk for high-impact chronic pain: Targets for population-level interventions","authors":"Marcus Beasley,&nbsp;Gary J. Macfarlane,&nbsp;on behalf of the CHIPP team and the CHIPP patient panel","doi":"10.1016/j.jpain.2025.105573","DOIUrl":"10.1016/j.jpain.2025.105573","url":null,"abstract":"<div><div>High-impact chronic pain significantly affects quality of life and poses burdens on healthcare systems. Public health strategies that shift modifiable risk factors at the population level may reduce its impact. A cross-sectional analysis was conducted using a population intervention model to estimate how changes in physical activity and body mass index might affect prevalence of high-impact chronic pain, using data from 166,926 UK Biobank participants. High-impact chronic pain was defined by the presence of chronic pain along with reduced health-related quality of life, measured using the Euroqol EQ-5D-5L instrument. The effects of shifts in risk factors varied across different levels of confounder adjustment were assessed. Increasing vigorous physical activity by two days per week and 20 min per session was associated with a reduction in high-impact chronic pain prevalence from 18.1% to 16.7% after adjusting for socio-demographic factors, and to 17.6% after further adjustment for comorbidities. A reduction in body mass index of 7% was associated with a reduction in high-impact chronic pain prevalence from 18.9% to 16.8% (unadjusted) and to 17.5% after full adjustment. Effects were consistent across subgroups defined by age, sex, and socioeconomic deprivation. These results provide estimates of how targeted population shifts might impact the prevalence of high-impact chronic pain, based on observed associations. This could help inform the development of public health strategies that promote physical activity and healthy weight at the population level to address the burden of high-impact chronic pain.</div></div><div><h3>Perspective</h3><div>This study estimates how population-wide changes in physical activity and BMI could reduce the prevalence of high-impact chronic pain. The findings support public health approaches that address shared environmental and social risk factors, rather than individual-level interventions.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"37 ","pages":"Article 105573"},"PeriodicalIF":4.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting daily pain fluctuations in fibromyalgia: The role of mental distress and sleep heart-rate","authors":"Shir Hanuka ,&nbsp;Naama Tamari ,&nbsp;Eden Eldar ,&nbsp;Marco L. Loggia ,&nbsp;Danny Horesh ,&nbsp;Roee Admon","doi":"10.1016/j.jpain.2025.105572","DOIUrl":"10.1016/j.jpain.2025.105572","url":null,"abstract":"<div><div>Fibromyalgia (FM) is a chronic pain condition that typically involves sharp fluctuations in pain intensity over short time periods. Both mental distress and sleep disturbances have been implicated in FM, yet their putative contributions to pain fluctuations have not been fully defined. We assessed simultaneous fluctuations in pain intensity, mental distress and sleep physiology and behavior among FM patients in natural settings. Specifically, seventy-nine adult FM patients reported their current pain and mental distress levels three times a day (morning, afternoon, evening) over two consecutive weeks via a dedicated smartphone app. During this period, sleep physiology (sleep heart rate) and behavior (sleep duration &amp; efficiency) were continuously monitored using a wearable sensor. Mixed model analyses characterized the contribution of mental distress and sleep to daily pain fluctuations. Results revealed that current levels of pain and mental distress both predict subsequent pain levels, yet current pain does not predict subsequent mental distress. These associations were consistent across different daily segments (morning to afternoon, afternoon to evening), but not from evening to following morning. Instead, sleep heart rate emerged as predictor of next day pain, such that nights with lower vs. higher sleep heart rate were associated with pain improvement vs. worsening, respectively, in the subsequent day. These results suggest that both mental distress and sleep play a role in determining pain dynamics in FM. The contribution of sleep heart rate to pain reduction or intensification in the following day highlights the role of sleep physiology in daily pain fluctuations in FM.</div></div><div><h3>Perspective</h3><div>This study reveals how mental distress and sleep physiology shape daily pain fluctuations in Fibromyalgia. Using wearable sensors and real-time assessments, we identified sleep heart-rate as a key predictor of next-day pain fluctuations. These findings highlight modifiable, non-invasive targets for improving symptom dynamics and guiding personalized treatment strategies in Fibromyalgia.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"37 ","pages":"Article 105572"},"PeriodicalIF":4.0,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145227800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amputation for complex regional pain syndrome: a systematic review.","authors":"Yannick L Gilanyi, Michael C Ferraro, Andreas Goebel, Neil E O'Connell, Matthew D Jones, Saurab Sharma, Debbie Bean, Sylvia M Gustin, James H McAuley","doi":"10.1016/j.jpain.2025.105571","DOIUrl":"https://doi.org/10.1016/j.jpain.2025.105571","url":null,"abstract":"<p><p>Complex regional pain syndrome (CRPS) is a disabling pain condition, usually confined to a single limb. Amputation of the affected limb is sometimes performed to improve pain and function for treatment-resistant CRPS. This systematic review evaluated the benefits and harms of amputation for CRPS. Primary studies of adults with CRPS that investigated the effects of amputation of a CRPS affected limb were included. Primary outcomes were pain intensity and adverse events. The following databases were searched from inception to 23 September 2024: PubMed, EMBASE, Scopus, CENTRAL, CINAHL, and PsycINFO for published literature, and BASE, Web of Science, OpenMD and MedNar for grey literature. Study methodological quality was assessed using Joanna Briggs Institute critical appraisal tools. Data were synthesised using systematic review without meta-analysis guidance. The review included 66 studies, comprising one comparative study, 23 case series and 42 case studies. Studies included 249 patients who received 263 amputations. Amputation indications included pain relief, functional improvement, infection, fracture, and prosthetic complications. The heterogeneous designs of included studies precluded quantitative estimation of treatment effects. The only included comparative study reported that CRPS patients had lower mean pain intensity scores post-amputation than non-amputated, non-matched control patients. The four studies that assessed pain intensity scores before amputation and at least 6 months post-operatively, reported reductions in average pain post-amputation. Adverse events in assessed patients included phantom pain (67%), residual limb pain (66%), and recurrence of CRPS (47%). The critically low quality of included evidence and incomplete reporting greatly reduced confidence in the results. This review found no clear evidence that amputation of a CRPS-affected limb offers greater pain relief than no amputation. High-quality, controlled prospective studies with embedded qualitative research are needed to determine the benefits and harms of amputation for CRPS, as well as the factors that drive patients to seek this permanent intervention that does not guarantee improvement. PERSPECTIVE: This article presents a systematic review of the benefits and harms of amputation for complex regional pain syndrome. The unclear benefits and likely harms can help inform individuals and clinicians considering amputation of the potential outcomes of this intervention.</p>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":" ","pages":"105571"},"PeriodicalIF":4.0,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Testing the activity pacing questionnaire for validity, reliability and responsiveness: An outcome measure validation study","authors":"Deborah Antcliff ,&nbsp;Gareth McCray ,&nbsp;Rosa MacKenzie ,&nbsp;Janiece Marriott-Smith ,&nbsp;Kathryn Cawley ,&nbsp;Melanie A. Holden","doi":"10.1016/j.jpain.2025.105568","DOIUrl":"10.1016/j.jpain.2025.105568","url":null,"abstract":"<div><div>Activity pacing aims to manage symptoms of chronic pain and improve function by modifying pain-related behaviours: avoidance, overdoing and overdoing-underdoing cycling. Research regarding the effectiveness of activity pacing is unclear, and hindered by the absence of a validated scale. The previously developed 28-item Activity Pacing Questionnaire (APQ-28) comprises five domains: Activity adjustment, Activity planning, Activity consistency, Activity progression and Activity acceptance. This study aimed to shorten the APQ and provide evidence for its validity, reliability and responsiveness. Paper-based questionnaires collected data from patients with chronic pain attending healthcare services in England, UK, at baseline (n=347), and again at 2-weeks (n=130) and 12-weeks (n=121). Outcome measures included the APQ-28, and other measures of pacing, avoidance, overdoing, pain, self-efficacy, quality of life, physical/mental function, depression and anxiety. Statistical analyses explored validity, reliability, responsiveness and measurement error. Factor analysis (n=347) showed poor model fit for the previous five-factor model, leading to selecting a four-factor model (removing Activity acceptance) with three items per domain, forming the APQ-12 (CFI=0.995, TLI=0.992, RMSEA=0.052, SRMR=0.050). The four domains showed satisfactory internal consistency (Cronbach’s alpha=0.70–0.84) and test-retest reliability (n=130, ICC=0.53–0.64). Only Activity consistency showed significant responsiveness (n=121, Rho=0.27, 95% CI=0.1–0.43). Measurement error of the APQ-12 domains included smallest detectable change (range=1.55–1.76), standard error of measurement (range=0.56–0.63) and minimally important change (range=-0.17–0.33). Confirmatory factor analysis on external data supported the four-domain structure (CFI=0.983, TLI=0.977, RMSEA=0.071, SRMR=0.106). The APQ-12 shows promise as a multi-domain measure of activity pacing for use in clinical practice and future research.</div></div><div><h3>Perspective</h3><div>This article presents the psychometric properties of the 12-item Activity Pacing Questionnaire (APQ-12). The APQ-12 provides a multi-domain measure of activity pacing. It has potential clinical and research use to assess changes in activity pacing and explore the effects of activity pacing on symptoms of chronic pain.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"37 ","pages":"Article 105568"},"PeriodicalIF":4.0,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk factors for long-term sickness absence in patients with high-impact chronic pain – A scoping review and Swedish register-based cohort study","authors":"Robin Larsson ,&nbsp;Enisa Guta ,&nbsp;Björn Äng ,&nbsp;Riccardo LoMartire","doi":"10.1016/j.jpain.2025.105570","DOIUrl":"10.1016/j.jpain.2025.105570","url":null,"abstract":"<div><div>High-impact chronic pain (HICP) affects 8% of individuals worldwide. Beyond its direct consequences, HICP increases the risk of long-term sickness absence (LTSA), leading to income loss and increased societal costs. Prevention is essential and understanding risk factors for LTSA is a critical first step. We conducted a joint scoping review and Swedish register-based cohort study, to first identify and subsequently analyze potential risk factors. A multivariable logistic regression model estimated the association between the risk factors and LTSA, defined as &gt;180 sickness absence days in the third year after specialist healthcare entry. The likelihood ratio chi-square test determined each factor’s contribution to model fit. Associations were reported as marginal risk ratios (mRR) with 95% confidence intervals (95% CI), comparing the 75th to the 25th sample percentiles. Of 57 identified risk factors, 34 were analyzed in a sample of 10,552 patients, 25% of whom experienced LTSA. Seven risk factors contributed significantly at a Bonferroni-adjusted alpha level: prior sickness absence, (mRR: 2.53; 95% CI: 2.40–2.66), comorbid neurological disorders (1.60; 1.38–1.81), self-rated work ability (1.42; 1.29–1.58), confidence in recovery (1.21; 1.13–1.30), female sex (1.18; 1.10–1.26), pain duration (1.11; 1.03–1.20), and household income, which showed a complex non-monotonic relationship. In line with previous research, the strongest association was with prior sickness absence. By targeting the aforementioned risk factors, workforce reintegration could be facilitated for individuals with HICP.</div></div><div><h3>Perspective</h3><div>Our scoping review and large sample Swedish register-based study identifies and quantifies key risk factors for long-term sickness absence in individuals with high-impact chronic pain, providing a foundation for early identification and targeted rehabilitation, which in the longer perspective could support workforce reintegration and reduce individual suffering and societal costs.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"37 ","pages":"Article 105570"},"PeriodicalIF":4.0,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expectations and uncertainty shape pain perception during learning","authors":"Mégane Lacombe-Thibault ,&nbsp;Michel-Pierre Coll","doi":"10.1016/j.jpain.2025.105569","DOIUrl":"10.1016/j.jpain.2025.105569","url":null,"abstract":"<div><div>Pain perception is modulated by expectations and learning processes, but the influence of uncertainty in this relationship is not well established. We aimed to examine the relationship between uncertainty, pain learning and perception using hierarchical Bayesian modeling. In an aversive learning task, fifty participants learned contingencies between auditory cues and painful stimulations under changing levels of uncertainty to create periods of stability and volatility. Model-free analysis of our data suggested unexpected trials resulted in reduced accuracy and greater response times. In unexpected trials, high pain perception was reduced, while low pain perception was increased, in line with documented effects of expectations on pain perception. Computational model fitting revealed participants’ learning was best described by a two-level hierarchical gaussian filter model, suggesting participants adapted their beliefs at multiple levels during the task. Uncertainty influenced pain perception in opposite patterns for high and low pain stimulations: high pain perception was greater under high levels of uncertainty, while there was a non-significant trend for low pain perception to be reduced. Analyses of individual differences suggested depressive symptoms were associated with a reduced learning rate throughout the task. These results shed light on processes involved in pain learning in changing environments. They also suggest a possible relationship between learning alterations and psychological traits commonly found in chronic pain, such as depressive symptoms.</div></div><div><h3>Perspective</h3><div>This article explores the influence of varying levels of uncertainty on pain perception and learning. Findings reveal that uncertainty modulates pain perception differently depending on pain intensity and that pain learning is influenced by psychological traits. These results contribute to our understanding of pain modulation in dynamic environments.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"37 ","pages":"Article 105569"},"PeriodicalIF":4.0,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of activity with the risk of developing musculoskeletal pain in the All of Us research program.","authors":"Salim Yakdan, Braeden Benedict, Pranay Singh, Madelyn R Frumkin, Burel R Goodin, Brian Neuman, Abby L Cheng, Jing Wang, Michael P Kelly, Wilson Z Ray, Jacob K Greenberg","doi":"10.1016/j.jpain.2025.105516","DOIUrl":"10.1016/j.jpain.2025.105516","url":null,"abstract":"<p><p>Physical activity (PA) is recommended to prevent chronic diseases; However, its precise benefit remains unclear. Orthopedic research tracking patients' activity primarily focuses on surgical outcomes, leaving a gap in understanding PA as a risk factor for musculoskeletal conditions. This study uses All of Us Research Program data to investigate the association between PA and musculoskeletal pain development. Adults who shared their Fitbit and electronic health record (EHR) data with at least 6 months of Fitbit tracking before their first documented pain episode in the EHR were included. Daily step counts and three activity levels (light, moderate, and vigorous) were analyzed using time-dependent Cox models to examine associations between PA and incident neck, low back, hip, and knee pain. Hazard ratios (HRs) were estimated by comparing the 75th to the 25th percentile of each PA measure (i.e., interquartile range increase), adjusting for age, sex, Body mass index (BMI), and educational level. Among 14,754 participants (median age 51.3 [IQR 25.7], 72% female), 796, 144, 1362, and 1754 developed back, neck, hip, and knee pain, respectively. Higher daily steps were associated with reduced risk of both low-back (HR 0.89 [0.8-0.98]) and neck pain (HR 0.69 [0.54-0.9]). Greater \"moderate activity\" was associated with a lower risk of low-back (HR 0.82 [0.72,0.95]) and hip pain (HR 0.87 [0.78,0.97]). In contrast, \"vigorous activity\" was associated with lower risk of neck (HR 0.53 [0.38-0.73]), low-back (HR 0.72 [0.62-0.84]), and hip pain (HR 0.93 [0.87-0.99]). PA was not related to knee pain. To our knowledge, this is the largest study on PA as a risk factor for musculoskeletal pain. Higher PA levels were associated with reduced risk of developing neck, low-back, and hip pain, with no association with knee pain. PERSPECTIVE: This is the largest study to our knowledge that highlights the association between objectively measured physical activity and reduced risk of developing neck, low-back, and hip pain. These findings support integrating activity recommendations into musculoskeletal health strategies, providing insight into how different activity levels influence pain risk.</p>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":" ","pages":"105516"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prolonged Aftersensations to Thermal Noxious Stimulation as a Screening Tool for Central Contributions to Chronic Ocular Pain.","authors":"Araliya N Gunawardene, Noa Dobzinski, David Valdes-Arias, Nicole B Kantor, Ana Zalvidar, Eric A Moulton, Pragnya R Donthineni, Robert C O'Brien, Anat Galor, Elizabeth R Felix","doi":"10.1016/j.jpain.2025.105561","DOIUrl":"https://doi.org/10.1016/j.jpain.2025.105561","url":null,"abstract":"<p><p>Painful aftersensations (AS) are sensations that persist after termination of a noxious stimulus, and prolonged AS may reflect abnormal somatosensory processing. We aimed to validate AS as indicators of central nervous system processing abnormalities in individuals with chronic ocular pain (COP). We examined two cohorts (Groups 1; n=278 and 2; n=64) who underwent an ocular surface examination, quantitative sensory testing (QST), and pain symptom assessment. Individuals were asked to rate pain intensity and unpleasantness (0-100) of AS at 15s and 30s after termination of a repeated stimulus protocol at two sites (forehead and forearm). Ratings >0 were considered positive for AS. Using Group 1 data, exploratory regression analyses determined which AS metrics most strongly related to central neuropathic-like or nociplastic ocular pain (NOP). The presence of unpleasant AS at 15 and 30s after hot pain on the forearm accounted for the most variability in indicators of NOP (i.e., scores on the Neuropathic Pain Symptom Indexmodified for the Eye (NPSI-Eye) and response to anesthetic eyedrops). We assessed the robustness of these AS metrics as indicators of NOP using data from a separate cohort (Group 2), by comparing NPSI-Eye scores, response to anesthetic eyedrops, and ocular signs (Schirmer's scores, tear film, and corneal fluorescein staining) between those with AS and those who did not report AS. The presence of AS was related to greater NPSI-Eye scores and persistence of eye pain after local anesthetic, but not to tear dysfunction signs, suggesting AS can differentiate patients with potential central mechanisms of COP. PERSPECTIVE: The presence of unpleasant aftersensations at 15 and 30 seconds after removal of a noxious hot stimulus was associated with other indicators of central somatosensory abnormalities in two disparate populations. This suggests that AS could be a clinical screening tool for central contributors to ocular pain.</p>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":" ","pages":"105561"},"PeriodicalIF":4.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cre-based functional profiling of RVM neurons implicates distinct populations in sensory-mediated behaviors","authors":"Eileen Nguyen ,&nbsp;Ruby A. Holland ,&nbsp;Sarah E. Ross","doi":"10.1016/j.jpain.2025.105565","DOIUrl":"10.1016/j.jpain.2025.105565","url":null,"abstract":"<div><div>The rostral ventromedial medulla (RVM) has an important role in descending modulation, yet the molecular and functional diversity of RVM neurons involved in nociception remains incompletely understood. Here, we used a combination of multiplex fluorescent in-situ hybridization (FISH), anatomical tracing, and behavioral testing to examine the selective roles of Cre-labeled neuronal populations in the RVM. At the neurochemical level, we confirmed that GABAergic neurons in the RVM include serotonergic (Tph2) and MOR-expressing (Oprm1) populations and that Tac1-expressing neurons were predominantly glutamatergic. We found that nNOS-expressing neurons exhibited a mixed phenotype, co-expressing both GABAergic and glutamatergic markers. We used a series of Cre-driver lines (Fev^Cre, Gad2^Cre, nNOS^CreER, Tac1^Cre, and MOR^Cre) to visualize RVM projections and perform behavioral experiments with chemogenetics. RVM neurons exhibited divergent projection patterns to the spinal cord, and, interestingly, we identified fluorescent labeling in the superior colliculus in both MOR^Cre and nNos^CreER populations. Behaviorally, activation of Gad2^Cre neurons significantly increased thermal thresholds, supporting their anti-nociceptive role. Activation of Tac1^Cre neurons facilitated mechanical and thermal nociception, whereas MOR^Cre activation suppressed scratching behaviors. Fev^Cre and nNOS^CreER manipulations did not significantly alter somatosensory responses. These findings highlight the molecular and behavioral complexity of RVM neurons and their distinct roles in sensory modulation.</div></div><div><h3>Perspective</h3><div>This study reveals the molecular and functional heterogeneity of RVM neuronal subpopulations based on their neurochemical identities, projection patterns, and behavioral roles in sensory modulation. By leveraging Cre genetics and chemogenetics, we delineate cell-type-specific contributions of RVM neurons to sensory behaviors. These results highlight the complexity of descending modulatory circuits.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"38 ","pages":"Article 105565"},"PeriodicalIF":4.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}