Pub Date : 2026-01-22DOI: 10.1097/j.pain.0000000000003903
Kirsten Barnes,Nicolas Andrew McNair,Cosette Saunders,Winston Tan,Ben Colagiuri
The current preregistered study compared subjective, autonomic, and neurophysiological correlates of nocebo hyperalgesia across 3 groups: Direct Experience (N = 20), Social Learning (N = 20), and Control (N = 20). Participants first underwent a Learning-Phase, where an association between treatment cues and painful thermal stimulation was established. Conditioned responses, induced via social or direct experience, were assessed during the Test-Phase, relative to the control comparator. Pain perception, autonomic arousal, and brain activity were measured via visual analogue scale, electrodermal activity, facial action units, and electroencephalography. Both direct and social learning produced significant nocebo hyperalgesia, as indicated by increased pain ratings, autonomic arousal, and modulation of event-related potentials. Increased N2 amplitude, associated with nociceptive processing, was comparable across the 2 conditioned groups, demonstrating expectancy-driven changes in brain activity irrespective of learning type. Although social learning elicited stronger nocebo hyperalgesia in subjective ratings, direct experience was associated with heightened autonomic response and greater activation of facial action units associated with pain during the Learning-Phase. Differences in the trajectory of the autonomic response during the Test-Phase were also observed, with phasic responses diminishing for direct experience but persisting social learning. These findings highlight the role of social information in shaping maladaptive pain responses and highlight the need to mitigate nocebo effects in clinical settings where maladaptive health outcomes can be both directly experienced and socially expressed. By demonstrating distinct behavioural and physiological patterns associated with direct and social learning, this research contributes to understanding the mechanisms underlying expectancy-driven pain modulation.
{"title":"Everybody hurts: behavioural, autonomic, and neuro-physiological correlates of directly compared to socially learnt nocebo hyperalgesia.","authors":"Kirsten Barnes,Nicolas Andrew McNair,Cosette Saunders,Winston Tan,Ben Colagiuri","doi":"10.1097/j.pain.0000000000003903","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003903","url":null,"abstract":"The current preregistered study compared subjective, autonomic, and neurophysiological correlates of nocebo hyperalgesia across 3 groups: Direct Experience (N = 20), Social Learning (N = 20), and Control (N = 20). Participants first underwent a Learning-Phase, where an association between treatment cues and painful thermal stimulation was established. Conditioned responses, induced via social or direct experience, were assessed during the Test-Phase, relative to the control comparator. Pain perception, autonomic arousal, and brain activity were measured via visual analogue scale, electrodermal activity, facial action units, and electroencephalography. Both direct and social learning produced significant nocebo hyperalgesia, as indicated by increased pain ratings, autonomic arousal, and modulation of event-related potentials. Increased N2 amplitude, associated with nociceptive processing, was comparable across the 2 conditioned groups, demonstrating expectancy-driven changes in brain activity irrespective of learning type. Although social learning elicited stronger nocebo hyperalgesia in subjective ratings, direct experience was associated with heightened autonomic response and greater activation of facial action units associated with pain during the Learning-Phase. Differences in the trajectory of the autonomic response during the Test-Phase were also observed, with phasic responses diminishing for direct experience but persisting social learning. These findings highlight the role of social information in shaping maladaptive pain responses and highlight the need to mitigate nocebo effects in clinical settings where maladaptive health outcomes can be both directly experienced and socially expressed. By demonstrating distinct behavioural and physiological patterns associated with direct and social learning, this research contributes to understanding the mechanisms underlying expectancy-driven pain modulation.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"270 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1097/j.pain.0000000000003906
Kuang-Hua Huang,Tsuei-Hung Wang,Tung-Han Tsai,Shuo-Yan Gau,Kun-Yu Su,Shiang-Wen Huang,Ya-Lan Chang,Chien-Ying Lee
This study investigated the association between pregabalin use and fracture risk in patients with postherpetic neuralgia (PHN) newly diagnosed between 2012 and 2021 in Taiwan. Patients treated with pregabalin formed the exposed group, whereas those not receiving pregabalin served as controls, with propensity score matching applied (1:3 ratio). Incident traumatic fractures were assessed over 30 days using Firth's logistic regression, with sensitivity analyses by dosage and time intervals. Patients on pregabalin had a higher fracture risk (adjusted odds ratio [aOR] = 1.51; 95% confidence interval [CI] = 1.07-2.15) compared to controls. By dosage, aORs were 1.54 (95% CI = 1.08-2.19) for ≤150 mg and 1.38 (95% CI = 0.59-3.23) for >150 mg. Fracture risks were elevated at 1 to 7 days (aOR = 2.10; 95% CI = 1.15-3.84) and 22 to 28 days (aOR = 2.31; 95% CI = 1.25-4.25), but not significantly at 8 to 14 or 15 to 21 days. Patients with PHN on pregabalin showed increased fracture risk, particularly at lower doses and during early/late treatment periods, without a clear dose-response relationship. Clinicians should monitor fracture risk in patients with PHN, even with low-dose or short-term pregabalin use.
本研究调查了2012年至2021年间台湾新诊断的带状疱疹后神经痛（PHN）患者普瑞巴林使用与骨折风险之间的关系。接受普瑞巴林治疗的患者为暴露组，未接受普瑞巴林治疗的患者为对照组，采用倾向评分匹配（1:3比例）。使用Firth逻辑回归对30天内的外伤性骨折进行评估，并根据剂量和时间间隔进行敏感性分析。与对照组相比，使用普瑞巴林的患者骨折风险更高（校正优势比[aOR] = 1.51； 95%可信区间[CI] = 1.07-2.15）。按剂量划分，≤150mg的aor为1.54 (95% CI = 1.08 ~ 2.19), > 150mg的aor为1.38 （95% CI = 0.59 ~ 3.23）。骨折风险在第1 - 7天（aOR = 2.10, 95% CI = 1.15-3.84）和22 - 28天（aOR = 2.31, 95% CI = 1.25-4.25）升高，但在第8 - 14天或15- 21天不明显。服用普瑞巴林的PHN患者骨折风险增加，特别是在低剂量和治疗早期/晚期，没有明确的剂量-反应关系。临床医生应监测PHN患者的骨折风险，即使是低剂量或短期使用普瑞巴林。
{"title":"Risk of fractures among patients with postherpetic neuralgia receiving pregabalin: real-world evidence from Taiwan.","authors":"Kuang-Hua Huang,Tsuei-Hung Wang,Tung-Han Tsai,Shuo-Yan Gau,Kun-Yu Su,Shiang-Wen Huang,Ya-Lan Chang,Chien-Ying Lee","doi":"10.1097/j.pain.0000000000003906","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003906","url":null,"abstract":"This study investigated the association between pregabalin use and fracture risk in patients with postherpetic neuralgia (PHN) newly diagnosed between 2012 and 2021 in Taiwan. Patients treated with pregabalin formed the exposed group, whereas those not receiving pregabalin served as controls, with propensity score matching applied (1:3 ratio). Incident traumatic fractures were assessed over 30 days using Firth's logistic regression, with sensitivity analyses by dosage and time intervals. Patients on pregabalin had a higher fracture risk (adjusted odds ratio [aOR] = 1.51; 95% confidence interval [CI] = 1.07-2.15) compared to controls. By dosage, aORs were 1.54 (95% CI = 1.08-2.19) for ≤150 mg and 1.38 (95% CI = 0.59-3.23) for >150 mg. Fracture risks were elevated at 1 to 7 days (aOR = 2.10; 95% CI = 1.15-3.84) and 22 to 28 days (aOR = 2.31; 95% CI = 1.25-4.25), but not significantly at 8 to 14 or 15 to 21 days. Patients with PHN on pregabalin showed increased fracture risk, particularly at lower doses and during early/late treatment periods, without a clear dose-response relationship. Clinicians should monitor fracture risk in patients with PHN, even with low-dose or short-term pregabalin use.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"34 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tonic pain is proposed to maintain homeostatic integrity during recovery from injury. A key untested prediction of this homeostatic model is that it modulates internal representations of phasic pain. We investigated whether lateralised tonic pain modulates phasic pain-predictive cues on that side. Using a virtual-reality Pavlovian revaluation-style paradigm, we assessed physiological and neural conditioned responses with electroencephalography in theta, alpha, and beta frequency bands. Pain-predictive cues elicited neural enhanced alpha and beta suppression and increased pupil diameter during conditioning acquisition. Critically, tonic pain altered neural correlates of phasic conditioned responses during extinction, with reduced midfrontal theta synchronisation when the laterality of tonic pain was congruent with predicted phasic pain. These findings provide neural evidence for a topographically specific modulation of cue-pain representations by tonic pain, suggesting that tonic pain dynamically reshapes neural predictions of potential threat.
{"title":"Tonic pain modulates neural correlates of associative phasic pain memories.","authors":"Danielle Hewitt,Shuangyi Tong,Sarah Schreiber,Ben Seymour","doi":"10.1097/j.pain.0000000000003917","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003917","url":null,"abstract":"Tonic pain is proposed to maintain homeostatic integrity during recovery from injury. A key untested prediction of this homeostatic model is that it modulates internal representations of phasic pain. We investigated whether lateralised tonic pain modulates phasic pain-predictive cues on that side. Using a virtual-reality Pavlovian revaluation-style paradigm, we assessed physiological and neural conditioned responses with electroencephalography in theta, alpha, and beta frequency bands. Pain-predictive cues elicited neural enhanced alpha and beta suppression and increased pupil diameter during conditioning acquisition. Critically, tonic pain altered neural correlates of phasic conditioned responses during extinction, with reduced midfrontal theta synchronisation when the laterality of tonic pain was congruent with predicted phasic pain. These findings provide neural evidence for a topographically specific modulation of cue-pain representations by tonic pain, suggesting that tonic pain dynamically reshapes neural predictions of potential threat.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"103 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1097/j.pain.0000000000003897
Wenxin Su,Chris G Antonopoulos,Elia Valentini
The sustained nature of tonic pain makes it a useful experimental analogue for studying the prolonged neural processing involved in chronic pain. However, research is yet to identify its consistent and generalisable biomarkers. Here, we analysed electroencephalography data recorded in 36 volunteers during 5-minute sessions of noxious hot and innocuous warm water immersion using network-based statistics and graph theory-based analysis. Our results revealed a brain-wide reorganisation of functional connectivity during tonic pain, marked by a global shift from segregation to integration. This shift was characterised by a transition from intra- to internetwork communication, with the Somato-Motor (SomMot) network playing a pivotal role. During innocuous warmth, the SomMot network exhibited significantly higher functional specialisation for localised sensory processing. During noxious heat, however, it shifted to an integrative coordinator, a finding reinforced by a significant discrepancy in global clustering coefficient when intranetwork connections were excluded. We also found that psychological traits modulated global network inferences (GNIs) in distinct, clinically relevant ways: pain catastrophising was positively associated with network segregation and integration during pain, whereas anxiety was negatively associated with segregation and integration during innocuous warmth. Notably, a machine learning model using these GNIs achieved 86% accuracy in classifying noxious heat from innocuous warmth. Together, our findings elucidate the transformation from segregated processing to integrated network dynamics induced by tonic pain, characterised by a transition in the SomMot network functioning as an integrator. Critically, global network inferences may serve as valuable predictors of pain experiences, highlighting their translational potential in pain neuroscience.
{"title":"Network reorganisation reveals somato-motor transition from segregation to integration during tonic pain.","authors":"Wenxin Su,Chris G Antonopoulos,Elia Valentini","doi":"10.1097/j.pain.0000000000003897","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003897","url":null,"abstract":"The sustained nature of tonic pain makes it a useful experimental analogue for studying the prolonged neural processing involved in chronic pain. However, research is yet to identify its consistent and generalisable biomarkers. Here, we analysed electroencephalography data recorded in 36 volunteers during 5-minute sessions of noxious hot and innocuous warm water immersion using network-based statistics and graph theory-based analysis. Our results revealed a brain-wide reorganisation of functional connectivity during tonic pain, marked by a global shift from segregation to integration. This shift was characterised by a transition from intra- to internetwork communication, with the Somato-Motor (SomMot) network playing a pivotal role. During innocuous warmth, the SomMot network exhibited significantly higher functional specialisation for localised sensory processing. During noxious heat, however, it shifted to an integrative coordinator, a finding reinforced by a significant discrepancy in global clustering coefficient when intranetwork connections were excluded. We also found that psychological traits modulated global network inferences (GNIs) in distinct, clinically relevant ways: pain catastrophising was positively associated with network segregation and integration during pain, whereas anxiety was negatively associated with segregation and integration during innocuous warmth. Notably, a machine learning model using these GNIs achieved 86% accuracy in classifying noxious heat from innocuous warmth. Together, our findings elucidate the transformation from segregated processing to integrated network dynamics induced by tonic pain, characterised by a transition in the SomMot network functioning as an integrator. Critically, global network inferences may serve as valuable predictors of pain experiences, highlighting their translational potential in pain neuroscience.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"85 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1097/j.pain.0000000000003913
Joe D Baal,Prinska Ghimire,Sagar Wagle,Monisha Lewis,Yingding Xu,Vivianne L Tawfik,Guido Davidzon,Christopher R McCurdy,Sandip Biswal,Daehyun Yoon
Complex regional pain syndrome (CRPS) is a poorly understood chronic pain condition of the extremities presenting severe pain disproportionate to the causative injury. Owing to its heterogeneous clinical presentation and the lack of specific diagnostic tests, CRPS is often a diagnostic and therapeutic challenge. Early diagnosis and treatment of CRPS improve quality of life and delay disease progression. Identification of focal peripheral pain generators would provide an opportunity for targeted treatments with more limited side effects. A highly selective sigma-1 receptor positron emission tomography (PET) radioligand, [18F]FTC-146, has been developed and has shown promise in identifying inflammatory or nociceptive processes. Our aim was to investigate the utility of [18F]FTC-146 PET/MRI for identifying peripheral pain generators and assessing its impact on subsequent clinical management of patients with CRPS. This single-center study enrolled 15 subjects with a clinical diagnosis of CRPS to undergo [18F]FTC-146 PET/MRI. PET/MRI findings were reviewed and discussed with referring pain specialists. Pain scores and subsequent changes in pain management for each patient were prospectively noted. Potential pain generators were observed in 10 of 15 subjects. Subsequent pain treatments guided by abnormally increased foci of uptake on [18F]FTC-146 PET/MRI resulted in an average 5-point improvement in pain score in 80% (8/10) of subjects. Overall, [18F]FTC-146 PET/MRI was able to identify potential peripheral pain generators in the affected limbs of subjects with CRPS and subsequently guided targeted treatments that resulted in varying degrees of improvement in subjective pain scores.
{"title":"Identification of peripheral pain generators with sigma-1 receptor Positron Emission Tomography/Magnetic Resonance Imaging in complex regional pain syndrome: initial study in a prospective trial.","authors":"Joe D Baal,Prinska Ghimire,Sagar Wagle,Monisha Lewis,Yingding Xu,Vivianne L Tawfik,Guido Davidzon,Christopher R McCurdy,Sandip Biswal,Daehyun Yoon","doi":"10.1097/j.pain.0000000000003913","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003913","url":null,"abstract":"Complex regional pain syndrome (CRPS) is a poorly understood chronic pain condition of the extremities presenting severe pain disproportionate to the causative injury. Owing to its heterogeneous clinical presentation and the lack of specific diagnostic tests, CRPS is often a diagnostic and therapeutic challenge. Early diagnosis and treatment of CRPS improve quality of life and delay disease progression. Identification of focal peripheral pain generators would provide an opportunity for targeted treatments with more limited side effects. A highly selective sigma-1 receptor positron emission tomography (PET) radioligand, [18F]FTC-146, has been developed and has shown promise in identifying inflammatory or nociceptive processes. Our aim was to investigate the utility of [18F]FTC-146 PET/MRI for identifying peripheral pain generators and assessing its impact on subsequent clinical management of patients with CRPS. This single-center study enrolled 15 subjects with a clinical diagnosis of CRPS to undergo [18F]FTC-146 PET/MRI. PET/MRI findings were reviewed and discussed with referring pain specialists. Pain scores and subsequent changes in pain management for each patient were prospectively noted. Potential pain generators were observed in 10 of 15 subjects. Subsequent pain treatments guided by abnormally increased foci of uptake on [18F]FTC-146 PET/MRI resulted in an average 5-point improvement in pain score in 80% (8/10) of subjects. Overall, [18F]FTC-146 PET/MRI was able to identify potential peripheral pain generators in the affected limbs of subjects with CRPS and subsequently guided targeted treatments that resulted in varying degrees of improvement in subjective pain scores.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"29 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The ability of human caregivers to decode and respond to the distress information encoded in a baby's cries is essential for the baby's survival. What are the factors that influence this aptitude, and how is this represented in the brain? Although previous neuroimaging studies have shown that hearing cries activates a set of brain areas that drive caregiver response behaviors, they have mainly focused on adults with parenting experience, especially mothers, and have not explored how the level of pain expressed in the cry modulates caregiver brain activation. In this study, we combine fMRI studies on a large sample of parents and nonparents with ground-breaking voice resynthesis tools enabling us to systematically control the level of pain expressed by babies' cries. We show that pain cries induce more specialized brain activation in parents than in nonparents, with greater connectivity within and between networks involved in mentalizing, emotional regulation, and vigilance. Mothers show higher overall connectome activity than fathers. Yet, it is among parents with the greatest emotional empathy-both fathers and mothers-that vocal roughness (a marker of distress in baby cries) most actively recruits the parental vigilance brain network. By taking advantage of acoustic resynthesis, which allows precise control over sound stimuli, and by paying attention to the ability to understand the emotions of others rather than focusing solely on sex, our study highlights that parental status interacts with empathetic capabilities to modulate how the brains of human adults respond when a baby's cry signals distress.
{"title":"Parenting and empathy capabilities drive brain response to pain cues in baby cries.","authors":"Camille Fauchon,Siloé Corvin,Isabelle Faillenot,Hugues Patural,David Reby,Roland Peyron,Nicolas Mathevon","doi":"10.1097/j.pain.0000000000003914","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003914","url":null,"abstract":"The ability of human caregivers to decode and respond to the distress information encoded in a baby's cries is essential for the baby's survival. What are the factors that influence this aptitude, and how is this represented in the brain? Although previous neuroimaging studies have shown that hearing cries activates a set of brain areas that drive caregiver response behaviors, they have mainly focused on adults with parenting experience, especially mothers, and have not explored how the level of pain expressed in the cry modulates caregiver brain activation. In this study, we combine fMRI studies on a large sample of parents and nonparents with ground-breaking voice resynthesis tools enabling us to systematically control the level of pain expressed by babies' cries. We show that pain cries induce more specialized brain activation in parents than in nonparents, with greater connectivity within and between networks involved in mentalizing, emotional regulation, and vigilance. Mothers show higher overall connectome activity than fathers. Yet, it is among parents with the greatest emotional empathy-both fathers and mothers-that vocal roughness (a marker of distress in baby cries) most actively recruits the parental vigilance brain network. By taking advantage of acoustic resynthesis, which allows precise control over sound stimuli, and by paying attention to the ability to understand the emotions of others rather than focusing solely on sex, our study highlights that parental status interacts with empathetic capabilities to modulate how the brains of human adults respond when a baby's cry signals distress.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"11 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peripheral nerve injury can lead to chronic mechanical hypersensitivity, yet the severity and persistence of pain are strongly influenced by the extent of axonal damage. Notably, partial sciatic nerve crush injury (PCI) produces persistent tactile hypersensitivity despite a less severe anatomical insult than full crush injury, yet the identity and postinjury state of the fibers that persist after PCI remain unclear. To define sensory neuron populations contributing to PCI-induced tactile hypersensitivity, we combined fiber-specific transgenic labeling (Thy1-YFP for Aβ mechanoreceptors and Nav1.8-tdTomato for nociceptors) with pharmacological silencing using QX-314 coapplied with transient receptor potential vanilloid 1 (TRPV1) (capsaicin) and toll-like receptor 5 (flagellin) agonists to selectively manipulate fiber subtypes. At day 7 after PCI, Nav1.8+ nociceptive terminals were still detectable in the hind paw. On day 30, acute silencing of TRPV1+ afferents transiently reduced mechanical hypersensitivity, indicating nociceptor activity in its maintenance. Whole-cell patch clamp recordings of retrogradely labeled dorsal root ganglia neurons showed that remaining medium-diameter neurons exhibited reduced rheobase and increased action potential firings in response to step current injections. Besides, electrical stimulation of nociceptive fibers increased phosphorylated extracellular signal-regulated protein kinase expression in the spinal dorsal horn, indicating enhanced nociceptive signaling after PCI. Early ablation of TRPV1+ fibers with high-dose capsaicin during the degeneration phase prevented the subsequent development of long-term tactile hypersensitivity. Collectively, our results suggest that spared nociceptors after PCI remain sensitized even during nerve repair, driving long-term tactile hypersensitivity. Targeting these spared nociceptive fibers after nerve injury may offer a potential strategy for preventing chronic pain associated with traumatic nerve injury.
{"title":"Spared Nav1.8-positive nociceptors drive persistent tactile hypersensitivity after sciatic nerve crush injury in mice.","authors":"Sang Wook Shim,Yoon Kyung Lee,Dahee Roh,Kihwan Lee,Hyoung Woo Kim,Seog Bae Oh","doi":"10.1097/j.pain.0000000000003892","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003892","url":null,"abstract":"Peripheral nerve injury can lead to chronic mechanical hypersensitivity, yet the severity and persistence of pain are strongly influenced by the extent of axonal damage. Notably, partial sciatic nerve crush injury (PCI) produces persistent tactile hypersensitivity despite a less severe anatomical insult than full crush injury, yet the identity and postinjury state of the fibers that persist after PCI remain unclear. To define sensory neuron populations contributing to PCI-induced tactile hypersensitivity, we combined fiber-specific transgenic labeling (Thy1-YFP for Aβ mechanoreceptors and Nav1.8-tdTomato for nociceptors) with pharmacological silencing using QX-314 coapplied with transient receptor potential vanilloid 1 (TRPV1) (capsaicin) and toll-like receptor 5 (flagellin) agonists to selectively manipulate fiber subtypes. At day 7 after PCI, Nav1.8+ nociceptive terminals were still detectable in the hind paw. On day 30, acute silencing of TRPV1+ afferents transiently reduced mechanical hypersensitivity, indicating nociceptor activity in its maintenance. Whole-cell patch clamp recordings of retrogradely labeled dorsal root ganglia neurons showed that remaining medium-diameter neurons exhibited reduced rheobase and increased action potential firings in response to step current injections. Besides, electrical stimulation of nociceptive fibers increased phosphorylated extracellular signal-regulated protein kinase expression in the spinal dorsal horn, indicating enhanced nociceptive signaling after PCI. Early ablation of TRPV1+ fibers with high-dose capsaicin during the degeneration phase prevented the subsequent development of long-term tactile hypersensitivity. Collectively, our results suggest that spared nociceptors after PCI remain sensitized even during nerve repair, driving long-term tactile hypersensitivity. Targeting these spared nociceptive fibers after nerve injury may offer a potential strategy for preventing chronic pain associated with traumatic nerve injury.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"56 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1097/j.pain.0000000000003896
Sang Wook Shim, Hyoung Woo Kim, Yoon Kyung Lee, Clifford J Woolf, Kihwan Lee, Seog Bae Oh
Abstract: Sympathetic sprouting in dorsal root ganglia (DRG) is a feature of sympathetically maintained pain (SMP) after peripheral nerve injury, yet the factors determining its occurrence remain unclear. Here, we compare transection and crush injury models to determine whether injury type or site influence sympathetic remodeling and pain. Using tyrosine hydroxylase-immunoreactivity staining and Phox2b reporter mice to selectively label sympathetic fibers, we found that an L5 spinal nerve transection triggered robust sympathetic fiber sprouting and elevated norepinephrine (NE) levels in the DRG, correlating with mechanical hypersensitivity that was reversed by chemical sympathectomy. By contrast, a partial sciatic nerve crush injury produced long-lasting mechanical hypersensitivity without sympathetic sprouting or NE elevation and was unaffected by sympathectomy. Importantly, sympathetic sprouting was consistently more pronounced after transection injuries at both spinal and sciatic nerve sites, suggesting that injury type, rather than location, is a dominant factor shaping sympathetic remodeling. These findings establish nerve transection as a key driver of sympathetic sprouting and SMP, whereas crush-induced pain likely involves distinct nonsympathetic mechanisms. This distinction has important implications for pain subtype identification and treatment strategies.
{"title":"Peripheral nerve transection predominantly drives sympathetic nerve sprouting in mouse dorsal root ganglia.","authors":"Sang Wook Shim, Hyoung Woo Kim, Yoon Kyung Lee, Clifford J Woolf, Kihwan Lee, Seog Bae Oh","doi":"10.1097/j.pain.0000000000003896","DOIUrl":"10.1097/j.pain.0000000000003896","url":null,"abstract":"<p><strong>Abstract: </strong>Sympathetic sprouting in dorsal root ganglia (DRG) is a feature of sympathetically maintained pain (SMP) after peripheral nerve injury, yet the factors determining its occurrence remain unclear. Here, we compare transection and crush injury models to determine whether injury type or site influence sympathetic remodeling and pain. Using tyrosine hydroxylase-immunoreactivity staining and Phox2b reporter mice to selectively label sympathetic fibers, we found that an L5 spinal nerve transection triggered robust sympathetic fiber sprouting and elevated norepinephrine (NE) levels in the DRG, correlating with mechanical hypersensitivity that was reversed by chemical sympathectomy. By contrast, a partial sciatic nerve crush injury produced long-lasting mechanical hypersensitivity without sympathetic sprouting or NE elevation and was unaffected by sympathectomy. Importantly, sympathetic sprouting was consistently more pronounced after transection injuries at both spinal and sciatic nerve sites, suggesting that injury type, rather than location, is a dominant factor shaping sympathetic remodeling. These findings establish nerve transection as a key driver of sympathetic sprouting and SMP, whereas crush-induced pain likely involves distinct nonsympathetic mechanisms. This distinction has important implications for pain subtype identification and treatment strategies.</p>","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1097/j.pain.0000000000003891
Muhammad Ali Hashmi,Javeria Ali Hashmi
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Pub Date : 2026-01-14DOI: 10.1097/j.pain.0000000000003902
Jemma Todd,Brydee Pickup,Julie Ji,Alice Norton,Emily A Holmes,Louise Sharpe
Mental imagery is a powerful cognitive process implicated in various psychological disorders, yet its role in chronic pain remains underexplored. This study examined the temporal relationship between mental imagery, pain-related psychological constructs, and pain outcomes in young adults with chronic pain. A sample of 121 university students with chronic pain completed baseline assessments of mental imagery (tendency, ability, intrusive imagery), pain-related psychological constructs (interpretation bias, fear of progression, pain anxiety), and general psychological constructs (depression, anxiety, stress, emotion regulation difficulties, trauma symptoms). Participants then completed an ecological momentary assessment delivered by smartphone app 3 times daily for 1 week, reporting on pain severity, pain interference, pain-related imagery (frequency, valence, vividness), and pain expectancy. Multilevel and cross-lagged models were used to assess within- and between-person predictors of pain outcomes. We found that pain-specific imagery, particularly intrusive imagery at baseline and momentary imagery frequency, was consistently associated with greater pain severity and interference, and predicted subsequent pain severity. General imagery tendency was inversely associated with pain outcomes, suggesting a potential protective effect. Increased pain imagery valence and vividness were differentially associated with increased pain severity and interference, respectively. Pain expectancy, interpretation bias, and fear of progression were also significant predictors of pain interference, while pain expectancy also predicted subsequent pain severity. These findings suggest that pain-specific mental imagery is a temporally relevant and potentially modifiable predictor of pain outcomes in young adults.
{"title":"Momentary assessment of mental imagery and pain-related psychological factors in youth with chronic pain.","authors":"Jemma Todd,Brydee Pickup,Julie Ji,Alice Norton,Emily A Holmes,Louise Sharpe","doi":"10.1097/j.pain.0000000000003902","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003902","url":null,"abstract":"Mental imagery is a powerful cognitive process implicated in various psychological disorders, yet its role in chronic pain remains underexplored. This study examined the temporal relationship between mental imagery, pain-related psychological constructs, and pain outcomes in young adults with chronic pain. A sample of 121 university students with chronic pain completed baseline assessments of mental imagery (tendency, ability, intrusive imagery), pain-related psychological constructs (interpretation bias, fear of progression, pain anxiety), and general psychological constructs (depression, anxiety, stress, emotion regulation difficulties, trauma symptoms). Participants then completed an ecological momentary assessment delivered by smartphone app 3 times daily for 1 week, reporting on pain severity, pain interference, pain-related imagery (frequency, valence, vividness), and pain expectancy. Multilevel and cross-lagged models were used to assess within- and between-person predictors of pain outcomes. We found that pain-specific imagery, particularly intrusive imagery at baseline and momentary imagery frequency, was consistently associated with greater pain severity and interference, and predicted subsequent pain severity. General imagery tendency was inversely associated with pain outcomes, suggesting a potential protective effect. Increased pain imagery valence and vividness were differentially associated with increased pain severity and interference, respectively. Pain expectancy, interpretation bias, and fear of progression were also significant predictors of pain interference, while pain expectancy also predicted subsequent pain severity. These findings suggest that pain-specific mental imagery is a temporally relevant and potentially modifiable predictor of pain outcomes in young adults.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"269 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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