Pain

Women are disproportionately affected by chronic pain, yet the neural mechanisms underlying sex differences in affective pain processing remain incompletely understood. The bed nucleus of the stria terminalis (BNST), a sexually dimorphic structure implicated in aversion and chronic pain, receives dense input from aversive calcitonin gene-related peptide (CGRP)-expressing neurons arising from the parabrachial nucleus (PBN). Although CGRP signaling has been implicated in sex differences in clinical pain conditions, whether CGRP transmission within the PBN[->]BNST pathway is sexually dimorphic has not been determined. Here, we tested the hypothesis that CGRP signaling in the BNST differs between sexes. Contrary to our prediction, PBN CGRP neurotransmitter release in the BNST was sex-independent. However, CGRP neuromodulation of BNST excitability exhibited sex-dependent features. While CGRP potentiated PBN[->]BNST glutamatergic signaling in both sexes, spontaneous inhibitory signaling was selectively increased in males. Together, these findings indicate that sex differences in this circuit arise not from differential peptide release, but from downstream modulation of inhibitory tone, biasing female BNST neurons toward greater excitation. Such circuit-specific sex differences may contribute to the enhanced susceptibility of females to affective components of chronic pain and highlight targets for sex-informed therapeutic interventions.

Despite being essential mediators of pain processing, the molecular identity of N-methyl-D-aspartate receptor (NMDAR) subtypes in nociceptive dorsal horn circuits is poorly understood, especially between sexes and in humans. Given the importance of GluN2 subunits in shaping NMDAR function and plasticity, we investigated the expression and localization of specific GluN2 NMDAR variants in the dorsal horn of viable spinal cord tissue from male and female rodents and human organ donors. Analysis of single-cell/nuclei sequencing datasets and quantitative reverse transcriptase polymerase chain reactions (qRT-PCR) revealed that the GluN2A (GRIN2A) and GluN2B (GRIN2B) subunits are robustly expressed in dorsal horn neurons of mice, rats and humans, with moderate expression of GluN2D (GRIN2D). Immunohistochemistry (IHC) with antigen retrieval demonstrated that GluN2A, GluN2B, and GluN2D proteins are all preferentially localized to the superficial dorsal horn of both adult rats and humans, which is conserved between males and females. Surprisingly, we found that these GluN2 NMDAR subunits are enriched in the lateral superficial dorsal horn in rats but not in humans, while presynaptic and neuronal markers are symmetrically distributed across the rat mediolateral axis. A dramatic shift in localization of GluN2A to the lateral superficial dorsal horn was observed across later postnatal development (PD21-PD90) in both male and female rats, with a corresponding change in synaptic NMDAR currents. This discovery of changes in NMDAR subunit distribution during maturation and between species will shed light on the physiological roles of NMDARs and their potential as therapeutic targets for pain. SIGNIFICANCE STATEMENTWe used complementary single-cell/nuclei analysis, immunostaining, quantitative reverse transcriptase polymerase chain reactions, RNAscope in situ hybridization, and electrophysiological approaches to compare the relative expression of N-methyl-D-aspartate receptor (NMDAR) GluN2 subunits in dorsal horn spinal cord pain circuits of mouse, rat, and human spinal cord tissue. Through these comparisons, we find that the transcripts and proteins of the GluN2A, GluN2B, and GluN2D NMDAR subunits are robustly expressed in superficial dorsal horn neurons, with conserved expression across sex but important differences in expression and localization patterns across late development and between species. These discoveries shed light on the physiological roles of NMDARs and their utility as potential therapeutic targets for pain.

Inflammatory bowel disease (IBD) is characterised by chronic pain, a debilitating symptom for which effective treatments are few and far between. IBD pathogenesis includes the prevalence of a variety of pro-inflammatory cytokines, including the Interleukin-6 (IL-6) family members Il-6 and Oncostatin M (OSM). Previous research has shown disruption of OSM signaling can modulate nociceptor sensitization and activation, however the downstream signalling pathway is unknown. When an in silico analysis of murine colonic sensory neuronal populations was undertaken for receptor expression for OSM and other factors necessary for intracellular signaling, we can find diverse expression indicative of functional signaling. We were able to observe that hyper Il-6 (Il-6 bound to the soluble Il-6 receptor) and OSM can elicit activation of a subset of murine sensory neurons by finding an increase in calcium mobilization following superfusion. This could then be attenuated by the pharmacologic inhibition of all janus kinases or interestingly, TYK2 alone. Furthermore, inhibition of transient receptor potential vanilloid 1 or transient receptor potential ankyrin 1 ion channels, which are known to be sensitized by OSM in other sensory neurons also reduced the proportion of OSM-responsive neurons. This further understanding of OSM signaling in sensory neurons creates avenues for more extensive research into the molecular mechanisms occurring as well as the potential to exploit these therapeutically to induce analgesia in a subset of neurons.

Objective: To evaluate whether glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with improvements in pain severity, disability, quality of life, and physical function in adults with obesity and chronic low back pain (cLBP), and to explore potential mechanisms. Design: Prospective, single-arm cohort study. Subjects: Thirty-five adults (median age 41 years; 86% women) with obesity (median BMI 39.9 kg/m2) and cLBP initiating GLP-1 RAs (tirzepatide, n=24; semaglutide, n=11). Methods: Participants completed questionnaires at baseline, 3, 6, 9, and 12 months. The primary outcome was Brief Pain Inventory-Short Form (BPI-SF) pain severity. Secondary outcomes included body mass index (BMI), BPI-SF pain interference, Numerical Rating Scale (NRS) back pain, Oswestry Disability Index (ODI), and Short Form-12 (SF-12). At baseline and 6 months, a subset (n=24) underwent quantitative sensory testing, physical performance testing, and blood draws for inflammatory biomarkers (C-reactive protein, TNF-, IL-6, IL-10), adipokines (leptin, adiponectin), and hemoglobin A1c. Results: Over 12 months, BMI decreased by 12.5% (median 39.9 to 34.9 kg/m2, 95% CI [-6.6, -4.2]). BPI-SF pain severity improved (median 4.8 to 2.0, 95% CI [-2.1, -0.8]), as did pain interference, ODI, NRS back pain, and SF-12 physical component scores. Hemoglobin A1c, leptin, and C-reactive protein decreased. Adiponectin increased and physical performance improved, but neither reached significance. Experimental pain sensitivity was unchanged. Conclusions: GLP-1 RAs were associated with clinically meaningful improvements in pain, disability, and quality of life. These findings suggest GLP-1 RAs may be a promising nonsurgical therapy for cLBP; randomized controlled trials are needed to establish causality and mechanisms.

Background. A substantial minority (~20%) of patients fail to achieve meaningful pain reduction following surgery intended to relieve pain. Risk is elevated in patients with nociplastic pain features, but available self-report measures were not designed for pre-surgical screening. We aimed to develop a brief, data- driven screener for poor analgesic response to surgery. Methods. Participants were recruited from tertiary orthopedic and chronic pelvic pain clinics. Total hip arthroplasty participants had Kellgren-Lawrence grades III-IV with hip pain greater than or equal to 1 year; hysterectomy participants had chronic pelvic pain greater than or equal to 6 months. The primary outcome was a 50% reduction in worst pain at six months. Items were selected via elastic net regression with k-fold cross-validation from 68 candidates. Results. Of 428 participants (81% female; mean age 51), 35% failed to achieve a 50% pain reduction. The resulting 11-item screener - the GenerAlized sensory sensitivity for sUrGical rEsponsiveness (GAUGE) - comprises pain across seven body regions and four symptom items measuring interoception (nausea, numbness/tingling) and exteroception (sensitivity to sound, sensitivity to odors). GAUGE outperformed the Central Sensitization Inventory, Fibromyalgia Survey Criteria, and PainDETECT for predicting surgical non-response (RR 1.535, 95% CI 1.342-1.55; AUC 0.738; sensitivity 0.741, specificity 0.635) and for predicting Patient Global Impression of Change. In an independent validation cohort of 54 total knee arthroplasty patients, GAUGE outperformed the Fibromyalgia Survey Criteria in predicting pain severity at six-months. Conclusions. GAUGE is a data-driven, theoretically grounded screener for poor analgesic response to surgery, with potential utility for pre-surgical counseling and clinical trial enrichment.

Chronic pelvic pain (CPP) affects up to 26% of women worldwide. While its pathophysiology is poorly understood, disturbances in body perception have been identified in various similar chronic musculoskeletal disorders. The Fremantle Perineal Awareness Questionnaire (FrePAQ) is a novel tool designed to specifically assess disturbed body perception in the pelvic region, but its structural validity and reliability require formal evaluation. Methods: Patient partners with lived experience contributed to study design. Participants with (n=417 and without (n=277) chronic pelvic pain completed the FrePAQ at baseline, as well as one week later. We assessed the validity and reliability of the FrePAQ following COSMIN guidelines for Classical Test Theory. Results: The validated FrePAQ comprises a two factor model, with a six item Distress & Disconnection (D&D) subscale and a two item Size & Shape (S&S) subscale. Confirmatory analysis showed excellent fit (CFI = .988; RMSEA = .048) and measurement invariance between diagnostic groups. Internal consistency was high (cronbach alpha = .838 CPP, .819 controls). Test retest reliability was high for D&D (ICC = .863) and acceptable for S&S (ICC = .695). FrePAQ scores showed a weak to moderate correlation with pain scores (r = .234 to .255), psychological distress (r = .226 to .443), and functional impact (r = .172 to .295), particularly for the D&D subscale. Conclusion: The FrePAQ is a reliable and valid instrument to measure perineal perceptual disturbances in CPP. Future research will evaluate the tools potential to support phenotyping and guide individualised interventions. Improved understanding of body perception disturbance in CPP can enhance diagnosis and treatment precision.

Nerve injury causes an imbalance of glutamatergic excitation over GABAergic inhibition, contributing thereby to lasting neuropathic pain. Transgenic GAD67-GFP knock-in reporter mice were developed to visualize GABAergic interneurons. The knock-in into glutamate decarboxylase (GAD67) causes haploinsufficiency that manifest in low GABA levels. In this model, we studied if diminished GABA exacerbates neuropathic pain after nerve injury. Adolescent male and female GAD67-GFP knock-in mice were subjected to Spared Sciatic Nerve Injury (SNI). At baseline, nociception and thermal preferences were equal but after SNI, GAD67-GFP mice developed thermal allodynia which was not detected in wildtype littermates. At the electrophysiology level, SNI caused a partial decrease in the excitability in layer 2/3 pyramidal neurons in the projection-hemisphere in wildtype mice. This effect was exacerbated in GAD67-GFP, affecting both sides, and was accompanied with imbalance of field-potential (FP) amplitudes between projection and non-projection hemisphere, which did not occur in wildtype mice. The results suggest that GABA deficiency can be compensated to protect from hyperexcitability at baseline, but it cannot be further upscaled, ultimately leading to network hyperactivity after injury. Metabolomic studies confirmed the moderate loss of GABA in ipsi- and contralateral cortex and lumbar spinal cord of GAD67-GFP mice and failure to raise GABA in the ipsilateral dorsal horn after injury. Carnosine, cystathionine, and glutathione, three important anti-oxidative metabolites, were co-reduced with GABA suggesting that GABAergic activity and anti-oxidative capacity are interconnected and failure of this axis contributes to neuropathic "pain".

Introduction: Acute low back pain is a leading cause of disability worldwide. Clinical guidelines recommend non-pharmacological therapies as first-line treatment and advise caution with opioid prescribing. However pharmacological therapies, including opioids and gabapentinoids, remain commonly used. The comparative risks of subsequent opioid use disorder (OUD) and overdose diagnosis associated with initial treatment modality in large, real-world populations is not well characterized. We estimated the incidence of new-onset OUD and overdose diagnosis among opioid-naive, Medicaid-insured adults with newly diagnosed acute low back pain and estimated the association between initial treatment modalities and subsequent OUD and overdose diagnosis risk. Methods: We conducted a retrospective cohort study using Medicaid T-MSIS Analytic files from 25 states (2016-2019). We identified opioid-naive adults with a new diagnosis of acute low back pain who initiated pharmacologic or non-pharmacologic treatment within 1 month of diagnosis. The primary outcome was incident OUD and overdose diagnosis (based on diagnosis codes in claims) during follow-up. Associations between initial treatment modality and OUD and overdose diagnosis risk were estimated using a non-parametric, doubly robust estimator to adjust for measured confounding. Results: The cohort included 525,002 opioid-naive adults initiating treatment for low back pain. The cumulative incidence of OUD and overdose diagnosis was 1.5% and 2.4% at 7 and 13 months, respectively. Compared to non-use, use of gabapentinoids during the first month of treatment was associated with the highest relative risk (increasing risk) by 130.1%, 95% confidence interval (CI): 117.8%, 142.3%), the second-highest relative risk was estimated for higher-dose opioids, defined as > 50 daily Morphine Milligram Equivalents (MME) (118.1%, 95% CI: 99.2%, 137.0%). Lower-dose, short-duration opioids ([≤] 50 MME, [≤] 7 days) were also associated with elevated risk, though substantially smaller in magnitude (20.8%, 95% CI: 13.8%, 27.9%). In contrast, non-pharmacologic, non-interventional therapies were associated with reduced OUD and overdose diagnosis risk, with physical therapy demonstrating the largest relative reduction of 34.0% (95% CI: -40.9%, -27.1%). Discussion: In opioid-naive Medicaid patients with acute low back pain, initial non-pharmacologic treatment was associated with reduced OUD and overdose diagnosis risk. Gabapentinoids and opioids were each associated with increased risk; for opioids, the degree of risk increased with higher doses and durations. These results support guideline recommendations favoring non-pharmacologic treatment as first-line therapy and indicate the importance of cautious prescribing when pharmacologic treatment is considered.

BackgroundAcute postoperative pain remains a major clinical therapeutic challenge. Current peripheral nerve blockade (PNB) techniques are effective for some patients but are limited by invasiveness, short duration, reliance on highly trained providers, and off-target motor and sensory effects. Focused ultrasound (FUS) is a novel neuromodulatory technology with the potential to achieve noninvasive, selective, reversible, and prolonged inhibition of peripheral nociceptive fibers to prevent and treat acute pain. We hypothesized that noninvasive transcutaneous targeting of the rat sciatic nerve using co-aligned diagnostic ultrasound (dUS) and FUS transducers could produce selective and reversible inhibition of nociceptive pain behaviors while preserving motor and non-nociceptive sensory functions. MethodsIn an in vivo rat hindpaw incisional (HPI) pain model, using a novel, transcutaneous dUS-guided FUS system, the sciatic nerve was located with dUS, and FUS energy was applied to it just prior to hindpaw incision. FUS parameters were iteratively adjusted to achieve reversible, selective inhibition of nociceptive behaviors without changing motor and non-pain sensory behaviors. Animals were randomized into six groups: No Intervention (Control), HPI Only (Disease Control), Sham FUS, FUS Only, FUS+HPI (Intervention), and LA+HPI (Positive Control). Primary outcomes were changes in nociceptive sensory functions, assessed by thermal and mechanical sensitivity. Secondary outcomes were changes in non-nociceptive sensory and motor functions, assessed by hindpaw flexion and extension reflexes. ResultsCompared with the HPI Only group, the FUS+HPI group demonstrated (1) significant attenuation of hindpaw thermal hypersensitivity from day 0 - week 5.0 and week 8.0 - 16.0 (p < 0.05-0.001); (2) significant attenuation of mechanical hypersensitivity from day 0 until week 4.0 (p < 0.05-0.001); (3) no significant attenuation of flexion; and (4) no significant attenuation of extension. ConclusionsTranscutaneous dUS-guided FUS enables selective, reversible inhibition of A{delta} and C nociceptive fiber mediated behaviors while sparing A motor and A{beta} sensory behaviors. FUS-induced PNB prevented both acute and persistent pain behaviors. These findings support FUS as a promising noninvasive peripheral nerve blockade strategy for acute pain management.

Background: Psychedelics are emerging as potential management options for chronic musculoskeletal pain due to preliminary evidence of effectiveness and low addictive potential, but patients perceptions remain unknown. This study assessed patient perceptions regarding psilocybin for musculoskeletal pain. Methods: We conducted a cross-sectional survey of adults ([&ge;]19) with musculoskeletal pain attending a hospital-based orthopaedic clinic. Participants reported demographics, perceptions of psychedelics for pain management, and willingness to participate in psychedelic research. Multivariable regression explored factors associated with perceived analgesic potential, and willingness to try a full therapeutic dose of psilocybin or a microdose. Results: Among 295 participants, 73% reported moderate-to-severe pain; 75% used analgesics; of these, 41% used opioids (86/209). While 24% reported prior psychedelic use, only 3% had discussed psychedelics with a healthcare provider. Most perceived that psilocybin had moderate-to-high effectiveness for pain (76%). Most respondents endorsed a moderate-to-high willingness to try microdoses (58%) and macrodoses (53%) of psilocybin for pain. Prior non-therapeutic psychedelic use predicted a 1.05-unit increase in perceived analgesic potential on the 10-point scale (p=.013). Willingness to try a macrodose of psilocybin was most strongly associated with prior non-therapeutic (B=3.16) and therapeutic (B=2.42) psychedelic use; in contrast, pain severity had a significant but modest association, with a 0.21-point increase in willingness for every 1-unit increase in pain severity (p=.017). Similarly, willingness to try a microdose of psilocybin was predicted by non-therapeutic (B=2.82) and therapeutic (B=2.48) use, whereas the effects of pain severity (B=0.20) and younger age (B=-0.30) were significant but small. Most respondents (52%) reported moderate-to-high willingness to participate in a trial of psilocybin for pain relief, and health risks were the primary concern (33%). Conclusions: Study findings suggest a majority hold neutral-to-positive perceptions of psilocybin for pain. Addressing perceived barriers, including health effects and gaps in patient knowledge, should be considered when designing future trials.

ObjectiveTo conduct de novo meta-analyses quantifying the association of five biopsychosocial risk factor domains with chronic pain or related treatment outcomes, and to construct a composite risk index with formal uncertainty propagation for interventional pain medicine. MethodsUmbrella review with de novo random-effects meta-analyses (DerSimonian-Laird and REML with Knapp-Hartung adjustment) across PubMed/MEDLINE, Scopus, and the Cochrane Library through March 2026. Five risk factor domains were evaluated: (1) sleep disturbance, (2) pain catastrophizing, (3) metabolic/obesity, (4) preoperative opioid exposure, and (5) benzodiazepine co-prescription. Publication bias was assessed via Eggers test and PET-PEESE regression. Primary study overlap was quantified using the Corrected Covered Area (CCA). We constructed a primary three-domain composite (sleep, catastrophizing, metabolic) and a secondary expanded six-domain composite (adding opioid, BZD, smoking), using the logistic link function with binary risk factor inputs (present/absent); composite score 95% confidence intervals were computed via delta method variance propagation. Risk of bias of the composite was assessed using PROBAST [Wolff RF et al., Ann Intern Med 2019]; TRIPOD+AI compliance is reported in Supplementary S6 [Collins GS et al., BMJ 2024]. Reviewer process (per registered protocol PROSPERO CRD420261360881): screening, data extraction, risk-of-bias assessment (AMSTAR-2/PROBAST/ROBINS-I), and GRADE certainty rating are conducted independently by at least two reviewers -- SPM (confirmed co-reviewer, registered in PROSPERO) as primary rater, with an external third reviewer to be identified and confirmed prior to peer-reviewed submission; JAD acts as guarantor and does not perform primary review tasks. All quantitative outputs reported here are preliminary estimates pending completion of the external third-reviewer audit; a triple-validated version will be posted as a subsequent preprint update before peer-reviewed submission. ResultsAdopted odds ratios: sleep disturbance 1.39 (95% CI 1.21-1.59; k=16; I{superscript 2}=51%), pain catastrophizing 2.10 (1.49-2.95; k=8; I{superscript 2}=0%), metabolic/obesity 1.43 (1.28-1.60; k=33), preoperative opioid exposure 5.32 (2.94-9.64; k=33; I{superscript 2}=99.96%; outcome: prolonged opioid use), and BZD co-prescription 1.77 (1.31-2.39; k=27; outcome: persistent opioid use). REML/Knapp-Hartung estimates produced wider confidence intervals for all loops (opioid: 1.87-15.13). PET-PEESE analysis suggested no substantial small-study effects for the sleep or catastrophizing loops. CCA=3.2% (slight overlap). Primary three-domain composite (sleep + catastrophizing + metabolic): delta method 95% confidence intervals for the composite score spanned 10-15 percentage points; PROBAST risk of bias: moderate. Secondary expanded six-domain composite (adding opioid, BZD, smoking): confidence intervals spanned 12-18 percentage points, crossing risk tier boundaries in moderate-risk patients; PROBAST risk of bias: high (driven by outcome heterogeneity in pharmacological domains). ConclusionsFive biopsychosocial risk factor domains are independently associated with chronic pain or related treatment outcomes. The PALF composite index is presented as a structured analytical framework for future prospective validation, not as a deployable clinical tool. The primary three-domain composite (sleep, catastrophizing, metabolic) achieves outcome homogeneity at the cost of reduced domain coverage; the expanded six-domain composite encompasses the pharmacological burden at the cost of outcome heterogeneity. Both composites carry wide confidence intervals that preclude clinical application without individual patient data validation. No claim to clinical validity is made in the absence of prospective individual-patient-data validation.

Previous brain decoding studies indicate that an individuals pain experience can be robustly predicted from distributed patterns of brain activity. Two brain decoders have notably been associated respectively with the nociceptive and cognitive aspects of pain experience, the Neurologic Pain Signature (NPS) and the Stimulus-Intensity Independent Pain Signature (SIIPS). Yet, we still do not know if these brain patterns are also causally related to pain experience. To evaluate this possibility, we used high-field (7-Tesla) fMRI to test whether humans can alter their pain experience by bidirectionally modulating their pain-related brain activity in decoded neurofeedback paradigm. In a double-blind design, participants were trained to up- and down-regulate the NPS or the SIIPS. Our results indicate that participants can achieve bidirectional control of both signatures. NPS expression reliably increased during pain stimulation and covaried with both stimulus intensity and subjective ratings. In contrast, SIIPS expression did not show consistent stimulus-locked effects in the primary analyses. Importantly, reduction in pain rating was specific for SIIPS-training, whereas NPS has failed to show any consistent behavioral effect. Based on these preliminary findings, we hereby preregister a follow-up study, with specified rationale, hypotheses, experimental design, and analysis protocols.

Background: Low-intensity focused ultrasound (LIFU) is an emerging noninvasive neuromodulation technique capable of targeting deep cortical and subcortical structures with high spatial precision. In healthy human volunteers, LIFU has demonstrated a favorable safety and tolerability profile across multiple studies. However, its safety and tolerability in clinical populations remains poorly characterized, representing a critical barrier to clinical translation. Here, we prospectively evaluate the safety and tolerability of LIFU targeting the left dorsal anterior insula (dAI) in patients with fibromyalgia (FM). Methods: In a single-blind, sham-controlled, within-subjects crossover design, 13 individuals with FM (43.1 +/- 13.2 years; 12 female) received 10 minutes of active LIFU (500 kHz, 1 kHz PRF, 36% duty cycle, 4.2 W/cm2 Isppa; 100 x 1-second pulse trains with a 5-second inter-train interval) targeting the left dorsal anterior insula (dAI) or sham on separate visits. Safety was evaluated through neuroradiological review of post vs. pre LIFU FLAIR MRI, quantitative voxel-wise FLAIR analysis, and patient report of symptoms (ROS). Tolerability was assessed using an experience assessment. Efficacy of the LIFU intervention was assessed using quantitative sensory testing (QST) including temporal summation of pain (TSP) and conditioned pain modulation (CPM). Results: Neuroradiological review identified no new evidence of edema, microhemorrhage, acute ischemia, or white matter injury on post-LIFU structural imaging. Quantitative FLAIR analysis using contralateral-mirror-referenced relative FLAIR (rFLAIR) showed no significant within-subject change in the stimulated beam volume (delta rFLAIR = 0.002 +/- 0.025, t(12) = 0.30, P = 0.769, Cohen's dz = 0.08). No serious adverse events were documented and ROS indicated no change due to LIFU sonication. Participants rated the procedure as comfortable and could not distinguish active from sham LIFU. LIFU did not result in statistically significant changes for TSP (p = 0.797) or CPM (p = 0.465). Conclusions: Ten minutes of LIFU targeting the left dAI was safe and well tolerated in individuals with FM, with no neuroradiological or quantitative MRI evidence of tissue effects and no serious adverse events. Blinding was preserved, and participants rated the procedure as comfortable. Although no significant changes were observed in experimental pain measures, these findings support the feasibility of targeting deep salience and pain amplification circuitry with LIFU in patients with FM and provide a foundation for adequately powered efficacy trials.

BackgroundRepeated exposure to acute antimigraine medication can promote medication overuse headache, but the mechanisms underlying this transition remain incompletely understood. We used a clinically relevant rat model of continuous sumatriptan exposure to investigate whether medication overuse is associated with persistent sensitisation of the trigeminovascular system and longer-lasting changes in brain perfusion. MethodsAdult male Sprague Dawley rats received continuous subcutaneous sumatriptan (0.6 mg/kg/day) or saline infusion for 6 days via osmotic minipumps. Periorbital and hindpaw mechanical thresholds were measured over 20 days. On day 6 and day 20, trigeminal ganglia and trigeminal nucleus caudalis were processed for immunohistochemistry for pERK, pp38, Iba-1, GFAP and NeuN. On day 20, a subgroup received sodium nitroprusside (SNP, 3 mg/kg, i.p.) to unmask latent sensitisation. Cerebral blood flow was assessed by MRI. ResultsSumatriptan induced reversible cephalic and extracephalic allodynia. Previously exposed rats showed evidence of persistent sensitisation, including enhanced biomarker and glial responses after withdrawal and following SNP challenge. pERK and pp38 expression increased in both the trigeminal ganglion and trigeminal nucleus caudalis. In the TNC, marker association shifted over time from predominantly neuronal at day 6 to greater apparent glial association at day 20. Iba-1 and GFAP expression increased after withdrawal of sumatriptan and was further enhanced by SNP challenge. Within the TNC, neuronal marker expression was greatest in the ophthalmic representation. Sumatriptan exposure also produced a persistent reduction in cerebral blood flow that remained evident after behavioural recovery. ConclusionContinuous sumatriptan exposure produces prolonged trigeminovascular neuronal and glial alterations together with persistent changes in brain perfusion. These data support a state of latent sensitisation after repeated triptan exposure and provide mechanistic insight into medication overuse headache. HIGHLIGHTSO_LIRepeated sumatriptan exposure induces reversible cephalic and extracephalic allodynia but leaves persistent trigeminovascular sensitisation after drug withdrawal. C_LIO_LIpERK and pp38 expression increase in the trigeminal ganglion and trigeminal nucleus caudalis, with the strongest regional changes seen in the ophthalmic representation of the TNC. C_LIO_LIDelayed increases in Iba-1 and GFAP in the TNC suggest that glial activation may contribute to maintenance of latent sensitisation, although the colocalisation findings are qualitative and should be interpreted cautiously. C_LIO_LIRepeated sumatriptan exposure is also associated with a persistent reduction in cerebral blood flow, indicating longer-lasting changes in brain perfusion beyond the period of overt allodynia. C_LI

Introduction Knee pain is a highly prevalent condition in the general population and is more common than knee osteoarthritis. Population-based evidence linking metabolic dysfunction to knee pain remains limited, and data on sex-specific effects are scarce. Therefore, we examined sex-specific associations between metabolic dysregulation and knee pain in a population-based cohort. Method We analyzed data from a population-based cohort of 1,512 adults (mean age 37.2 years at baseline), of whom 250 completed follow-up after a mean of 9.4 years. Metabolic dysfunction was assessed using a continuous MetS severity score (cMetS) derived from waist circumference, triglycerides, HDL cholesterol, fasting glucose, and systolic blood pressure. Knee pain at follow-up was defined using a combined measure based on a standardized question and a body manikin. Logistic regression models were used to examine associations between baseline cMetS and knee pain, including interaction analyses by sex. Results At follow-up, 28.5% of participants reported knee pain. Higher baseline cMetS was associated with increased odds of knee pain in males (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.17-1.69) but not in females (OR 0.94, 95% CI 0.84-1.07), with evidence of interaction by sex (interaction P < 0.001). Findings were consistent across sensitivity analyses. Conclusions These results indicate that metabolic dysfunction is associated with knee pain in males but not in females, suggesting sex-specific mechanisms linking metabolic dysfunction and knee pain.

Background. Lifetime exposure to trauma is associated with chronic pain. Separate studies of chronic pain and trauma report overlapping alterations in white matter microstructure, yet their distinct and cumulative effects remain unclear. Methods. White matter microstructure (fractional anisotropy [FA] and mean diffusivity [MD]) from the UK Biobank (N = 21,995) were analysed using linear mixed-effects models. First, group effects (chronic pain versus control) on white matter integrity within this cohort were established. To investigate distinct and cumulative impacts of trauma exposure at different developmental stages, main and interactive effects of group and trauma severity on FA and MD were examined in separate groups exposed to childhood maltreatment only, adulthood trauma only, and both. Sex-stratified analyses were conducted. Results. Chronic pain was associated with widespread alterations and was spatially refined to brainstem tracts and cingulum when accounting for maltreatment/trauma severity. Accounting for chronic pain, cumulative trauma severity was associated with alterations in brainstem, frontal and parietal tracts, whereas adulthood trauma showed comparable but attenuated patterns. Childhood maltreatment severity was associated with localised FA and MD reductions in brainstem tracts, sagittal stratum and superior longitudinal fasciculus. These effects were more pronounced in females than males. A chronic pain-by-maltreatment/trauma severity interaction was observed for FA in the superior cerebellar peduncle in females exposed to childhood maltreatment only. Conclusions. Distinct and interactive effects of chronic pain and maltreatment/trauma severity on white matter microstructure were evident. The findings suggest that trauma-informed care should be tailored by timing of exposure and sex in this population.

Introduction Dysmenorrhoea is highly prevalent globally and interferes with engagement in education, work, social participation, and quality of life. Although evidence suggests that sociocultural beliefs influence how menstrual pain is understood and managed, relatively little research has explored dysmenorrhoea-related knowledge and beliefs within South Africa. This study aimed to (1) determine the frequency of dysmenorrhoea, (2) assess dysmenorrhoea-related knowledge and compare knowledge between menstruating and non-menstruating individuals, and (3) explore commonly held generational, cultural, and religious beliefs related to dysmenorrhoea in a South African university cohort. Methods We analysed data collected as part of a cross-sectional survey conducted among staff and students at a South African university. Participants completed demographic questions, items assessing dysmenorrhoea-related knowledge, and an adapted Working Ability, Location, Intensity, Days of Pain, Dysmenorrhoea (WaLIDD) questionnaire. Participants were also invited to provide free-text responses describing generational, cultural, and religious beliefs about dysmenorrhoea. Quantitative data were analysed descriptively and compared between menstruating and non-menstruating participants. Free-text responses were analysed using reflexive thematic analysis. Results A total of 863 participants completed the survey, including 578 current or past menstruators. The frequency (95%CI) of dysmenorrhoea was 75.4% (71.7-78.9). Most participants were classified as having moderate (53%) or severe (31%) dysmenorrhoea on the WaLIDD scale. Awareness of dysmenorrhoea was higher among participants who had menstruated than among those who had never menstruated (80.4% vs 55.3%, p<0.001). Most participants (85.1%) reported wanting more education about dysmenorrhoea and its impact. Reflexive thematic analysis of 246 free-text responses identified five themes: (1) menstrual pain is normalised, dismissed, and expected to endure, (2) reproductive meanings attached to menstrual pain, (3) moral, spiritual, and cultural interpretations of menstrual pain, (4) negotiating competing explanations for menstrual pain, and (5) managing and controlling menstrual pain symptoms. Across themes, dysmenorrhoea was interpreted through social, cultural, reproductive, spiritual, and biomedical frameworks that shaped how pain was understood, communicated, and managed. Conclusion Dysmenorrhoea is common in this South African university cohort, and is rarely understood as a purely biological symptom. Instead, menstrual pain is understood and managed through broader social, cultural, reproductive, moral, and biomedical narratives, which shape how pain is recognised, disclosed, legitimised, and treated. These findings highlight the importance of considering sociocultural beliefs alongside clinical factors when developing menstrual health education, support strategies, and healthcare services.

Background: Midurethral sling placement is often performed during prolapse repair to treat or prevent stress urinary incontinence. However, some women experience persistent or new-onset stress or urgency urinary incontinence after surgery. It is unclear how prolapse repair, with or without a concomitant midurethral sling, alters urethral morphology and support, and how these changes relate to urinary continence outcomes. Objectives: To compare postoperative urethral morphology (dimensions, angles, shape) and support (position, mobility) after transvaginal prolapse repair with vs without a concurrent midurethral sling, and to explore associations between postoperative urethral characteristics and urinary outcomes (stress, urgency symptoms). Study Design: This ancillary analysis used magnetic resonance imaging and urinary outcome data from the Defining Mechanisms of Anterior Vaginal Wall Descent Study conducted across 8 clinical sites within the United States Pelvic Floor Disorders Network. Eighty-two women (median age, 65 years) underwent transvaginal prolapse repair (vaginal mesh hysteropexy or vaginal hysterectomy with uterosacral ligament suspension) with or without a concurrent midurethral sling between April 2013 and February 2015. Postoperative imaging at rest and during strain was performed 30-42 months after surgery (or earlier if they chose reoperation) between June 2014 and May 2018. Prolapse recurrence, defined as descent beyond the vaginal introitus during strain, was recorded. The urethra was segmented from postoperative scans to create 3-dimensional models for measuring urethral diameters, length, surface area, volume, angles, shape (principal component scores from a statistical shape model), position, and mobility (rest-to-strain displacement). Preoperative and 24-48-month postoperative urinary continence outcomes were assessed using validated questionnaires: the Urogenital Distress Inventory, Urinary Impact Questionnaire, and the Incontinence Severity Index. Comparisons of urethral and urinary outcomes by (1) midurethral sling and (2) stress urinary incontinence were made using Wilcoxon rank-sum tests, principal component analysis, and multivariate models as appropriate. Associations between urethral and urinary outcomes were evaluated with Spearmans rank correlation. Results: Forty-six women (22 hysteropexy, 24 hysterectomy) were in the sling group, and 36 (19 hysteropexy, 17 hysterectomy) were in the no-sling group. Among the 48 women without prolapse recurrence (28 sling, 20 no-sling), those with a sling (vs without) had larger urethral dimensions (all P<.03), a more anterior-superior position of the proximal urethra (indicating better bladder neck support) (P=.04), a straighter urethral shape (P=.006), and reported less bothersome postoperative stress incontinence (P=.02). Overall, 14 women (17%) experienced postoperative stress incontinence. Stress urinary incontinence was linked to a more acute proximal urethral sagittal angle (more aligned with axial plane) (P=.01), and a lower proximal urethra position (P=.04) and mid-urethra position (P=.03). Poorer stress and urgency urinary outcomes were associated with a shorter urethral length (P=.01), a more posterior-inferior urethral position (all P<.05), increased C or S-shaped urethral concavity (P=.008; P=.006), and smaller rest-to-strain displacement of the proximal (P=.03) and distal (P=.009) urethra. Conclusions: Urethral morphology and support differed with concomitant midurethral sling (vs no sling) and stress urinary incontinence after vaginal surgery. Urethral characteristics were also associated with postoperative urinary symptoms. Urethral configuration may influence urinary outcomes and could be considered during prolapse and stress urinary incontinence repairs.

Introduction: Reduced or lost sensation and movement after a spinal cord injury (SCI) impairs the brain s ability to accurately localize paralyzed body parts, causing deficits in its internal body map, or mental body representations (MBR). These deficits hinder functional recovery and contribute to neuropathic pain. Medications for neuropathic pain are often ineffective and carry side effects. Our pilot trials found that in-person Cognitive Multisensory Rehabilitation (CMR), a physical therapy restoring MBR, led to prolonged pain reduction, improved sensorimotor function, and enhanced brain function, to greater extent than adaptive fitness. To explore more accessible interventions for those in rural areas or with transportation challenges, we examined whether 12 weeks of remotely delivered CMR or exercise would (1) improve function and reduce pain; (2) increase brain activity and connectivity related to sensorimotor function and MBR in adults with SCI. Methods: Of 19 adults with SCI who consented, 15 (51+/-15 years old, 8+/-10 years post-SCI) were randomized to 12 weeks of remotely delivered CMR or exercise (45min, 3x/week). Eight reported neuropathic pain equal or greater than 3/10. The Numeric Pain Rating Scale (NPRS), ASIA Impairment Scale (AIS), and Neuromuscular Recovery Scale (NRS) assessed pain and sensorimotor function at baseline, post-intervention, and 6-month follow-up. Functional MRI included resting-state and four tasks: imagining feeling the left leg, imagining moving the left leg, whole-body movement imagery, and a sensation task. Results: After CMR (n=8), participants improved on AIS (large effect sizes: touch: d=1.30; pinprick: d=1.21; lower limb motor function: d=1.83). Exercise (n=7) produced smaller improvements (touch: d=0.35; pinprick: d=0.36; lower limb motor function: d=0.80). CMR showed greater NRS effect sizes (core: d=1.48; upper limb: d=0.69; lower limb: d=1.25) than exercise (core: d=0.31; upper limb: d=0.74; lower limb: d=0.83). Benefits persisted at follow-up for both AIS and NRS, especially in the CMR group. Highest neuropathic pain intensity decreased in both groups post-intervention (CMR: d=-0.61; exercise: d=-0.73) and at 6-month follow-up (CMR: d=-0.55; exercise: d=-0.55). Unlike previous studies, group effects for CMR were not found due to high heterogeneity. Increased task-based activation, including in the lateral occipital cortex involved in visual body perception and spatial awareness, was seen for the exercise group (n=5). Discussion: These preliminary results support the potential of remotely delivered CMR and exercise to improve function and reduce neuropathic pain in adults with SCI, highlighting the need for larger trials. Clinicaltrial.gov: NCT05870189

ObjectiveNeurogenic lower urinary tract dysfunction (NLUTD) impairs bladder control and remains difficult to treat. We aim to define how electrical stimulation (ES) parameters of the external urethral sphincter (EUS) affect urinary leakage thresholds to guide neuromodulation strategies for NLUTD. MethodsWe performed direct EUS stimulation in anesthetized rats using charge-balanced biphasic pulses while systematically varying current amplitude (0.5-3.0 mA), frequency (20-100 Hz), and pulse duration (0.5-3 ms). Urine leakage thresholds were mapped across the multidimensional parameter space. ResultsStimulation parameters exhibited strong nonlinear interdependence in determining leakage onset. At a fixed pulse duration, higher current amplitudes required lower stimulation frequencies to evoke leakage. Increasing pulse duration substantially reduced both current and frequency thresholds. Age and sex caused modest shifts in absolute thresholds but did not alter the fundamental parameter-response relationships. ConclusionPulse duration, current amplitude, and frequency jointly govern urinary leakage thresholds, with pulse duration serving as the dominant modulator of stimulation efficiency. SignificanceThis work establishes a quantitative framework for charge-efficient stimulation parameter selection, enabling the design of energy-aware, precision neuromodulation protocols and implantable systems for NLUTD rehabilitation.