Pain

Nav1.7 voltage-gated sodium channels are strongly expressed in human primary painsensing neurons (nociceptors) and selective Nav1.7 inhibitors have been developed as possible therapeutic agents for treating pain, so far with disappointing clinical results. In contrast, a selective Nav1.8 channel inhibitor (suzetrigine) has had successful clinical trials. Because nociceptors express both Nav1.7 and Nav1.8 channels, it is of interest to compare effects of Nav1.7 and Nav1.8 inhibitors on the excitability of human nociceptors. To compare with previous results with suzetrigine, we characterized the effects of a selective Nav.7 inhibitor, AM-2099, on action potential generation and repetitive firing of dissociated human dorsal root ganglion neurons, studied at 37{degrees}C. Inhibition of Nav1.7 channels by 600 nM AM-2099 generally produced a substantial depolarizing shift of action potential threshold, an increase in rheobase, a decrease in action potential upstroke velocity, decrease in action potential peak, and prolongation of refractory period. Compared to inhibition of Nav1.8 channels, inhibition of Nav1.7 channels had larger effects on threshold and maximal upstroke velocity, while action potential peak was reduced similarly by both. Nav1.8 inhibition produced much more dramatic reduction of repetitive firing than Nav1.7 inhibition. The results show that although the excitability of human DRG neurons is affected by inhibition of Nav1.7 channels, most notably by an increase in threshold and increase in refractory period, repetitive firing of the neurons in response to strong stimuli is little affected. Significance statementNav1.7 sodium channels are highly expressed in primary pain-sensing neurons and humans with null mutations in Nav1.7 channels have loss of pain sensation. However, unlike the Nav1.8 inhibitor suzetrigine, Nav1.7 inhibitors have so far not reached clinical use. We compared effects of Nav1.7 on electrical excitability of human dorsal root ganglion neurons with those of suzetrigine and found that while Nav1.7 inhibition affects spike threshold more than suzetrigine, there is little effect on repetitive firing with strong stimuli.

Childhood adversity is linked to persistent pain in adulthood. Nociceptive upregulation may play a role in this relationship. We investigated whether childhood adversity is associated with measures of nociceptive processing, and whether these associations differ by sex. In this experimental observational study, we enrolled pain-free adults with varying severity of childhood adversity, scored on the Childhood Trauma Questionnaire-Short Form. Measures of nociceptive processing included the surface area and magnitude of induced secondary hyperalgesia, temporal summation, and conditioned pain modulation. We used linear regression to investigate whether childhood adversity was associated with increased surface area or magnitude of secondary hyperalgesia, increased temporal summation, or reduced conditioned pain modulation, and whether these relationships differed by sex. Ninety-five participants (61 female; median age 23 [IQR: 9] years) completed the study. Childhood adversity was positively associated with the surface area of secondary hyperalgesia ({beta}=0.32 [95%CI: 0.01; 0.62], p = 0.04), with no evidence of an interaction effect of sex. Childhood adversity was unrelated to the magnitude of secondary hyperalgesia, temporal summation, or conditioned pain modulation. These data suggest that childhood adversity may influence the distribution rather than the magnitude of evoked ascending nociception. Perspective

BackgroundNeuropathic pain (NP) is a debilitating chronic pain condition caused by injury or disease of the somatosensory nervous system. Accumulating evidence indicates that astrocytes play a central role in neuroinflammatory regulation and synaptic remodeling, thereby critically influencing the initiation and persistence of neuropathic pain. However, a comprehensive overview of research trends and knowledge structures in this field is still lacking. MethodsThe analysis was conducted based on publications retrieved from the Web of Science Core Collection and Scopus, covering the period from 2000 to 2025. Studies focusing on astrocytes and neuropathic pain were systematically identified. Visualization and network analyses were performed using CiteSpace, VOSviewer, and the R package bibliometrix. Collaboration networks, co-citation patterns, keyword co-occurrence, and thematic evolution were analyzed to delineate research hotspots, developmental trajectories, and scholarly contributions across countries, institutions, authors, and journals. Results1,828 publications were included, showing a 15% average annual growth in output, which accelerated post-2010. The USA and China led in research and international collaboration, with studies concentrated in North American and East Asian institutions. Author productivity was uneven, with key researchers (Ji RR, Zhang Y, Watkins LR) contributing heavily to publications and citations. Pain and Molecular Pain were the core journals. Key themes included spinal astrocytic mechanisms, glial activation, and therapeutic modulation, with the focus evolving from injury models/markers to astrocytic activation and targeted pathways. ConclusionOur analysis shows a substantial growth in astrocyte-related NP research the past 25 years, underscoring astrocytes key role in chronic pain pathophysiology. Current trends underscore the integration of mechanistic insights with translational relevance, thereby informing future therapeutic and mechanistic advancements in NP.

Chronic pain involves sensory, emotional, and functional disruption, yet diagnostic labels rarely capture this variability, limiting individualized care. Multidimensional models, such as fear-avoidance and predictive coding, suggest that high emotional burden may disrupt expectation-based pain modulation and midbrain pain regulatory pathways, particularly within the periaqueductal gray (PAG). We tested whether chronic pain phenotypes defined by pain intensity, disability, and affective distress (PDA) differ in expectation-induced pain modulation, PAG connectivity, and behavioral markers including catastrophizing, hypervigilance, and medication use, and whether these features aid phenotype classification. We studied 159 patients with fibromyalgia or chronic low back pain and 72 controls. Our data-driven clustering approach identified high and low PDA groups. High PDA patients showed impaired modulation when positive expectations were violated and reported greater cognitive and behavioral burden (P<0.05). They also exhibited more negative connectivity between the dorsolateral/lateral PAG (dl/lPAG) and the dorsomedial prefrontal cortex (dmPFC) (corrected). Machine learning models classified PDA subtypes above chance, with accuracy improving when PAG connectivity was included. Findings highlight disrupted expectation-driven regulation and altered PAG pathways as markers for chronic pain stratification.

Chronic pain and its underlying biological mechanisms have been studied for many decades, with a myriad of molecules, receptors and cell types known to contribute to abnormal pain sensations. We now know that besides an obvious role for neuronal populations in the peripheral and central nervous system, immune cells like microglia, macrophages and T cells are also important drivers of persistent pain. While neuroinflammation has therefore been widely studied in pain research, there is one cell-type that appears to be rather neglected in this context: the humble fibroblast. Fibroblasts may seem unassuming, but actually play a major part in regulating immune cell function and driving chronic inflammation. What is known about them in the context chronic pain? Here we set out to analyze the literature on this topic - using systematic screening and data extraction methods to obtain a balanced view on what has been published. We found that there has been surprisingly little research in this area: 134 articles met our inclusion criteria, only a tiny minority of which directly investigated interactions between fibroblasts and peripheral neurons. We categorized the articles we included - stratifying them according to what was investigated, the estimated quality of results, and any common conclusions. Fibroblasts are a ubiquitous cell type and a prominent source of many pro-algesic mediators in a wide variety of tissues. We think that they deserve a more central role in pain research and propose a new, testable model of how fibroblasts might drive peripheral neuron sensitization.

Neuropathic pain is a leading cause of high impact pain, is often disabling and is poorly managed by current therapeutics. Here we focused on a unique group of neuropathic pain patients undergoing thoracic vertebrectomy where the DRG is removed as part of the surgery allowing for molecular characterization and identification of mechanistic drivers of neuropathic pain independently of preclinical models. Our goal was to quantify whole transcriptome RNA abundances using RNA-seq in pain-associated human DRGs from these patients, allowing comprehensive identification of molecular changes in these samples by contrasting them with non-pain associated DRGs. We sequenced 70 human DRGs, including over 50 having mRNA libraries with neuronal mRNA. Our expression analysis revealed profound sex differences in differentially expressed genes including increase of IL1B, TNF, CXCL14, and OSM in male and including CCL1, CCL21, PENK and TLR3 in female DRGs associated with neuropathic pain. Co-expression modules revealed enrichment in members of JUN-FOS signaling in males, and centromere protein coding genes in females. Neuro-immune signaling pathways revealed distinct cytokine signaling pathways associated with neuropathic pain in males (OSM, LIF, SOCS1) and females (CCL1, CCL19, CCL21). We validated cellular expression profiles of a subset of these findings using RNAscope in situ hybridization. Our findings give direct support for sex differences in underlying mechanisms of neuropathic pain in patient populations.

Conditioned pain modulation (CPM) paradigms provide a proxy measure of activity in the descending pain modulatory system. Cuff-pressure-algometry offers a standardised CPM assessment tool although comprehensive validation in large samples is lacking. To address this, we pooled cuff-algometry CPM data from 324 healthy participants across 8 studies. CPM magnitude was calculated as pain detection (PDT) and tolerance (PTT) threshold changes, assessed on the dominant leg in the presence and absence of a painful "conditioning" cuff stimulus on the contralateral leg. CPM-effects were robust for both changes in PDT and PTT (p<0.001). Using a classification approach where a [&ge;]20% change in threshold designated a CPM responder, 69% of participants were CPM-responders for PDT and 59% for PTT. Test-retest reliability data were assessed in a subset of participants (n=72; interval 16.49{+/-}18.39days) using intraclass correlation coefficients (ICC). Test-retest reliability was poor for CPM-effects (ICC=0.25-0.37) despite moderate-to-good reliability for PDT and PTT (ICC=0.69-0.87). Responder classification showed none-to-minimal agreement across sessions (Cohens {kappa}=0.17-0.21), with 38% of participants switching classification for both PDT and PTT. Bootstrap analysis revealed that smaller samples provide highly variable ICC estimates, potentially explaining discrepancies with previous reliability reports. Despite producing large group-level CPM-effects, poor test-retest reliability of cuff algometry suggests it captures dynamic, state-dependent processes rather than a stable trait-like individual characteristic. This highlights the need to consider the temporal instability of CPM when interpreting data and considering its deployment within precision pain medicine.

BackgroundChronic pain is a global health priority. Mapping pain occurring at different body sites, and variability in brain circuitry related to widespread chronic pain, can elucidate nuanced roles of the central nervous system underlying chronic pain conditions. Chronic pain triples suicide risk; however, whether brain circuitry can inform this risk relationship has not been investigated. Methods11,298 participants (mean age: 64 years (range: 58-70), 55% female) with brain MRI from the UK Biobank with pain for more than 3 months in the head, neck/shoulders, back, abdomen, or hips and knees, were age-and-sex-matched to 11,298 pain-free controls. Regression models assessed cortical and subcortical structure differences between individuals reporting chronic pain and those without; mediation models determined the relationship between pain, brain structure and history of attempted suicide. OutcomesChronic pain, regardless of site was associated with, lower surface area throughout the cortex, lower volume in the brainstem, ventral diencephalon, cerebellum, and pallidum, lower cortical thickness in the anterior insula, and greater cortical thickness in the superior parietal cortex. When differentiated by pain site, participants with chronic headaches distinctly showed an overall thicker cortex compared with controls. Chronic pain was associated with an elevated risk for suicide attempt and this relationship was mediated by lower cerebellum volume. InterpretationThere are shared cortical mechanisms underlying chronic pain across body sites. An extensive thicker cortex in chronic headache was consistent with previous research. Cerebellum volume mediates the relationship between chronic pain and suicide attempt, serving as a potential biomarker prognostic for suicidal behaviors in chronic pain patients. FundingNational Science Foundation, National Institutes of Health Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSChronic pain is the leading cause of disability and disease burden globally, and its prevalence is increasing. As perception of pain occurs in the brain, alterations in brain structure have been investigated in various chronic pain conditions. However, published works, to date, report inconsistent findings, and typically do not compare a wide range of chronic pain types within the same study. Chronic pain is a risk factor for suicidal ideation, which can occur in up to 41% of individuals with chronic pain, but the role of specific brain systems in mediating the relationship between chronic pain and suicide has not been investigated. Added value of this studyThe present study reports alterations of brain structure in the largest and most well-powered sample reporting chronic pain to date (N = 11,298) compared to 11,298 pain-free controls, while taking into account age, sex, socioeconomic status, anxiety and depression. The effect of chronic pain on the brain is also evaluated as a function of pain across one or more of six different sites in the body (i.e. headaches, neck and shoulder, back, abdominal, hip and knee pain). Lower cortical surface area throughout the brain was related to chronic pain, and shown to be far more extensive than previously recognized. We, for the first time, show that participants with chronic headaches compared to controls have, on average, thicker gray matter throughout the cortex, a distinct and opposite pattern of effects than when individuals with other systemic pain conditions are compared to controls. A higher prevalence of suicide attempt history was noted in participants reporting chronic pain than controls. The relationship between chronic pain and suicide attempt, was mediated by the volume of the cerebellum, implicating spinocerebellar mechanisms. Implications of all the available evidenceBrain structure plays a key role in chronic pain, and mediates the role between pain and suicidal behaviors, independent of commonly presenting comorbidities. Our results highlight the concept of central sensitization and the role of the brains interacting networks in the presence of chronic pain. The thicker cortical gray matter in chronic headaches vs. controls - compared to other chronic pain conditions - indicates different mechanisms underlie these conditions and suggests that a clinically different approach to treatment is warranted. The cerebellum volume is a reliable mediator between chronic pain and suicide attempt, a finding that provides insight into potential underlying spinocerebellar mechanisms and to how treatments such as ketamine infusions may be beneficial in chronic pain and suicidal risk behavior management. Our work shows reliable neurobiological support for the multiple brain networks impacted and in regulating mood in the chronic pain phenotype.

There is increasing evidence of sex differences in underlying mechanisms causing pain in preclinical models, and in clinical populations. There are also important disconnects between clinical pain populations and the way preclinical pain studies are conducted. For instance, osteoarthritis pain more frequently affects women but most preclinical studies have been conducted using males in animal models. The most widely used painkillers, nonsteroidal anti-inflammatory drugs (NSAIDs), act on the prostaglandin pathway by inhibiting cyclooxygenase (COX) enzymes. The purpose of this study was to analyze the preclinical and clinical literature on the role of prostaglandins and COX in inflammation and pain. We aimed to specifically identify studies that used both sexes and investigate whether any sex-differences in the action of prostaglandins and COX inhibition had been reported, either in clinical or preclinical studies. We conducted a PubMed search and identified 369 preclinical studies and 100 clinical studies that matched our inclusion/exclusion criteria. Our analysis shows that only 17% of preclinical studies on prostaglandins used both sexes and, out of those, only 19% analyzed or reported data in a sex-aware fashion. In contrast, 79% of the clinical studies analyzed used both sexes. However, only 6% of those reported data in a sex-aware fashion. Interestingly, 14 out of 15 preclinical studies and 5 out of 6 clinical studies that analyzed data in a sex-aware fashion have identified sex-differences. This builds on the increasing evidence of sex-differences in prostaglandin signaling and the importance of sex-awareness in data analysis. The preclinical literature identifies a sex difference in prostaglandin D2 synthase (PTGDS) expression where it is higher in female than in male rodents in the nervous system. We experimentally validated that PTGDS expression is higher in female human dorsal root ganglia (DRG) neurons recovered from organ donors. Our semi-systematic literature review reveals a need for continued inclusivity of both male and female animals in prostaglandins studies and sex-aware analysis in data analysis in preclinical and clinical studies. Our finding of sex-differences in neuronal PTGDS expression in humans exemplifies the need for a more comprehensive understanding of how the prostaglandin system functions in the DRG in rodents and humans.

We performed the first systematic review and meta-analysis of the prevalence of pain with neuropathic characteristics using Bayesian methods to correct prevalence estimates for the use of screening tools with imperfect sensitivity and specificity (CRD42023416845). We searched major databases for national or regional epidemiological studies that reported the prevalence of pain with neuropathic characteristics, as identified by the PainDETECT, S-LANSS, or DN4-interview. Of the 1,251 unique records retrieved, 8 were finally extracted. The uncorrected (apparent) prevalence data were pooled using a random-effects meta-analysis for proportions. The corrected (true) prevalence was estimated using Bayesian models incorporating sensitivity and specificity distributions under non-informative [beta(1,1)] and informative priors [beta(4.389, 29.522); based on apparent prevalence]. Using the mean values from Bayesian credible intervals, a pooled estimate of true prevalence was generated using a random-effects model. The pooled estimate for the apparent prevalence was 10.6% (95% CI: 8.5; 12.9). The pooled estimate for true prevalence was 4.9% (95% CI: 3.8; 6.1) using informative priors, and 2.3% (95% CI: 1.5; 3.2) using non-informative priors. The use of imperfect screening tools may have overestimated the prevalence of neuropathic pain. PerspectiveThe prevalence of neuropathic pain may be lower than previously estimated. A lower prevalence should not be equated with reduced societal or clinical significance, but it may have implications for healthcare resource allocation and research funding policies for neuropathic pain.

Psychological distress predicts the onset and worsening of persistent pain, but the mechanisms that underpin this influence are poorly understood. Pro-inflammatory signalling is a plausible mechanistic link, given its known connections to distress, pain, and neural upregulation. Sustained distress may prime the inflammatory system to respond more strongly to a phasic noxious challenge, supporting neuroimmune upregulation of central nociceptive signalling and persistent pain. This cross-sectional study tested the hypotheses that in vitro endotoxin-provoked expression of typically pro-inflammatory cytokines (IL1{beta}, IL6) is a partial mediator between distress and persistent pain, and that it is associated with the secondary hyperalgesia response to an experimental noxious challenge, in people with suppressed HIV. Study participants were 99 adults (mean (range) age: 43(28-64y/o; 72 females) with either no pain (n=54) or persistent pain (n=45), mostly of black South African ethnicity, low socio-economic status, and with high social support. The results replicated previous reports that distress is associated with persistent pain status and pain severity, and also showed an association between distress and the anatomical extent of pain. However, distress was not associated with provoked cytokine expression, nor was provoked cytokine expression associated with secondary hyperalgesia. The conflict between our findings and the evidence on which our hypotheses were based could reflect masking of an effect by differentially trained immune systems or a more complex relationship arising from diverse psychoneuroimmunological interactions in this sample. Our samples combination of HIV status, African genetic ancestry, financial impoverishment, and rich social interconnectedness is poorly represented in current research and represents an opportunity to deepen insight into psychoneuroimmunological interactions related to distress and persistent pain.

Inflammatory joint pain features in numerous musculoskeletal disorders that affect millions globally. The Prdm12 gene encodes a conserved zinc finger transcriptional regulator expressed selectively in the nervous system. In humans, PRDM12 mutations can cause congenital insensitivity to pain (CIP) or midface toddler excoriation syndrome (MiTES). Prdm12 is prominently expressed in developing somatosensory ganglia, where it plays a crucial role in nociceptive neuron development, its expression being maintained in mature C-LTMRs (C-low threshold mechanoreceptors) and nociceptive neurons. Despite enhanced understanding of Prdm12s role in neuronal excitability and pain behavior, the impact of Prdm12 overexpression in mature nociceptive neurons has not been explored. Here, we conducted intravenous injection of AAV-PHP.S viral vectors encoding Prdm12-GFP (Prdm12-AAV) or GFP alone (Control-AAV), observing no overt changes in mouse behavior. When examining the properties of Prdm12 overexpressing sensory neurons in vitro, we observed an increase in rheobase alongside decreased neuronal responses to capsaicin and ATP, indicating a downregulation of TRPV1 and P2X ion channels activity, respectively. We next conducted intraarticular administration of viral constructs in female mice to determine how Prdm12 overexpression in knee-innervating sensory neurons alters their excitability and influences inflammatory joint pain induced by intraarticular administration of complete Freunds adjuvant (CFA). Prdm12 overexpression in knee-innervating neurons decreased inflammation-induced changes in digging and weight bearing, prevented inflammation-induced neuronal hyperexcitability, and decreased macroscopic voltage-gated ion channel conductance. Our findings illustrate that Prdm12 overexpression strongly modulates neuronal excitability in adult animals, highlighting its importance in pain perception and its potential as an analgesic target. SummaryOverexpression of the transcriptional regulator Prdm12 in knee-innervating neurons of mice reduces inflammatory joint pain and counteracts inflammation-induced neuronal hyperexcitability.

Chronic Primary Pain (CPP) is a new diagnostic category including chronic pain conditions lacking clinical signs or a clear etiopathogenetic origin. These disorders may share a common neural mechanism known as central sensitization, where nociceptive neurons become hyper-responsive to standard or subthreshold pain stimuli, resulting in pain hypersensitivity. In this context, non-invasive brain stimulation (NIBS) seems a promising tool to improve CPP symptoms by targeting maladaptive brain activity and connectivity. To date, NIBS effects on CPP symptoms remain unexplored. To fill this gap, we conducted a meta-analysis, investigating the effect of NIBS in improving the three core symptoms of CPP, namely pain intensity, emotional distress, and functional disability. Following PRISMA guidelines, we screened four databases up to the end of January 2023. Thirty-five English-written randomized clinical trials were included, comprising 874 participants assigned to the real stimulation condition and 713 to the sham. Findings highlighted the effect of the real over the sham stimulation in improving CPP core symptoms immediately after the treatment. For pain intensity and functional disability, the improvement persisted also at the one-month follow-up. Meta-regression analyses highlighted that a longer CPP duration reduced the effects of NIBS, while an increased number of sessions was associated with greater pain relief at follow-up. Taken together, our results suggest that NIBS can effectively alleviate CPP symptoms in the short and medium term. Further research is needed to define standardized NIBS protocols for CPP management and explore whether combining NIBS with other therapeutic interventions can enhance effects duration and efficacy.

NaV1.7, a membrane-bound voltage-gated sodium channel, is preferentially expressed along primary sensory neurons, including their peripheral & central nerve endings, axons, and soma within the dorsal root ganglia and plays an integral role in amplifying membrane depolarization and pain neurotransmission. Loss- and gain-of-function mutations in the gene encoding NaV1.7, SCN9A, are associated with a complete loss of pain sensation or exacerbated pain in humans, respectively. As an enticing pain target supported by human genetic validation, many compounds have been developed to inhibit NaV1.7 but have disappointed in clinical trials. The underlying reasons are still unclear, but recent reports suggest that inhibiting NaV1.7 in central terminals of nociceptor afferents is critical for achieving pain relief by pharmacological inhibition of NaV1.7. We report for the first time that NaV1.7 mRNA is expressed in putative projection neurons (NK1R+) in the human spinal dorsal horn, predominantly in lamina 1 and 2, as well as in deep dorsal horn neurons and motor neurons in the ventral horn. NaV1.7 protein was found in the central axons of sensory neurons terminating in lamina 1-2, but also was detected in the axon initial segment of resident spinal dorsal horn neurons and in axons entering the anterior commissure. Given that projection neurons are critical for conveying nociceptive information from the dorsal horn to the brain, these data support that dorsal horn NaV1.7 expression may play an unappreciated role in pain phenotypes observed in humans with genetic SCN9A mutations, and in achieving analgesic efficacy in clinical trials.

Neuropathic pain affects approximately 10% of the adult population and is commonly treated with gabapentin (GBP), a repurposed anticonvulsant drug. Despite its widespread clinical use, GBPs efficacy varies significantly among patients, highlighting the need to better understand its functional and molecular impacts on human pain-sensing neurons. In this study, we characterized the electrophysiological and transcriptomic effects of GBP on primary sensory neurons derived from the dorsal root ganglia (DRG) of ethically consented human donors. Using patch-clamp electrophysiology, we demonstrated that GBP treatment reduced neuronal excitability, with more pronounced effects in multi-firing vs. single-firing neuronal subtypes. Notably, significant donor-specific variability was observed in electrophysiological responsiveness to GBP treatment in vitro. RNA sequencing of DRG tissue from the GBP-responsive donor revealed differences in the transcriptome-wide expression of genes associated with ion transport, synaptic transmission, inflammation, and immune response relative to non-responsive donors. Cross-transcriptomic analyses further showed that GBP treatment counteracted these altered processes, rescuing aberrant gene expression at the pathway level and for several key genes. This study provides a comprehensive electrophysiological and transcriptomic profile of the effects of GBP on human DRG neurons. These findings enhance our understanding of GBPs mechanistic actions on peripheral sensory neurons and could help optimize its clinical use for neuropathic pain management.

Repetitive peripheral magnetic stimulation (rPMS) is a non-pharmacological, non-invasive analgesic modality with limited side effects. However, there is a paucity of controlled studies demonstrating its efficacy compared to existing pain management tools. Here, in an initial sample of 100 healthy participants (age 18-40), we compared the analgesic efficacy of two rPMS stimulation protocols--continuous theta burst stimulation (ctbPMS) and intermittent TBS (itbPMS)--against transcutaneous electric nerve stimulation (TENS), a peripheral stimulation technique that is commonly used for pain management. We also included a sham rPMS protocol where participants heard the sound of rPMS stimulation while the coil was placed over their arm, but received no peripheral stimulation. We hypothesized that itbPMS and ctbPMS--but not sham--would reduce pain intensity, pain unpleasantness, and secondary hyperalgesia evoked by a phasic heat pain (PHP) paradigm on the volar forearm with similar efficacy to TENS. Neither rPMS nor TENS reduced reported pain intensity or unpleasantness (p>0.25). However, ctbPMS and itbPMS significantly reduced the area of secondary hyperalgesia, whereas TENS did not (F3,96= 4.828, p= 0.004). Unexpectedly, sham rPMS, which involved auditory but no peripheral nerve stimulation, also significantly reduced secondary hyperalgesia compared to TENS. We performed a second study (n=32) to investigate auditory contributions to rPMS analgesia. Masking the rPMS stimulation sound with pink noise eliminated its analgesic effect on secondary hyperalgesia (p=0.5). This is the first study to show that the analgesic properties of rPMS in acute experimental pain may be largely attributed to its auditory component rather than peripheral nerve stimulation.

BackgroundPersistent Spinal Pain Syndrome (PSPS) type II represents a challenging clinical entity with limited therapeutic options. Various spinal cord stimulation (SCS) modalities have emerged as potential treatments, but their comparative effectiveness remains unclear. ObjectiveOur goal in this paper is to systematically evaluate and compare the efficacy of different SCS modalities in patients with PSPS type II through meta-analysis of available randomized controlled trials. Evidence ReviewWe conducted a systematic review following PRISMA guidelines, searching major databases for randomized controlled trials evaluating SCS modalities in PSPS type II patients until the end of May 2025(search updated on October 3rd). Primary outcomes included pain intensity (VAS) and functional disability (ODI) at 6 and 12 months. Subgroup analyses compared tonic versus burst stimulation and high-frequency versus low-frequency SCS. FindingsNine randomized controlled trials were included, encompassing 565 patients across different SCS modalities. For the primary outcome of clinically meaningful pain relief ([&ge;]50% reduction), pooled analysis demonstrated that 45% (95% CI: 18-75%, I{superscript 2} = 92.2%) of patients achieved this threshold for back pain and 55% (95% CI: 45-65%, I{superscript 2} = 0%) for leg pain. Subgroup analysis revealed significant differences in back pain responder rates by stimulation modality: High-frequency SCS demonstrated responder rates of 92% (95% CI: 79-98%) versus 28% (95% CI: 13-49%) for conventional frequencies (p < 0.001). For leg pain, no significant difference was observed between tonic (51%, 95% CI: 37-65%) and burst stimulation (60%, 95% CI: 45-74%, p = 0.36) and mean VAS scores demonstrated significantly lower pain with high-frequency SCS (13.30, 95% CI: 8.82-17.78) compared to conventional frequency (28.42, 95% CI: 24.02-32.88, p<0.0001). For back pain, mean VAS scores decreased from a baseline of 73.03 to 41.67 (95% CI: 36.12-47.22, I{superscript 2}=22.8%) at 6 months and remained stable at 35.66 (95% CI: 25.39-45.93, I{superscript 2}=75.0%) at 12 months. Leg pain showed more pronounced improvement, with VAS scores declining from a baseline of 61.81 to 23.75 (95% CI: 17.69-29.81, I{superscript 2}=78.8%) at 6 months and 29.16 (95% CI: 24.81-33.52, I{superscript 2}=0%) at 12 months). Meta-regression identified longer pain duration and older age as positive predictors of response, while higher baseline leg pain predicted lower responder rates. Serious adverse events occurred in 10%, with a 16% revision surgery rate. Only two studies demonstrated a low risk of bias across all domains. ConclusionsCurrent evidence demonstrates that various SCS modalities provide clinically meaningful pain relief in PSPS type II patients, with approximately half achieving [&ge;]50% pain reduction. High-frequency SCS shows significantly superior responder rates for back pain compared to conventional tonic stimulation, while burst stimulation yields significantly superior reductions in continuous pain intensity metrics. However, the limited number of studies, substantial heterogeneity, and lack of head-to-head comparisons prevent definitive recommendations regarding optimal stimulation parameters. Future large-scale randomized trials with standardized protocols and responder-based outcomes are needed to establish evidence-based treatment algorithms for PSPS type II patients.

ObjectivesSensitization of C-fiber nociceptors plays a critical role in spontaneous and ongoing pain in patients with chronic pain. We recently demonstrated that C-fiber afferents can be reversibly blocked through activity-dependent conduction slowing, suggesting that selective activation of C-fiber afferents may represent a novel strategy for pain relief. We hypothesized that electrical peripheral nerve stimulation (ePNS) and dorsal root ganglion (DRG) stimulation exhibit distinct activation thresholds for unmyelinated C-fiber afferents. Materials and MethodsWe characterized the activation thresholds of A- and C-fiber afferents during ePNS and DRG stimulation using single-fiber electrophysiological recordings from split nerve filaments and optical GCaMP6f imaging of intact DRGs. We further quantified the distribution of the sodium channel subtype NaV1.6 in afferent axons and somata and evaluated its contribution to neuronal excitability using NEURON-based computational modeling. ResultsSingle-fiber recordings showed that activation of C-fiber axons required approximately tenfold higher stimulus amplitudes than A/{beta}-fiber axons during ePNS. In contrast, DRG stimulation within a narrow amplitude range robustly activated both small- and large-diameter DRG neurons, with putative C-fiber afferents comprising 57% of the activated population, indicating markedly reduced differential activation thresholds compared with ePNS. Analysis of published single-cell RNA-sequencing datasets revealed high NaV1.6 expression in TRPV1-positive C-fiber nociceptors. Immunohistochemical staining demonstrated prominent clustering of NaV1.6 in the stem axons of most DRG neurons, including small-diameter C-fiber afferents, whereas NaV1.6 was absent from C-fiber axons in the sciatic nerve. NEURON simulations further showed that NaV1.6 clustering at the stem axon is a key determinant of activation thresholds during DRG stimulation. ConclusionsThese findings identify a structural and molecular mechanism underlying the efficient activation of C-fiber afferents by DRG stimulation and provide mechanistic insight into the superior therapeutic efficacy of DRG stimulation for the treatment of C-fiber-mediated chronic pain.

Fibromyalgia syndrome (FMS) is a chronic pain disorder with hypersensitivity to painful stimuli. A subgroup of patients shows damage to small peripheral nerve fibers. Previous studies support the hypothesis that increased activation of the pain-processing insular cortex is mediated by an imbalance of insular glutamate and {gamma}-aminobutyric acid (GABA) concentrations. Here, we aimed to test this hypothesis in a large cohort of FMS patients comparing data of patients and healthy controls. In addition, we tested the hypothesis whether a reduction in small peripheral nerve fibers relates to glutamate concentrations in the insular cortex. We recruited 102 subjects (all female, 44 FMS patients, 40 healthy age-matched controls, and 19 patients with rheumatoid arthritis (RA) as disease controls. Study participants underwent single-voxel magnetic resonance spectroscopy of the right and left insular cortex. All patients completed questionnaires on symptom severity (pain intensity, impairment due to symptoms, depression). FMS patients were further stratified into subgroups with and without reduced intraepidermal nerve fiber density (IENFD) assessed on skin punch biopsies. We found no intergroup difference of the glutamate/GABA metabolite concentrations between FMS and RA patients and healthy controls. Glutamate/GABA levels did not correlate with symptom severity. Cerebral glutamate concentrations were independent of skin innervation. We found similar insular glutamate/GABA concentrations in FMS patients and disease and healthy controls. Therefore, our data cannot support the hypothesis that a glutamate/GABA mismatch leads to a sensitization of the insular cortex of fibromyalgia patients and thereby induces the symptoms.

BackgroundNeuropathic pain is difficult to treat in clinical practice, and the underlying mechanisms are insufficiently elucidated. Previous studies have demonstrated that Fc{gamma} receptor I (Fc{gamma}RI) is expressed in the neurons of the dorsal root ganglion (DRG) and may be involved in chronic pain. MethodsChronic constriction injury (CCI) was used to induce neuropathic pain in rats. Primary neuron-specific Fcgr1 conditional knockout (CKO) rats were established by crossing rats carrying a Fcgr1loxP+/+ with the PirtCRE+ line. Behavioral and molecular studies were conducted to evaluate the differences between wild-type and CKO rats after CCI. ResultsWe first revealed that CCI activated neuronal Fc{gamma}RI-related signaling in the DRG. CCI-induced neuropathic pain was alleviated in CKO rats. C-reactive protein (CRP) was increased in the DRG after nerve injury. Intraganglionic injection or overexpression of the recombinant CRP protein in the DRG evoked pain accompanied and activated neuronal Fc{gamma}RI. CRP-evoked pain was significantly reduced in CKO rats. Furthermore, microinjection of native IgG into the DRG alleviated neuropathic pain and the activation of neuronal Fc{gamma}RI-related signaling. ConclusionsOur results indicate that the activation of neuronal CRP/Fc{gamma}RI-related signaling plays an important role in the development of pain in CCI. Our findings may provide novel insights into the neuroimmune responses after peripheral nerve injury and might suggest potential therapeutic targets for neuropathic pain.