Pub Date : 2026-02-01Epub Date: 2025-11-13DOI: 10.1097/j.pain.0000000000003860
Donovan A Argueta, Kalpna Gupta
{"title":"New kid on the block: hemorphins in sickle cell disease.","authors":"Donovan A Argueta, Kalpna Gupta","doi":"10.1097/j.pain.0000000000003860","DOIUrl":"10.1097/j.pain.0000000000003860","url":null,"abstract":"","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":" ","pages":"249-250"},"PeriodicalIF":5.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605518","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 : 2026-01-30DOI: 10.1097/j.pain.0000000000003889
Erica B Lee,Randal A Serafini,Aarthi Ramakrishnan,Rachana Suresh,Aidan Weitzner,Neelakshi S Patne,Zahra Farzinpour,Emma Rowley,Visakha Suresh,Li Shen,Venetia Zachariou,Sami Tuffaha
Chronic pain resulting from neuroma formation is a prevalent and challenging problem to treat. Clinical studies suggest (1) surgically intervening at the time of nerve injury rather than in a delayed fashion and (2) providing denervated muscle targets, such as vascularized denervated muscle targets (VDMTs), leads to greater pain resolution than innervated muscle targets (bury-in-muscle [BIM]), although the mechanisms underlying these benefits are unclear. We compared behavioral, histological, and transcriptional signatures associated with nerve transection, immediate VDMT (I-VDMT), BIM, and delayed/postneuroma VDMT (D-VDMT). Immediate VDMT most effectively reduced injury- or inflammation-associated signatures. Bioinformatic analysis predicted that MEF2C repression was associated with injury signaling, which was reversed in I-VDMT. BML-210, a small molecule inhibitor of HDAC4-MEF2C interactions, treatment reduced sensory hypersensitivity in rodent nerve injury models. This study elucidates the benefits of denervated muscle targets over innervated muscle targets and identifies pharmacologic interventions in HDAC4 protein interactions as treatment avenues for neuroma-related symptoms.
{"title":"Behavioral and molecular characterization of various muscle-based surgical strategies for neuroma treatment in a peroneal nerve transection rat model.","authors":"Erica B Lee,Randal A Serafini,Aarthi Ramakrishnan,Rachana Suresh,Aidan Weitzner,Neelakshi S Patne,Zahra Farzinpour,Emma Rowley,Visakha Suresh,Li Shen,Venetia Zachariou,Sami Tuffaha","doi":"10.1097/j.pain.0000000000003889","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003889","url":null,"abstract":"Chronic pain resulting from neuroma formation is a prevalent and challenging problem to treat. Clinical studies suggest (1) surgically intervening at the time of nerve injury rather than in a delayed fashion and (2) providing denervated muscle targets, such as vascularized denervated muscle targets (VDMTs), leads to greater pain resolution than innervated muscle targets (bury-in-muscle [BIM]), although the mechanisms underlying these benefits are unclear. We compared behavioral, histological, and transcriptional signatures associated with nerve transection, immediate VDMT (I-VDMT), BIM, and delayed/postneuroma VDMT (D-VDMT). Immediate VDMT most effectively reduced injury- or inflammation-associated signatures. Bioinformatic analysis predicted that MEF2C repression was associated with injury signaling, which was reversed in I-VDMT. BML-210, a small molecule inhibitor of HDAC4-MEF2C interactions, treatment reduced sensory hypersensitivity in rodent nerve injury models. This study elucidates the benefits of denervated muscle targets over innervated muscle targets and identifies pharmacologic interventions in HDAC4 protein interactions as treatment avenues for neuroma-related symptoms.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"43 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073273","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 : 2026-01-30DOI: 10.1097/j.pain.0000000000003922
Yan Li,Megan L Uhelski,Robert Y North,Hajira Elahi,German Corrales,Taylor J Abercrombie,Katherine N Sheffield,Tejaswi Marri,Theodore J Price,Patrick M Dougherty
Oncostatin M (OSM), a member of the interleukin 6 (IL-6) pro-inflammatory cytokine family, is upregulated in the dorsal root ganglia of patients with neuropathic pain and thus may be an important contributor to this condition. Although suggested to contribute to itch in mice, the effects of OSM on nociceptive behavior and nociceptors in rats remain undefined. Here we show that a singular intrathecal dose of OSM (10 ng) induces significant mechanical hypersensitivity in both sexes of rats, yet does not alter thermal withdrawal latencies. When applied to cultured rat dorsal root ganglion (DRG) neurons, OSM (10 ng/mL) elicited robust action potential discharges and exaggerated fluctuations in membrane potential that was not mitigated by an IL-6 receptor antagonist. Neurons reactive to OSM typically did not respond to capsaicin, aligning with the behavioral observations. Immunohistochemical analysis revealed frequent co-localization of OSM and its receptor (OSMR) with isolectin B4-positive and calcitonin gene-related peptide-positive DRG neurons, but only scarce co-localization in transient receptor potential vanilloid 1-positive DRG neurons. In a model of paclitaxel chemotherapy-induced peripheral neuropathy, there is a notable increase in DRG neurons expressing OSM or its receptor (OSMR), alongside an upsurge in several OSM/OSMR downstream signaling molecules. These findings suggest that OSM acts as a signal for mechanical nociception and that heightened OSM expression and OSMR signaling in the DRG may be a key factor in the sensitization of specific nociceptor subsets. Consequently, targeting the OSM/OSMR pathway may offer a promising avenue for treatment in particular neuropathic pain phenotypes.
{"title":"Oncostatin M promotes chronic pain through direct regulation on nociceptors in rats.","authors":"Yan Li,Megan L Uhelski,Robert Y North,Hajira Elahi,German Corrales,Taylor J Abercrombie,Katherine N Sheffield,Tejaswi Marri,Theodore J Price,Patrick M Dougherty","doi":"10.1097/j.pain.0000000000003922","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003922","url":null,"abstract":"Oncostatin M (OSM), a member of the interleukin 6 (IL-6) pro-inflammatory cytokine family, is upregulated in the dorsal root ganglia of patients with neuropathic pain and thus may be an important contributor to this condition. Although suggested to contribute to itch in mice, the effects of OSM on nociceptive behavior and nociceptors in rats remain undefined. Here we show that a singular intrathecal dose of OSM (10 ng) induces significant mechanical hypersensitivity in both sexes of rats, yet does not alter thermal withdrawal latencies. When applied to cultured rat dorsal root ganglion (DRG) neurons, OSM (10 ng/mL) elicited robust action potential discharges and exaggerated fluctuations in membrane potential that was not mitigated by an IL-6 receptor antagonist. Neurons reactive to OSM typically did not respond to capsaicin, aligning with the behavioral observations. Immunohistochemical analysis revealed frequent co-localization of OSM and its receptor (OSMR) with isolectin B4-positive and calcitonin gene-related peptide-positive DRG neurons, but only scarce co-localization in transient receptor potential vanilloid 1-positive DRG neurons. In a model of paclitaxel chemotherapy-induced peripheral neuropathy, there is a notable increase in DRG neurons expressing OSM or its receptor (OSMR), alongside an upsurge in several OSM/OSMR downstream signaling molecules. These findings suggest that OSM acts as a signal for mechanical nociception and that heightened OSM expression and OSMR signaling in the DRG may be a key factor in the sensitization of specific nociceptor subsets. Consequently, targeting the OSM/OSMR pathway may offer a promising avenue for treatment in particular neuropathic pain phenotypes.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"74 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073380","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 : 2026-01-30DOI: 10.1097/j.pain.0000000000003909
Yue Zhang,Kai Wei,Kunming Tao,Min Ma,Zhijie Lu
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer often accompanied by persistent abdominal pain and stress, significantly compromising patients' quality of life. Previous studies have identified mast cells as crucial contributors to pancreatic cancer-related pain. This study aimed to investigate the role of the mast cell receptor corticotropin-releasing factor receptor 1 (CRFR1) and delineate its underlying mechanisms in mediating pancreatic pain. In the current study, we demonstrated that painful patients with PDAC exhibited markedly increased mast cell infiltration in peritumoral tissues, but not in tumor tissues, along with elevated levels of CRF and mast cell-specific CRFR1 expression, compared to asymptomatic patients. Consistently, in orthotopic PDAC mice models, flow cytometry and immunofluorescence staining confirmed increased CRFR1 expression in mast cells. Both pharmacological inhibition of CRFR1 and mast cell-specific CRFR1 knockout suppressed mast cell degranulation and alleviated cancer pain in male and female mice. Mechanistically, RNA sequencing, western blotting, and enzyme-linked immunosorbent assay indicated that CRFR1 activated mitogen-activated protein kinase (MAPK) pathway signaling, upregulated sphingosine kinases type 1 (SPHK1) expression, and increased sphingosine-1-phosphate (S1P) levels. A rescue experiment revealed that MAPK inhibition blocked CRFR1-induced SPHK1 upregulation in vitro. Importantly, the SPHK1 inhibitor PF543 reduced abdominal hyperalgesia in mice, whereas this effect was abolished in mast cell deficient mice. Moreover, SPHK1 knockdown by siRNA abolished CRFR1-induced mast cell degranulation. These findings highlight the critical role of mast cell CRFR1 in mediating abdominal hyperalgesia and identify the MAPK/SPHK1/S1P axis as an essential pathway, suggesting that targeting mast cell CRFR1 may be a promising therapeutic strategy for managing pancreatic cancer pain.
{"title":"Mast cell CRFR1 contributes to pancreatic cancer pain via MAPK/SPHK1 signaling.","authors":"Yue Zhang,Kai Wei,Kunming Tao,Min Ma,Zhijie Lu","doi":"10.1097/j.pain.0000000000003909","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003909","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer often accompanied by persistent abdominal pain and stress, significantly compromising patients' quality of life. Previous studies have identified mast cells as crucial contributors to pancreatic cancer-related pain. This study aimed to investigate the role of the mast cell receptor corticotropin-releasing factor receptor 1 (CRFR1) and delineate its underlying mechanisms in mediating pancreatic pain. In the current study, we demonstrated that painful patients with PDAC exhibited markedly increased mast cell infiltration in peritumoral tissues, but not in tumor tissues, along with elevated levels of CRF and mast cell-specific CRFR1 expression, compared to asymptomatic patients. Consistently, in orthotopic PDAC mice models, flow cytometry and immunofluorescence staining confirmed increased CRFR1 expression in mast cells. Both pharmacological inhibition of CRFR1 and mast cell-specific CRFR1 knockout suppressed mast cell degranulation and alleviated cancer pain in male and female mice. Mechanistically, RNA sequencing, western blotting, and enzyme-linked immunosorbent assay indicated that CRFR1 activated mitogen-activated protein kinase (MAPK) pathway signaling, upregulated sphingosine kinases type 1 (SPHK1) expression, and increased sphingosine-1-phosphate (S1P) levels. A rescue experiment revealed that MAPK inhibition blocked CRFR1-induced SPHK1 upregulation in vitro. Importantly, the SPHK1 inhibitor PF543 reduced abdominal hyperalgesia in mice, whereas this effect was abolished in mast cell deficient mice. Moreover, SPHK1 knockdown by siRNA abolished CRFR1-induced mast cell degranulation. These findings highlight the critical role of mast cell CRFR1 in mediating abdominal hyperalgesia and identify the MAPK/SPHK1/S1P axis as an essential pathway, suggesting that targeting mast cell CRFR1 may be a promising therapeutic strategy for managing pancreatic cancer pain.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"8 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073272","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 : 2026-01-30DOI: 10.1097/j.pain.0000000000003888
Caitlin B Murray,Stephanie P Goldstein,Tonya M Palermo
{"title":"Optimizing engagement in digital behavioral interventions for chronic pain: challenges and opportunities.","authors":"Caitlin B Murray,Stephanie P Goldstein,Tonya M Palermo","doi":"10.1097/j.pain.0000000000003888","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003888","url":null,"abstract":"","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"1 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073271","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}
Pain perception involves somatosensory-discriminative and affective-motivational components, mediated by separate brain circuits. Traditional mouse behavioral assays lack the resolution to disentangle this complexity. Recent studies using subanesthetic ketamine doses in the hot-plate test revealed a dissociation between paw lifts (somatosensory) and bites & licks (affective). In this study, we investigated these pain components in a mouse model of oxaliplatin-induced cold allodynia. Behavioural endpoints included paw lifts, bites & licks, toe spreads, and shakes & flinches. Data were collected from 6 inbred mouse strains (129S1/SvlmJ, A/J, Balb/cJ, C3H/HeJ, C57BL/6NJ, SJL/J). Ketamine plasma levels and metabolites norketamine and hydroxynorketamine were quantified using liquid chromatography-mass spectrometry. Subanaesthetic ketamine significantly reduced affective bites & licks across all strains and toe spreads in most, but had no significant effect on somatosensory responses (paw lifts and shakes & flinches). These effects were transient and reversed within minutes. Notably, ketamine-induced suppression of affective behaviours exhibited sex differences, whereas somatosensory behaviours did not. Ketamine plasma concentrations ranged from 2600 to 6200 ng/mL in male mice and 1300 to 3900 ng/mL in female mice, with significant sex differences in A/J, Balb/cJ, C3H/HeJ, C57BL/6NJ, and SJL/J. Hydroxynorketamine levels were significantly higher in female mice compared with male mice in the A/J, C3H/HeJ, Balb/cJ, and SJL/J strains (1700-2900 ng/mL in male mice and 2200-3300 ng/mL in female mice), whereas norketamine levels (3000-5100 ng/mL) showed no sex differences. These findings demonstrate that subanesthetic ketamine parses cold allodynia pain responses into somatosensory and affective components, similar to the hot-plate pain model. Additionally, sex-dependent metabolic differences influence analgesic efficacy.
{"title":"Dissociating pain dimensions in cold allodynia: subanesthetic ketamine reveals heritable affective-motivational traits in mice.","authors":"Nicole Richter,Stefanie Schmidt,Glauce Regina Pigatto,Roland Chike Eluaka Francis,Jürgen Schüttler,Thiago Mattar Cunha,Katharina Zimmermann","doi":"10.1097/j.pain.0000000000003912","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003912","url":null,"abstract":"Pain perception involves somatosensory-discriminative and affective-motivational components, mediated by separate brain circuits. Traditional mouse behavioral assays lack the resolution to disentangle this complexity. Recent studies using subanesthetic ketamine doses in the hot-plate test revealed a dissociation between paw lifts (somatosensory) and bites & licks (affective). In this study, we investigated these pain components in a mouse model of oxaliplatin-induced cold allodynia. Behavioural endpoints included paw lifts, bites & licks, toe spreads, and shakes & flinches. Data were collected from 6 inbred mouse strains (129S1/SvlmJ, A/J, Balb/cJ, C3H/HeJ, C57BL/6NJ, SJL/J). Ketamine plasma levels and metabolites norketamine and hydroxynorketamine were quantified using liquid chromatography-mass spectrometry. Subanaesthetic ketamine significantly reduced affective bites & licks across all strains and toe spreads in most, but had no significant effect on somatosensory responses (paw lifts and shakes & flinches). These effects were transient and reversed within minutes. Notably, ketamine-induced suppression of affective behaviours exhibited sex differences, whereas somatosensory behaviours did not. Ketamine plasma concentrations ranged from 2600 to 6200 ng/mL in male mice and 1300 to 3900 ng/mL in female mice, with significant sex differences in A/J, Balb/cJ, C3H/HeJ, C57BL/6NJ, and SJL/J. Hydroxynorketamine levels were significantly higher in female mice compared with male mice in the A/J, C3H/HeJ, Balb/cJ, and SJL/J strains (1700-2900 ng/mL in male mice and 2200-3300 ng/mL in female mice), whereas norketamine levels (3000-5100 ng/mL) showed no sex differences. These findings demonstrate that subanesthetic ketamine parses cold allodynia pain responses into somatosensory and affective components, similar to the hot-plate pain model. Additionally, sex-dependent metabolic differences influence analgesic efficacy.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"16 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056861","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 : 2026-01-28DOI: 10.1097/j.pain.0000000000003893
Nahian S Chowdhury,Marom Bikson,Sylvia M Gustin
{"title":"A roadmap for transcranial direct current stimulation for chronic pain.","authors":"Nahian S Chowdhury,Marom Bikson,Sylvia M Gustin","doi":"10.1097/j.pain.0000000000003893","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003893","url":null,"abstract":"","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"47 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056512","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.0000000000003907
Martina Morchio,Ishwarya Sankaranarayanan,Diana Tavares-Ferreira,Natalie Wong,Simon Atkins,Emanuele Sher,Theodore J Price,Daniel W Lambert,Fiona M Boissonade
Injuries to the trigeminal nerve, responsible for sensory innervation to the face, may occur during routine dental procedures, resulting in the formation of a neuroma accompanied by loss of sensation and/or symptoms of pain. To gain insight into the molecular mechanisms underpinning the sensory changes, single nuclei RNA sequencing and spatial transcriptomics were used to profile the transcriptional landscape at single cell resolution of human trigeminal nerves and neuromas. Cellular and transcriptional changes were identified that correlated with the presence of pain, including an expansion of endothelial cells with a proinflammatory phenotype and overexpression of HLA-A, CXCL2, and CXCL8. Interactome analysis highlighted signaling changes linked with the presence of pain. HLA-A protein expression was confirmed in neuromas and positively correlated with symptoms of pain. Our data provide a detailed spatial overview of the cell types that populate human peripheral trigeminal nerves, in health and injury, and their transcriptional profile. The comparison of painful and nonpainful samples highlights several changes in cellular composition, transcriptome and inferred molecular signaling linked specifically with the presence of pain, and also a novel role for HLA-A in neuropathic pain. Our findings represent a valuable resource for pain research, highlighting the role of inflammation, endothelial cell dysfunction, and chemokine signaling in neuropathic pain.
{"title":"Spatially resolved single-cell analysis of transcriptomic changes linked with neuropathic pain in human neuromas.","authors":"Martina Morchio,Ishwarya Sankaranarayanan,Diana Tavares-Ferreira,Natalie Wong,Simon Atkins,Emanuele Sher,Theodore J Price,Daniel W Lambert,Fiona M Boissonade","doi":"10.1097/j.pain.0000000000003907","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003907","url":null,"abstract":"Injuries to the trigeminal nerve, responsible for sensory innervation to the face, may occur during routine dental procedures, resulting in the formation of a neuroma accompanied by loss of sensation and/or symptoms of pain. To gain insight into the molecular mechanisms underpinning the sensory changes, single nuclei RNA sequencing and spatial transcriptomics were used to profile the transcriptional landscape at single cell resolution of human trigeminal nerves and neuromas. Cellular and transcriptional changes were identified that correlated with the presence of pain, including an expansion of endothelial cells with a proinflammatory phenotype and overexpression of HLA-A, CXCL2, and CXCL8. Interactome analysis highlighted signaling changes linked with the presence of pain. HLA-A protein expression was confirmed in neuromas and positively correlated with symptoms of pain. Our data provide a detailed spatial overview of the cell types that populate human peripheral trigeminal nerves, in health and injury, and their transcriptional profile. The comparison of painful and nonpainful samples highlights several changes in cellular composition, transcriptome and inferred molecular signaling linked specifically with the presence of pain, and also a novel role for HLA-A in neuropathic pain. Our findings represent a valuable resource for pain research, highlighting the role of inflammation, endothelial cell dysfunction, and chemokine signaling in neuropathic pain.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":"99 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994919","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.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。
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