Journal of PainPub Date : 2025-09-16DOI: 10.1016/j.jpain.2025.105564
Javier A. Tamargo , Glenn Smith , Li Chen , Yenisel Cruz-Almeida
{"title":"High-impact pain predicts subjective cognitive decline and interacts with APOE4 genotype in the development of objective cognitive impairment","authors":"Javier A. Tamargo , Glenn Smith , Li Chen , Yenisel Cruz-Almeida","doi":"10.1016/j.jpain.2025.105564","DOIUrl":"10.1016/j.jpain.2025.105564","url":null,"abstract":"<div><div>Chronic pain is the most common health challenge for older adults and a significant risk factor for cognitive impairments and dementia. This study examined the relationship of high-impact pain (i.e., pain that limits daily activities) with subjective cognitive decline (SCD) and objective cognitive impairment in 13,763 adults aged 50 and older from the Health and Retirement Study (2004–2020). High-impact pain was associated with a higher prevalence (32.4%) and incidence of SCD compared to no pain (18.0%) and low-impact pain (21.3%). High-impact pain also predicted an increased risk of objective cognitive impairment, particularly in individuals without the APOE4 allele. The adjusted hazard ratio (aHR) for incident SCD in high-impact pain versus no pain was 1.31 (95% CI: 1.31, 1.42). The aHR for objective cognitive impairment compared to no or low-impact pain was 1.21 (95% CI: 1.07, 1.36) in APOE4-negative individuals, controlling for SCD and relevant biopsychosocial factors. Our findings suggest that high-impact pain is a stronger predictor of future cognitive impairments than SCD alone in most of the population who do not carry the APOE4 allele. Interventions targeting high-impact pain, starting in middle age, may help mitigate the risk of cognitive decline and dementia. Future research is needed to understand potential mechanisms whereby pain either directly or indirectly impacts cognition to develop preventive and effective therapeutic strategies.</div></div><div><h3>Perspective</h3><div>This study highlights high-impact pain as a predictor of subjective and objective cognitive decline in older adults. High-impact pain may contribute to cognitive impairment, especially in individuals without the high-risk APOE4 allele, and may represent a modifiable target for early interventions to reduce the risk of dementia.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"37 ","pages":"Article 105564"},"PeriodicalIF":4.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of PainPub Date : 2025-09-16DOI: 10.1016/j.jpain.2025.105563
Stefanie Hefner , George Oprita , Sebastian Pantke , Axel Hage , Andreas Leffler
{"title":"Nav1.8, TRPV1 and TRPA1 as possible targets of ambroxol when used for topical treatment of neuropathic pain","authors":"Stefanie Hefner , George Oprita , Sebastian Pantke , Axel Hage , Andreas Leffler","doi":"10.1016/j.jpain.2025.105563","DOIUrl":"10.1016/j.jpain.2025.105563","url":null,"abstract":"<div><div>Sodium channels and the capsaicin receptor TRPV1 in epidermal sensory nerve endings are established targets for topical treatment of neuropathic pain. The secretolytic ambroxol induces effective topically analgesia, a property that may involve a preferential block of Nav1.8. We here examined to what extent ambroxol inhibits human and rat (r) Nav1.8, but also the human (h) orthologues of the irritant receptors TRPV1 and TRPA1 by performing whole-cell patch clamp recordings. Ambroxol-induced tonic inhibition was stronger on rNav1.8 (IC<sub>50</sub> 18 µM) than on hNav1.8 (IC<sub>50</sub> 279 µM) and TTX-sensitive Na<sup>+</sup> channels (IC<sub>50</sub> 76 µM). Non-inactivating currents of both hNav1.8 and rNav1.8 displayed a higher sensitivity to ambroxol than transient currents. A weak but concentration-dependent activation of hTRPV1 and hTRPA1 exceeded an unspecific increase in intracellular calcium by high concentrations of ambroxol. While the activation mechanism for hTRPV1 involves the vanilloid-binding domain, residues required for menthol-sensitivity of hTRPA1 seems to dictate ambroxol-sensitivity. Ambroxol also inhibited capsaicin-induced currents on hTRPV1 in a concentration-dependent and partly reversible manner. This inhibition was independent of intracellular calcium and preserved on the non-desensitizing mutant hTRPV1-Y672K. Currents induced by mustard oil or carvacrol on hTRPA1 exhibited a concentration-dependent reduction by ambroxol that was stronger on outward as compared to inward currents. We conclude that inhibition of Nav1.8 by ambroxol exhibits a pronounced species-specificity with rNav1.8 > hNav1.8. Furthermore, high concentrations of ambroxol modulate hTRPV1 and hTRPA1 in a manner that might contribute to topical analgesia.</div></div><div><h3>Perspective</h3><div>Topically applied ambroxol is a well-known off the label approach for treatment of focal neuropathic pain, but it still lacks a mechanistic foundation. This in vitro study presents human Nav1.8, TRPA1 and TRPV1 as possible pharmacological targets of ambroxol in sensory neurons.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"37 ","pages":"Article 105563"},"PeriodicalIF":4.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of PainPub Date : 2025-09-14DOI: 10.1016/j.jpain.2025.105562
Jinyang Gao , Yansong He , Benjin Li , Yanqing Wang
{"title":"Dissecting the neurogenetic architecture of chronic pain: A brain-wide genetics study","authors":"Jinyang Gao , Yansong He , Benjin Li , Yanqing Wang","doi":"10.1016/j.jpain.2025.105562","DOIUrl":"10.1016/j.jpain.2025.105562","url":null,"abstract":"<div><div>Chronic pain (CP) is a widespread and debilitating condition with complex neurobiological and genetic foundations. To better understand the brain-based and genetic mechanisms underlying CP, we integrated bidirectional Mendelian randomization (MR), local genetic correlation analysis (LAVA), and multi-trait colocalization (HyPrColoc) using data from 3935 brain imaging-derived phenotypes (IDPs). CP was characterized using three definitions: multisite chronic pain (MCP), chronic widespread pain (CWP), and general chronic pain (GCP). MR analyses highlighted several brain IDPs, cortical areas such as the anterior cingulate, superior frontal, and inferior frontal gyri, as having potential causal effects on CP risk. Additional findings pointed to the role of resting-state connectivity and cerebellar white matter microstructure. LAVA results indicated local genetic correlations between brain features and CP in regions involved in synaptic remodeling, immune-inflammatory activity, and neurodevelopment. Multi-trait colocalization pinpointed the shared variant - rs1873914, potentially linking CP, IDPs, and SUOX gene expression. Together, these findings suggest that some brain structures and their functions may play a causal role in the development of chronic pain.</div></div><div><h3>Perspective</h3><div>This study integrates brain imaging phenotypes with genetic analyses to clarify causal links in chronic pain. By combining MR, LAVA, and HyPrColoc, we identify structural and functional brain features, pathways, and candidate genes that may underlie pain chronification, offering targets for mechanistic studies and interventions.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"37 ","pages":"Article 105562"},"PeriodicalIF":4.0,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of PainPub Date : 2025-09-13DOI: 10.1016/j.jpain.2025.105560
John K Neubert, Kyle Allen, Tamara Alliston, Alejandro J Almarza, Kyriacos A Athanasiou, Basak Donertas-Ayaz, Bruna Balbino de Paula, Roxanne Bavarian, Nidhi Bhutani, Brian E Cairns, Robert M Caudle, Yang Chai, Jian-Fu Chen, Yong Chen, Glenn T Clark, Yenisel Cruz-Almeida, Alexandre F DaSilva, Paul L Durham, Airam Vivanco Estela, Millie Embree, Roger Fillingim, Fernando Guastaldi, Shruti Handa, Sunil D Kapila, David Keith, Keith L Kirkwood, Phillip Kramer, Katherine T Martucci, Niall P Murphy, Andrea G Nackley, Richard Ohrbach, Benedikt Sagl, Shad B Smith, Feng Tao, Beth Winkelstein, Hai Yao, Simon Young, Michael S Gold
{"title":"Preclinical perspectives on disorders of the temporomandibular joint: Tracing the past, navigating the present, and shaping the future.","authors":"John K Neubert, Kyle Allen, Tamara Alliston, Alejandro J Almarza, Kyriacos A Athanasiou, Basak Donertas-Ayaz, Bruna Balbino de Paula, Roxanne Bavarian, Nidhi Bhutani, Brian E Cairns, Robert M Caudle, Yang Chai, Jian-Fu Chen, Yong Chen, Glenn T Clark, Yenisel Cruz-Almeida, Alexandre F DaSilva, Paul L Durham, Airam Vivanco Estela, Millie Embree, Roger Fillingim, Fernando Guastaldi, Shruti Handa, Sunil D Kapila, David Keith, Keith L Kirkwood, Phillip Kramer, Katherine T Martucci, Niall P Murphy, Andrea G Nackley, Richard Ohrbach, Benedikt Sagl, Shad B Smith, Feng Tao, Beth Winkelstein, Hai Yao, Simon Young, Michael S Gold","doi":"10.1016/j.jpain.2025.105560","DOIUrl":"10.1016/j.jpain.2025.105560","url":null,"abstract":"<p><p>Temporomandibular disorders (TMDs) are complex conditions characterized by orofacial pain and dysfunction, affecting a significant portion of the population. TMDs may involve joint and/or muscle pain, dysfunction (e.g., noise, limited or altered jaw movements), or both, leading to a marked decrease in quality of life. Patients often experience functional limitations that hinder eating, speaking, and daily activities. Additionally, TMDs are frequently associated with psychological distress, including anxiety and depression, which further impacts overall well-being. Despite the profound individual and societal impact of TMDs, effective therapies remain elusive, partly due to deficiencies in translational research. A primary limitation in the TMD field is the scarcity of animal models that accurately replicate disease features in humans. This may ultimately be due to species differences, but likely also reflects the etiological and symptomatic heterogeneities of TMDs, as there are over 30 different conditions in this umbrella term. Both factors pose a significant challenge in developing and using animal models for TMD research. This review highlights preclinical TMD research to enhance clinical care, focusing on anatomy/physiology, pain and behavior models, functional and tissue modeling, biopsychosocial factors, and technological considerations. The \"TMD Research Community\" collaborated to produce this review, with the Discussion offering a proposal for a path forward.</p>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":" ","pages":"105560"},"PeriodicalIF":4.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of PainPub Date : 2025-09-11DOI: 10.1016/j.jpain.2025.105559
Emanuelle Chrysilla , Sarah Fischer , Ji-Mi Jang , Krishna Rao Maddipati , Tanzy M.T. Love , Mitchell A. Linder , Megan L. Falsetta
{"title":"A cautionary tale: Non-steroidal anti-inflammatory drug use and localized provoked vulvodynia","authors":"Emanuelle Chrysilla , Sarah Fischer , Ji-Mi Jang , Krishna Rao Maddipati , Tanzy M.T. Love , Mitchell A. Linder , Megan L. Falsetta","doi":"10.1016/j.jpain.2025.105559","DOIUrl":"10.1016/j.jpain.2025.105559","url":null,"abstract":"<div><div>Localized provoked vulvodynia (LPV) is characterized by chronic vulvar pain upon light touch to the vulvar vestibule, a specialized ring of tissue immediately surrounding the vaginal opening. LPV affects ∼14 million people in the US. Current treatments for LPV include nonsteroidal anti-inflammatory drugs (NSAIDs), but clinical evidence has demonstrated that they are ineffective for vulvar pain. Here, the effects of NSAID treatment on inflammation and resolution in an <em>in vitro</em> model of LPV were explored using enzyme-linked immunosorbent assays (ELISAs), calcium imaging, and metabololipidomics. Additionally, the effectiveness of NSAID treatment on mitigating chronic vulvar pain was assessed using a validated LPV mouse model that mimics key features of vulvodynia. These findings indicate that although NSAID treatment reduced pro-inflammatory eicosanoid production in vulvar fibroblasts, lipidomic analysis revealed that COX inhibition also downregulated levels of pro-resolving lipids, namely epoxyeicosatrienoic acids (EETs), lipoxins (LXs), and resolvin E-series (RvEs). <em>In vivo</em>, NSAID treatment did not restore vulvar pain thresholds back to baseline levels in mice. Overall, this study offers one possible explanation for previous reports of the ineffectiveness of NSAIDs on managing LPV-associated vulvar pain.</div></div><div><h3>Perspective</h3><div>Taking NSAIDs to manage chronic vulvar pain may downregulate levels of specialized pro-resolving lipid mediators, thereby resulting in prolonged pain and delayed inflammation resolution. This study provides one possible explanation for clinical reports of the ineffectiveness of NSAIDs in the mitigation of vulvodynia-associated pain.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"36 ","pages":"Article 105559"},"PeriodicalIF":4.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of PainPub Date : 2025-09-11DOI: 10.1016/j.jpain.2025.105551
Bukola Mary Ibitoye , Bernie Garrett , Manon Ranger , Jennifer N. Stinson
{"title":"You only work with what you know: Healthcare providers’ experiences using non-pharmacological interventions in managing sickle cell crisis pain in adolescents","authors":"Bukola Mary Ibitoye , Bernie Garrett , Manon Ranger , Jennifer N. Stinson","doi":"10.1016/j.jpain.2025.105551","DOIUrl":"10.1016/j.jpain.2025.105551","url":null,"abstract":"<div><div>Sickle cell crises are the leading reason for hospitalization in adolescents with sickle cell disease. Non-pharmacological interventions are recommended for sickle cell crisis pain management in high and low-resource settings. Preliminary evidence suggests high use of non-pharmacological interventions among adolescents with sickle cell disease in home settings in Nigeria, including potentially harmful ones, and limited use in hospitals, possibly due to healthcare providers’ reluctance to use them. Using an interpretive description design, this study explored healthcare providers’ perceptions of non-pharmacological interventions and their experience using and recommending these interventions for managing sickle cell crisis pain in adolescents in Nigeria. Individual, semi-structured interviews were conducted. Data were analyzed using constant comparison analysis. Fourteen healthcare providers were recruited from healthcare settings across Nigeria. Five broad themes were identified: 1) Perceptions, 2) Safety and risks of non-pharmacological interventions, 3) Recommended non-pharmacological interventions, 4) Influencing factors, and 5) Non-pharmacological intervention education. Some providers held misconceptions about non-pharmacological interventions, such as believing they were only effective for patients faking pain. These interventions may be recommended for pain management, depending on the provider. The use of questionable interventions, like herbal concoctions, poses a significant health challenge with serious consequences, including death. Identified barriers to the implementation of non-pharmacological interventions include providers’ inadequate knowledge about these interventions. The patients’ desire to use safe, effective interventions should be supported. Developing contextually relevant educational resources on these interventions might equip providers to support their use during hospitalization, potentially improving their pain outcomes and limiting the use of harmful interventions.</div></div><div><h3>Perspective</h3><div>This article presents a qualitative summary of the experiences of healthcare providers in recommending and using non-pharmacological interventions for pain management. This information can guide clinicians and researchers interested in developing educational resources on how these interventions are used, providers’ educational needs in Nigeria and dissemination avenues for these resources.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"37 ","pages":"Article 105551"},"PeriodicalIF":4.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of PainPub Date : 2025-09-11DOI: 10.1016/j.jpain.2025.105552
K. Jane Chalmers , Leanne Slater , Karen Crudden , Ebony Ryan , Rachelle Symons , Stephanie Dwyer , Nadine Yassin , Alanna Barwood , Laura Yammouni , Judith Thompson , Mark J. Catley
{"title":"Screening psychological factors in pelvic pain: Validation of the pelvic pain psychological screening questionnaire (3PSQ)","authors":"K. Jane Chalmers , Leanne Slater , Karen Crudden , Ebony Ryan , Rachelle Symons , Stephanie Dwyer , Nadine Yassin , Alanna Barwood , Laura Yammouni , Judith Thompson , Mark J. Catley","doi":"10.1016/j.jpain.2025.105552","DOIUrl":"10.1016/j.jpain.2025.105552","url":null,"abstract":"<div><div>The Pelvic Pain Psychological Screening Questionnaire (3PSQ) was developed to assess psychological distress in people with persistent pelvic pain. This study aimed to investigate its psychometric properties and determine its convergent validity with seven existing measures of psychological distress. People with pelvic pain, with or without a formal diagnosis, were recruited via social media, health professional referral, and word of mouth to complete an online survey. Rasch analysis was conducted to investigate unidimensionality, targeting, response category functioning and item bias. Correlational analysis was then used to establish its relationship with existing measures. Data was available for 761 participants, predominantly female (93.3%), and the 3PSQ was shown to represent a unidimensional scale that well-targeted the sample and has negligible floor and ceiling effects. The response categories functioned as expected and minimal item bias was detected. The 3PSQ demonstrated moderate to strong relationships with the Pain Anxiety Symptom Scale (<em>r</em> =.76), Pain Catastrophizing Scale (<em>r</em> =.83), Pain Self-Efficacy Questionnaire (<em>r</em> = -.66), Pain Vigilance & Awareness Questionnaire (<em>r</em> =.57), Patient Health Questionnaire 4 (<em>r</em> =.64), Perceived Stress Scale (<em>r</em> =.42) and Whiteley Index (ρ =.55). These findings suggest the 3PSQ can be used as a valid measure of psychological distress in people with PPP and, at the individual item level, identify factors that warrant further investigation. Future research could explore the 3PSQ’s relevance in culturally and linguistically diverse, male and non-binary populations.</div></div><div><h3>Perspective</h3><div>The Pelvic Pain Psychological Screening Questionnaire (3PSQ) is a psychometrically sound measure of psychological distress and shows significant correlation with existing psychological measures. This tool could potentially guide clinicians’ decision making when working with people with persistent pelvic pain.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"37 ","pages":"Article 105552"},"PeriodicalIF":4.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of PainPub Date : 2025-09-11DOI: 10.1016/j.jpain.2025.105555
Nils Runge , Zosia Goossens , Liesbet De Baets , Céline Labie , Aurore Roland , Sabine Verschueren , Dieter Van Assche , Anneleen Malfliet , Veerle De Pourcq , Tessa Blanken , Eiko I. Fried , Olivier Mairesse
{"title":"Understanding the complex relationship between sleep and pain symptoms in people with chronic musculoskeletal pain – A pre-registered network analysis","authors":"Nils Runge , Zosia Goossens , Liesbet De Baets , Céline Labie , Aurore Roland , Sabine Verschueren , Dieter Van Assche , Anneleen Malfliet , Veerle De Pourcq , Tessa Blanken , Eiko I. Fried , Olivier Mairesse","doi":"10.1016/j.jpain.2025.105555","DOIUrl":"10.1016/j.jpain.2025.105555","url":null,"abstract":"<div><div>Although chronic musculoskeletal pain and sleep disturbances are often viewed as bi-directionally linked, intervention studies show only small effects of sleep-specific interventions on pain. This suggests a more complex relationship in which only certain sleep parameters may be causally relevant, while other factors such as depression or fatigue may confound the association. Network analysis is a promising statistical approach to disentangle the complex relationships between sleep and chronic musculoskeletal pain variables by identifying key associations between specific variables while accounting for others. This pre-registered study applied Gaussian Graphical Models to examine the complex network linking subjective sleep and pain variables in a sample of 1536 individuals with chronic musculoskeletal pain. Additionally, network structures were compared across subgroups with widespread pain and comorbid insomnia disorder versus controls to identify relevant differences. The results showed eleven direct associations between sleep and pain variables, all very weak (regularized partial correlation coefficients ≤0.07), with no indirect paths involving only one other variable. Findings were mostly comparable across subgroups, with no relevant differences in network structures. These results cautiously challenge the notion that subjective sleep and pain variables are tightly linked. While limitations of the applied methods should be considered, this may partially explain why sleep-focused interventions show only small effects on pain in chronic musculoskeletal pain populations. These findings underscore the need for future studies to apply transparent causal inference methods to move beyond statistical associations and to better understand potential causal relationships between sleep and chronic musculoskeletal pain.</div></div><div><h3>Perspective</h3><div>This study is the first to examine sleep–pain links within a complex network in chronic musculoskeletal pain, revealing weaker-than-expected associations. This may (partially) explain why interventions targeting subjective sleep improvements, such as cognitive behavioural therapy for insomnia, often show limited effects on reducing pain.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"36 ","pages":"Article 105555"},"PeriodicalIF":4.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145049081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of PainPub Date : 2025-09-11DOI: 10.1016/j.jpain.2025.105553
Michael J. Lacagnina , Kendal F. Willcox , Nathan T. Fiore , Anamaria R. Grieco , Jiahe Li , Cobi J. Heijnen , Peter M. Grace
{"title":"Fc gamma receptor IIa signaling from spinal cord astrocytes promotes neuropathic pain in rats","authors":"Michael J. Lacagnina , Kendal F. Willcox , Nathan T. Fiore , Anamaria R. Grieco , Jiahe Li , Cobi J. Heijnen , Peter M. Grace","doi":"10.1016/j.jpain.2025.105553","DOIUrl":"10.1016/j.jpain.2025.105553","url":null,"abstract":"<div><div>Injury to somatosensory nerves can lead to neuropathic pain. We recently identified that B cells play a crucial role in the development of neuropathic pain through a mechanism involving secreted immunoglobulin G (IgG) signaling at Fc gamma receptors (FcγRs). Here, we demonstrate that Fc gamma receptor IIa (FcγRIIa), expressed by astrocytes in the spinal cord, contributes to the development of mechanical allodynia after nerve injury in male and female rats. Following unilateral chronic constriction injury (CCI) of the sciatic nerve, <em>Fcgr2a</em> gene transcription increased specifically in the ipsilateral dorsal horn of the spinal cord, but remained unaltered in the dorsal root ganglia (DRGs) and contralateral spinal cord. FcγRIIa immunoreactivity increased in the ipsilateral spinal dorsal horn after CCI, and its expression colocalized primarily with GFAP<sup>+</sup> astrocytes. Genetic disruption of <em>Fcgr2a</em> in GFAP-expressing spinal astrocytes using adeno-associated virus (AAV)-mediated CRISPR-Cas9 gene editing attenuated mechanical allodynia for weeks after CCI. In purified cultures of primary astrocytes, IgG immune complexes (IgG-IC) increased transcription of proinflammatory cytokines and chemokines. Expression of these cytokines and chemokines was reduced by siRNA-mediated knockdown of <em>Fcgr2a</em>, or by inhibition of the FcγRIIa effectors spleen tyrosine kinase (Syk) or nuclear factor-κB (NF-κB). These data suggest that FcγRIIa expressed by spinal astrocytes are activated following peripheral nerve injury and may directly contribute to injury-induced tactile pain through the release of proinflammatory mediators. These findings expand our understanding of how neuroimmune signaling from astrocytes contributes to the development of mechanical allodynia.</div></div><div><h3>Perspective</h3><div>Activation of FcγRIIa signaling in spinal astrocytes promotes mechanical allodynia following nerve injury and initiates neuroinflammatory pathways in response to IgG immune complexes. These findings reveal autoantibody IgG signaling at glial Fcγ receptors as a potential therapeutic approach to alleviate neuropathic pain.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"36 ","pages":"Article 105553"},"PeriodicalIF":4.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145049080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of PainPub Date : 2025-09-11DOI: 10.1016/j.jpain.2025.105556
Samuel N. Rodgers-Melnick , Douglas Gunzler , Thomas E. Love , Siran M. Koroukian , Mark Beno , Jeffery A. Dusek , Johnie Rose
{"title":"Impact of sociodemographic, clinical, and intervention characteristics on pain intensity within a single music therapy session","authors":"Samuel N. Rodgers-Melnick , Douglas Gunzler , Thomas E. Love , Siran M. Koroukian , Mark Beno , Jeffery A. Dusek , Johnie Rose","doi":"10.1016/j.jpain.2025.105556","DOIUrl":"10.1016/j.jpain.2025.105556","url":null,"abstract":"<div><div>Several studies support the efficacy of music therapy (MT) for reducing pain, but few have examined which interventions are most effective or which patients are more likely to respond. This study investigated which sociodemographic, clinical, and intervention characteristics are associated with clinically significant reductions in pain intensity (0–10 numeric rating scale reduction ≥2 units) within a single MT session. We conducted a retrospective review of 2039 MT sessions provided across a large health system among 1203 adult patients reporting pre-session pain ≥4/10, a complete post-session pain score, and a complete pre-session stress score. We employed a multivariable logistic mixed effects model to evaluate binary pain reduction response (≥2 units vs. < 2 units) where patients were considered nested within therapists. The model included a fixed covariate for MT intervention type: receptive only, recreative (i.e., singing or active instrument play), compositional/creative (e.g., songwriting), or music-assisted relaxation and imagery (MARI). Covariates in the model associated with higher adjusted odds ratios (aOR [95% CI]) included (1) recreative (1.37 [1.00, 1.86]) and MARI (1.48 [1.01, 2.17]) MT interventions as compared to receptive; (2) 15-minute increases in session length (1.40 [1.22, 1.61]); (3) 1-unit increases in pre-session pain (1.19 [1.11, 1.28]), (4) 5-unit increases in Elixhauser comorbidity count (1.29 [1.05, 1.60); and (5) a documented MT session goal of pain management (3.58, [2.64, 4.86]). MT interventions involving singing, active instrument play, and relaxation/imagery may be more effective for reducing pain intensity than interventions only involving live or recorded music among patients with high pre-session pain.</div></div><div><h3>Perspective</h3><div>This study examined factors associated with meaningful reductions in pain (0–10 numeric rating scale reduction ≥2 units) within a single music therapy session. Among hospitalized patients, interventions involving singing, active instrument play, and relaxation/imagery may be more effective for reducing pain than interventions only involving live or recorded music.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"36 ","pages":"Article 105556"},"PeriodicalIF":4.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}