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
{"title":"Chronic pain and the limits of artificial intelligence: why expert knowledge matters.","authors":"Muhammad Ali Hashmi,Javeria Ali Hashmi","doi":"10.1097/j.pain.0000000000003891","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003891","url":null,"abstract":"","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"316 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994937","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.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}
Pub Date : 2026-01-12DOI: 10.1097/j.pain.0000000000003919
Helena Hartmann,Philipp Dahmen,Ulrike Bingel,Markus Rütgen
Changes to one's pain processing system through external or cognitive influences may influence how we interact with other people. To investigate the causal effects of different pain modulations on social emotions and behaviour, we conducted a pre-registered PRISMA-guided systematic literature review. Our main aim was to investigate how directly or indirectly interfering with pain perception through (psycho)pharmacological manipulations affects our abilities to perceive, process, and react to positive and negative emotions (including pain) in other individuals. We included and synthesized 50 of 2060 screened studies. Included studies investigated the effects of opioids, opioid antagonists, acetaminophen, capsaicin, cannabinoids, ketamine, alcohol, placebo analgesia, and hypnotic analgesia. Overall risk of bias was low in 23, medium in 12, and high in 14 studies, while only 24% of studies checked whether their employed manipulation reduced first-hand pain (which it did in all of these). In summary, studies report inconsistent results, with findings generally showing small effects in both directions, ie, an increase or decrease of social emotions or abilities. The strongest and most consistent effect was observed for placebo analgesia decreasing empathy for pain. These results can be attributed to study heterogeneity, pharmacological effects, modes of action, as well as dosage differences. This review thus shows that we are far away from understanding the intricacies of different (psycho)pharmacological pain manipulations and their effects on social emotions and behaviour. To advance as a field and better understand the mechanisms of this interplay, we need well-powered studies, large-scale replications, and systematic meta-analyses.
{"title":"The effects of different types of pain modulation on social emotions and behaviour-a systematic literature review.","authors":"Helena Hartmann,Philipp Dahmen,Ulrike Bingel,Markus Rütgen","doi":"10.1097/j.pain.0000000000003919","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003919","url":null,"abstract":"Changes to one's pain processing system through external or cognitive influences may influence how we interact with other people. To investigate the causal effects of different pain modulations on social emotions and behaviour, we conducted a pre-registered PRISMA-guided systematic literature review. Our main aim was to investigate how directly or indirectly interfering with pain perception through (psycho)pharmacological manipulations affects our abilities to perceive, process, and react to positive and negative emotions (including pain) in other individuals. We included and synthesized 50 of 2060 screened studies. Included studies investigated the effects of opioids, opioid antagonists, acetaminophen, capsaicin, cannabinoids, ketamine, alcohol, placebo analgesia, and hypnotic analgesia. Overall risk of bias was low in 23, medium in 12, and high in 14 studies, while only 24% of studies checked whether their employed manipulation reduced first-hand pain (which it did in all of these). In summary, studies report inconsistent results, with findings generally showing small effects in both directions, ie, an increase or decrease of social emotions or abilities. The strongest and most consistent effect was observed for placebo analgesia decreasing empathy for pain. These results can be attributed to study heterogeneity, pharmacological effects, modes of action, as well as dosage differences. This review thus shows that we are far away from understanding the intricacies of different (psycho)pharmacological pain manipulations and their effects on social emotions and behaviour. To advance as a field and better understand the mechanisms of this interplay, we need well-powered studies, large-scale replications, and systematic meta-analyses.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"21 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956062","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 : 2026-01-09DOI: 10.1097/j.pain.0000000000003789
Remi Shrivastava,Aurelie Ginisty,Gisela Da Silva Borges,Amelie Descheemaeker,Radhouane Dallel,Lenaic Monconduit
Parthenolide (PTL) and salicin (SA), the main active components in Feverfew (Tanacetum parthenium) and White Willow (Salix alba), respectively, have been traditionally used as a remedy for various types of pain, including headaches. Because PTL and SA have different mechanisms of action, we hypothesize that a combination of these drugs would result in an additive effect. We investigated the effects of local and/or systemic administration of PTL, SA, or their combination on cephalic mechanical hypersensitivity (MH) in acute and chronic model of migraine induced by dural application of inflammatory soup (IS) in rats of both sexes. We also studied the effect of combination of PTL and SA on the sensitization of the trigeminocervical complex (TCC) induced by IS application using immunohistochemical (calcitonin gene-related peptide [CGRP] expression) and electrophysiological approaches. When combining low doses of PTL (2.5 mg/kg) and SA (5 mg/kg), we found that single systemic administration of combination prevented acute cephalic MH only in females. However, when administered daily, the combination prevented both chronic ictal and interictal cephalic MH as well as the IS-induced increase in CGRP-immunoreactivity within the TCC, in both sexes. Notably, a single dural application of the combination also prevented acute sensitization of TCC wide dynamic range neurons. Combining PTL and SA have an antimigraine effect in both male and female rats. The combination exerts its preventive effect, at least in part, by blocking the afferent inputs from the dura during the induction phase, preventing thus the establishment of central sensitization.
{"title":"Association of parthenolide and salicin as a preventive treatment on a migraine model induced by dural inflammatory soup application.","authors":"Remi Shrivastava,Aurelie Ginisty,Gisela Da Silva Borges,Amelie Descheemaeker,Radhouane Dallel,Lenaic Monconduit","doi":"10.1097/j.pain.0000000000003789","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003789","url":null,"abstract":"Parthenolide (PTL) and salicin (SA), the main active components in Feverfew (Tanacetum parthenium) and White Willow (Salix alba), respectively, have been traditionally used as a remedy for various types of pain, including headaches. Because PTL and SA have different mechanisms of action, we hypothesize that a combination of these drugs would result in an additive effect. We investigated the effects of local and/or systemic administration of PTL, SA, or their combination on cephalic mechanical hypersensitivity (MH) in acute and chronic model of migraine induced by dural application of inflammatory soup (IS) in rats of both sexes. We also studied the effect of combination of PTL and SA on the sensitization of the trigeminocervical complex (TCC) induced by IS application using immunohistochemical (calcitonin gene-related peptide [CGRP] expression) and electrophysiological approaches. When combining low doses of PTL (2.5 mg/kg) and SA (5 mg/kg), we found that single systemic administration of combination prevented acute cephalic MH only in females. However, when administered daily, the combination prevented both chronic ictal and interictal cephalic MH as well as the IS-induced increase in CGRP-immunoreactivity within the TCC, in both sexes. Notably, a single dural application of the combination also prevented acute sensitization of TCC wide dynamic range neurons. Combining PTL and SA have an antimigraine effect in both male and female rats. The combination exerts its preventive effect, at least in part, by blocking the afferent inputs from the dura during the induction phase, preventing thus the establishment of central sensitization.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"4 1","pages":"297-307"},"PeriodicalIF":7.4,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937877","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}
Patterns of sensory involvement in diabetic neuropathy vary between studies and diagnostic approaches. Although some report early thermal deficits, others find predominant large-fiber changes, and hypersensitivity in early disease is inconsistently observed. Elevated heat pain thresholds (HPTs) may indicate either selective loss of heat transduction or advanced peripheral denervation of polymodal nociceptors. We examined whether thermal and mechanical pain functions align with psychophysical axonal excitability by combining German Research Network on Neuropathic Pain-quantitative sensory testing with slow depolarizing transdermal electrical stimulation of polymodal C-fibers in 66 adults with diabetes mellitus. Neuropathy was assessed by Toronto Consensus Criteria, quantitative sensory testing (QST), questionnaires, and serum neurofilament light chain (NfL) as a marker of axonal damage. Mechanical pain sensitivity correlated with electrically evoked pain (r ≈ 0.60-0.62, both P < 0.0001), consistent with parallel changes in mechanical transduction and axonal excitability, whereas HPT did not correlate with electrical pain. Many individuals with elevated HPT still exhibited strong electrically evoked pain responses, suggesting impaired heat transduction despite preserved superficial axonal excitability. Participants with sensory loss in QST showed reduced sensitivity to electrical stimuli and higher detection and pain thresholds, consistent with more advanced afferent dysfunction. NfL levels generally correlated with sensory impairment, although at low electrical intensities, higher NfL values were associated with stronger pain ratings, indicating intensity-dependent links between axonal pathology and nociceptor hyperexcitability. Combining QST with C-fiber-targeted electrical testing refines phenotyping of small-fiber dysfunction in diabetic neuropathy by revealing dissociation between thermal and electrical pain modalities and capturing the heterogeneous course from preserved function to selective thermal hypoalgesia and eventual sensory loss.
{"title":"Mismatch between intact electrical excitability and lost heat pain in diabetic neuropathy.","authors":"Omar Eldesouky,Lukas Seebauer,Roman Rukwied,Richard Carr,Mani Roshan,Hannah Gottlieb,Dimitrios Tsilingiris,Stefan Kopf,Stephan Herzig,Thomas Fleming,Jens Kessler,Julia Szendroedi,Martin Schmelz,Zoltan Kender","doi":"10.1097/j.pain.0000000000003898","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003898","url":null,"abstract":"Patterns of sensory involvement in diabetic neuropathy vary between studies and diagnostic approaches. Although some report early thermal deficits, others find predominant large-fiber changes, and hypersensitivity in early disease is inconsistently observed. Elevated heat pain thresholds (HPTs) may indicate either selective loss of heat transduction or advanced peripheral denervation of polymodal nociceptors. We examined whether thermal and mechanical pain functions align with psychophysical axonal excitability by combining German Research Network on Neuropathic Pain-quantitative sensory testing with slow depolarizing transdermal electrical stimulation of polymodal C-fibers in 66 adults with diabetes mellitus. Neuropathy was assessed by Toronto Consensus Criteria, quantitative sensory testing (QST), questionnaires, and serum neurofilament light chain (NfL) as a marker of axonal damage. Mechanical pain sensitivity correlated with electrically evoked pain (r ≈ 0.60-0.62, both P < 0.0001), consistent with parallel changes in mechanical transduction and axonal excitability, whereas HPT did not correlate with electrical pain. Many individuals with elevated HPT still exhibited strong electrically evoked pain responses, suggesting impaired heat transduction despite preserved superficial axonal excitability. Participants with sensory loss in QST showed reduced sensitivity to electrical stimuli and higher detection and pain thresholds, consistent with more advanced afferent dysfunction. NfL levels generally correlated with sensory impairment, although at low electrical intensities, higher NfL values were associated with stronger pain ratings, indicating intensity-dependent links between axonal pathology and nociceptor hyperexcitability. Combining QST with C-fiber-targeted electrical testing refines phenotyping of small-fiber dysfunction in diabetic neuropathy by revealing dissociation between thermal and electrical pain modalities and capturing the heterogeneous course from preserved function to selective thermal hypoalgesia and eventual sensory loss.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"84 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907570","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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