BACKGROUNDPostpartum depression (PPD) is a common complication after childbirth, especially in primiparae.OBJECTIVE(S)This trial sought to evaluate whether prophylactic administration of esketamine during the perinatal period could prevent PPD in primiparae without predisposition to prenatal depression.DESIGNA prospective, double-blind, multicentre, randomised controlled trial.SETTINGThree academic hospitals.PATIENTSPrimiparae scheduled for elective caesarean section with an Edinburgh Postnatal Depression Scale (EPDS) score less than 10.INTERVENTIONSPostnatal women were randomly assigned to receive either i.v. esketamine in a single dose of 0.25 mg kg-1 followed by 80 mg of esketamine as an adjunct to 24-h patient-controlled intravenous analgesia (PCIA). Women in the control group received an equal volume of saline.MAIN OUTCOME MEASURESThe primary outcome was the total incidence of PPD within 3 months postpartum. Secondary outcomes included postoperative EPDS scores, numeric rating scale scores, sufentanil consumption, the number of effective presses for postoperative intravenous analgesia and adverse events.RESULTSA total of 322 patients were included in the modified intention-to-treat analysis. The total incidence of PPD in the esketamine group (11.59%) was significantly less than the control group (20.89%) [adjusted relative ratio (RR), 0.57; 95% CI, 0.35 to 0.94; P = 0.028] as was the incidence at 7 days postpartum (4.89 vs. 15.19%; adjusted RR, 0.32; 95% CI, 0.15 to 0.72; P = 0.005). However, there were no significant differences in PPD incidence and EPDS scores at 1, 2 and 3 months postpartum, respectively. Several mild central nervous events, such as dizziness (10.98%), hallucination (10.37%) and dissociation (5.49%), were observed during esketamine treatment.CONCLUSIONPeri-operative adjunctive administration of esketamine is relatively safe and can prevent PPD in primi-parae without predisposition to prenatal depression in the short term.TRIAL REGISTRATIONClinicaltrials.gov. Identifier: NCT04860661

BACKGROUND:Idiopathic trigeminal neuralgia (ITN) affects approximately 0.16% to 0.3% of the population, with severe complications occurring in 15% of cases. Existing treatments often yield suboptimal outcomes. CASE REPORT:This study evaluates the clinical efficacy of Gasserian ganglion stimulation (GGS) for ITN management in 2 patients. GGS led to significant symptom improvement in both patients, with one patient achieving complete remission. Compared to conventional therapies, GGS demonstrated a 30% higher efficacy rate, suggesting its potential as a superior therapeutic option. However, limitations include the small sample size and the mandibular nerve branch restriction. CONCLUSIONS:Despite the constraints, our findings are noteworthy, as previous GGS research has primarily focused on treatment failure or nerve damage. Our study suggests GGS could transform ITN management by providing a more effective and less invasive treatment alternative.

Trigeminal neuralgia (TN) is a severe neuropathic pain disorder in which peripheral neurovascular compression alone does not fully explain the associated central pain manifestations. Although diffusion tensor imaging studies have reported white matter (WM) alterations in TN, findings have been heterogeneous, partly due to limited sensitivity to complex fibre architecture. Fixel‑based analysis (FBA) enables fibre‑specific assessment of WM microstructural and macrostructural properties and may provide improved anatomical and biological specificity. This cross‑sectional study included 65 patients with primary TN and 42 healthy controls (HCs). Diffusion MRI data were analyzed using FBA to quantify fibre density (FD), fibre‑bundle cross‑section (FC), and the combined metric (FDC). Group differences were assessed using connectivity‑based fixel enhancement with family‑wise error correction. Associations between fixel‑based metrics and clinical variables were subsequently examined. Compared to controls, patients with TN showed reduced FD in the splenium of the corpus callosum, fornix, and superior cerebellar peduncle. Reductions in FC were observed in the corticospinal tracts (CST), inferior fronto‑occipital, and inferior longitudinal fasciculi. Decreased FDC involved the bilateral CST, middle cerebellar peduncle, and anterior spinocerebellar tract (all FWE‑corrected P < 0.05). Pain severity was associated with reduced FC and FDC in motor and cerebellar pathways, whereas FD showed no consistent associations. Age‑related reductions in FC and FDC were present in the TN group but not in HCs. TN is characterized by distributed, tract‑specific WM alterations extending beyond trigeminal pathways to involve motor, cerebellar, interhemispheric, and associative networks. The selective association between pain severity and macrostructural bundle measures supports a network‑level model of TN and suggests that chronic neuropathic pain is linked to large‑scale WM alterations rather than isolated axonal changes. FBA provides a sensitive framework for investigating clinically relevant central mechanisms in TN.

BACKGROUND:Trigeminal neuralgia (TN) has traditionally been attributed to peripheral neurovascular compression at the trigeminal nerve root entry zone. Recent evidence, however, suggests central mechanisms may contribute to disease pathogenesis. We investigated whether glymphatic system dysfunction occurs in TN and contributes to its pathophysiology. METHODS:This cross-sectional study enrolled 71 patients with classical TN and 52 age-matched healthy controls. All participants underwent comprehensive multimodal MRI assessment, including: (1) diffusion tensor imaging along perivascular spaces (DTI-ALPS) index measurement, (2) free water fraction (FWF) mapping, (3) perivascular space (PVS) burden quantification, and (4) choroid plexus (CP) volumetric analysis using deep learning segmentation to evaluate glymphatic system function. RESULTS:TN patients demonstrated selective glymphatic dysfunction characterized by reduced DTI-ALPS index and increased FWF. Compared to controls, patients showed significantly reduced DTI-ALPS indices (1.34 ± 0.12 vs. 1.41 ± 0.13; p = 0.027) and elevated FWF values (0.34 ± 0.04 vs. 0.32 ± 0.03, p = 0.027), indicating compromised cerebrospinal fluid dynamics. In contrast, structural measures including PVS burden and CP volumes remained comparable between groups (all p > 0.05). Age-related analysis revealed significant correlations with DTI-ALPS decline (ρ = -0.286, p = 0.020) and FWF elevation (ρ = 0.658, p < 0.001), suggesting progressive glymphatic deterioration with aging. However, there is a lack of correlation between glymphatic indicators and pain intensity as well as disease course. CONCLUSIONS:These findings indicate that TN is associated with functional impairment of the glymphatic system in the absence of overt perivascular structural abnormalities. This dissociation between functional and structural glymphatic measures challenges conventional neuroimaging paradigms in TN and highlights a previously underrecognized central mechanism.

BACKGROUND AND PURPOSE:Morphine is among the most powerful analgesic, but its long-term use can cause tolerance. Synaptic ATP supply is critical for maintaining synaptic transmission. Microtubule-based mitochondrial transport ensures synaptic energy supply. How synaptic energy changes with morphine and the role of microtubule tracks in synaptic mitochondrial energy supply remain elusive. Chronic morphine treatment can destroy microtubule cytoskeletons. We investigated the effect of the microtubule cytoskeleton on synaptic mitochondrial energy supply and the mechanism of microtubule dynamics after morphine exposure. EXPERIMENTAL APPROACH:Rats were treated with long-term morphine and the effect on thermal pain thresholds was evaluated by the tail-flick latency test. Various antagonists and agonists were used elucidated the role and mechanism of synaptic mitochondrial energy supply and microtubules in morphine tolerance in vivo and in SH-SY5Y cells. KEY RESULTS:Chronic morphine treatment reduced synaptic mitochondrial ATP production. Improving mitochondrial oxidative phosphorylation (OXPHOS) alleviated the downregulation of synaptic ATP levels. Microtubule-stabilizing agents prevented microtubule disruption and ameliorated synaptic energy deficit via microtubule-based microtubule transport. In SH-SY5Y cells, morphine exposure reduced microtubule expression. And re-opening the synaptic Ca2+ channel by agonist alleviated microtubule decrease by calcium/calmodulin-dependent protein kinase 2 (CAMKK2)/AMP-activated protein kinase (AMPK) pathway. CONCLUSION AND IMPLICATIONS:This study demonstrates that the microtubule cytoskeleton regulated by the Ca2+-CAMKK2-AMPK axis is critical for synaptic mitochondrial transport and ATP production, explaining an interplay between chronic morphine-induced abnormal neuroadaptation and synaptic energetic dysfunction. These findings implicated a potential clinical strategy for prolonging the opioid antinociceptive effect during long-term pain control.

Opioids are the most effective option for severe pain. However, it is well documented that the side effects associated with prolonged opioid use significantly constrain dosage in the clinical setting. Recently, researchers have concentrated on the development of biased opioid receptor agonists that preferentially activate the G protein signaling pathway over β-arrestin signaling. This approach is based on the hypothesis that G protein signaling mediates analgesic effects, whereas β-arrestin signaling is implicated in adverse side effects. Although certain studies have demonstrated that the absence or inhibition of β-arrestin signaling can mitigate the incidence of side effects, recent research appears to challenge these earlier findings. In-depth investigations into biased signal transduction of opioid receptor agonists have been conducted, potentially offering novel insights for the development of biased opioid receptors. Consequently, this review elucidates the contradictory roles of β-arrestin signaling in the adverse reactions associated with opioid receptor activation. Furthermore, a comparative analysis was conducted to evaluate the efficacy of the classic G protein-biased agonists, TRV130 and PZM21, relative to the traditional non-biased agonist morphine. This review aims to inform the development of novel analgesic drugs that can optimize therapeutic efficacy and safety, while minimizing adverse reactions to the greatest extent possible.

Purpose:Vitamin D is important for host immunity and a large proportion of herpes zoster patients experience vitamin D insufficiency (VDI). However, the role of vitamin D in herpetic neuralgia (HN) remains controversial. This study aims to explore the potential relationship between vitamin D status and HN characteristics. Patients and methods:This prospective observational cohort study was conducted from February 2024 to November 2024 with 160 HN patients within 12 weeks after rash onset. Demographic and clinical data of patients were collected. The serum 25-hydroxyvitamin D level, triglyceride and other laboratory parameters were measured at patients' admission. Comprehensive pain evaluations including the Brief Pain Inventory (BPI), 11-point Numerical Rating Scale (NRS) and Douleur Neuropathique 4 questionnaires were performed at admission, as well as 1, 2, and 3 months after treatment. Results:VDI was prevalent (121 VDI, 39 VDS) in the cohort. Although no significant correlation emerged between vitamin D levels and BPI or NRS scores, Female (n = 82, odds ratio [OR] 2.80, 95% CI 1.30-6.33, P < 0.05) and high serum triglyceride level (OR 3.20, 95% CI 1.41-8.86, P < 0.05) were identified as independent predictors of VDI. Female patients exhibited a significant negative correlation between vitamin D status and burning pain (Spearman's ρ = -0.347, P < 0.001) and a concomitantly lower early pain relief rate compared to males, in whom the correlation was non-significant (n = 78, ρ = 0.7, P > 0.05). Conclusion:Low vitamin D levels are common in HN patients. The sex-specific association between VDI and burning pain, as well as short-term prognosis, Triglyceride levels served as a predictive indicator for VDI in HN patients. Future studies are needed to elucidate the underlying mechanisms of the pain-vitamin D association specifically in female patients.

Chronic neuropathic pain is frequently accompanied by cognitive impairment, which seriously influence the quality of the patient's life. The stability of synapse is the basis for maintaining neural circuits. And overactive microglia can prune normal synapses through phagocytosis, leading to cognitive impairment. This study aims to investigate the role of microglial synaptic pruning in chronic neuropathic pain-induced cognitive impairment, and explore the mechanisms of microglial activation through Interleukin-17A (IL-17A) activation and copper accumulation. We found that chronic neuropathic pain resulted in cognitive impairment, and microglial activation, abnormal microglial synaptic pruning, synaptic loss in hippocampus. Depleting microglia ameliorated the activations of microglial and complement pathways, and rescued synaptic loss and cognitive impairment. The copper was accumulated in hippocampus, and copper chelator tetrathiomolybdate (TTM) inhibited microglial and complement activations and rescued synaptic loss and cognitive impairment. Further research found that suppressing mitochondrial oxidative stress response inhibited copper accumulation-induced microglial activation. Finally, IL-17A was found to be increased in serum and hippocampus. IL-17A neutralization antibody (anti-IL-17A Abs) alleviated copper accumulation by inhibiting six transmembrane epithelial antigens of prostate 4 (STEAP4) / copper transporter 1 (CTR1), and inhibited microglial and complement activation, interrupting abnormal synaptic elimination and ameliorating cognitive impairment. Our results suggest that IL-17A can induce copper accumulation in microglia through STEAP4/CTR1, the latter promotes complement-mediated microglia synaptic pruning, reducing synapse number, and ultimately resulting in cognitive impairment. These provide a new potential therapeutic target for the treatment of chronic neuropathic pain-induced cognitive impairment.

Chronic pain is an extremely prevalent healthcare issue that has a profound impact on individuals and society. Sex and sex hormones regulate the pain threshold differently in males and females in pain processing. However, the regulatory mechanisms of sex differences in response to painful stimuli are still unclear, which contributes to the difficulty of analgesic drug development. Interleukins mediate neuroinflammation and are involved in the development of chronic pain. Recent studies have found that sex and sex hormones are involved in the regulation of pain thresholds by interleukins. Most previous studies used male animals to study the analgesic effects of treatments due to the complexity of estrogen. This review summarizes studies that used only female animals or both sexes to examine the impact of sex on interleukin-regulated chronic pain, to provide a theoretical basis for the development of more targeted precision medicines for pain.

BACKGROUND:Trigeminal neuralgia (TN) involves complex neural network alterations beyond the trigeminal system. Network Control Theory (NCT) offers a novel framework to quantify how brain network architecture constrains neural dynamics. This study investigated structural network controllability in TN to elucidate disease-specific alterations in brain network control properties. METHODS:Eighty-two TN patients and 42 healthy controls (HCs) underwent diffusion tensor imaging. Structural connectomes were constructed using deterministic tractography and parcellated with the Brainnetome atlas. Average controllability (AC), reflecting the ease of driving networks toward accessible states, and modal controllability (MC), indicating the capacity for difficult state transitions, were calculated at whole-brain, network, and regional levels. Age-related effects on controllability were examined. RESULTS:TN patients demonstrated significantly reduced whole-brain AC (P = 0.009) and increased MC (P = 0.009) compared to HCs. Network-level analyses revealed decreased AC and increased MC in the dorsal attention network (P = 0.018) and default mode network (P = 0.009), with reduced AC in subcortical regions (P = 0.041). No regional differences survived False Discovery Rate correction. Notably, controllability metrics correlated significantly with age in TN patients across multiple networks, whereas HCs showed no age-related correlations. Neither pain laterality nor neurovascular compression influenced controllability patterns. CONCLUSIONS:TN is characterized by aberrant network controllability, manifesting as reduced efficiency in routine state transitions and increased energy requirements for network control. The unique age-controllability relationship in TN suggests disease-specific alterations in network dynamics distinct from normal aging. These findings establish NCT as a valuable framework for understanding TN pathophysiology and highlight the disorder's network-level rather than focal nature.

AIMS:Communication within glial cells acts as a pivotal intermediary factor in modulating neuroimmune pathology. Meanwhile, an increasing awareness has emerged regarding the detrimental role of glial cells and neuroinflammation in morphine tolerance (MT). This study investigated the influence of crosstalk between astrocyte and microglia on the evolution of morphine tolerance. METHODS:Sprague-Dawley rats were intrathecally treated with morphine twice daily for 9 days to establish morphine-tolerant rat model. Tail-flick latency test was performed to identify the analgesic effect of morphine. The role of microglia, astrocyte and C3-C3aR axis in morphine tolerance were elucidated by real-time quantitative polymerase chain reaction, Western blot, and immunofluorescence. RESULTS:Chronic morphine treatment notably promoted the activation of microglia, upregulated the production of proinflammatory mediators (interleukin-1 alpha (IL-1α), tumor necrosis factor alpha (TNFα), and complement component 1q (C1q)). Simultaneously, it programed astrocytes to a pro-inflammatory phenotype (A1), which mainly expresses complement 3 (C3) and serping1. PLX3397 (a colony-stimulating factor 1 receptor (CSF1R) inhibitor), Compstain (a C3 inhibitor) and SB290157(a C3aR antagonist) could reverse the above pathological process and alleviate morphine tolerance to different extents. CONCLUSION:Our findings identify C3-C3aR axis as an amplifier of microglia-astrocyte crosstalk, neuroinflammation and a node for therapeutic intervention in morphine tolerance.

Morphine tolerance caused by long-term use of morphine is a major medical problem. Neuroinflammation plays an important role in morphine tolerance, and currently no drugs have been found for clinical use to alleviate neuroinflammation during morphine tolerance. Cordycepin is the main active component of fungus cordycepin militaris, has been demonstrated to have anti-oxidative stress and anti-inflammatory properties in various diseases. In this study, we established a rat model of morphine tolerance, examined the effect of cordycepin on the development of morphine tolerance, and evaluated its potential regulatory mechanisms. We found that cordycepin treatment ameliorated the development of morphine tolerance, improved mitochondrial damage associated with ferroptosis, by reducing the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and Fe2+, increasing superoxide dismutase (SOD) and glutathione (GSH) levels, and decreasing the secretion of pro-inflammatory factors (IL-1β, IL-6, and TNF-α). Besides, cordycepin upregulated the expression of SIRT1, SLC7A11 and GPX4. Further research found that the above effects of cordycepin on morphine-tolerant rats were abolished by SIRT1 selective inhibitor EX-527. Thus, these findings indicated that cordycepin could ameliorate the development of morphine tolerance by inhibiting spinal cord ferroptosis and inflammation via targeting SIRT1. Collectively, these results demonstrated the protective effects of cordycepin and highlighted its therapeutic potential as a drug component for morphine tolerance treatment and prevention.

Background and Hypothesis Despite the well-documented structural and functional brain changes in schizophrenia, the potential role of glymphatic dysfunction remains largely unexplored. This study investigates the glymphatic system's function in schizophrenia, utilizing diffusion tensor imaging (DTI) to analyze water diffusion along the perivascular space (ALPS), and examines its correlation with clinical symptoms.Study Design A cohort consisting of 43 people with schizophrenia and 108 healthy controls was examined. We quantified water diffusion metrics along the x-, y-, and z-axis in both projection and association fibers to derive the DTI-ALPS index, a proxy for glymphatic activity. The differences in the ALPS index between groups were analyzed using a 2-way ANCOVA controlling for age and sex, while partial correlations assessed the association between the ALPS index and clinical variables.Study Results People with schizophrenia showed a significantly reduced DTI-ALPS index across the whole brain and within both hemispheres (F = 9.001, P = .011; F = 10.024, P = .011; F = 5.927, P = .044; false discovery rate corrected), indicating potential glymphatic dysfunction in schizophrenia. The group by cognitive performance interaction effects on the ALPS index were not observed. Moreover, a lower ALPS index was associated with poorer cognitive performance on specific neuropsychological tests in people with schizophrenia.Conclusion Our study highlights a lower ALPS index in schizophrenia, correlated with more pronounced cognitive impairments. This suggests that glymphatic dysfunction may contribute to the pathophysiology of schizophrenia, offering new insights into its underlying mechanisms.

Background Neuropathic pain typically arises following injury or damage to the somatic nervous system, a chronic and debilitating condition with complex mechanisms. Synaptic plasticity, the changes in neuronal connection strength, has long been recognized to participate in the progression of neuropathic pain. Nevertheless, there has been a lack of bibliometric research on synaptic plasticity in neuropathic pain. Methods A total of 688 papers were retrieved from the WoSCC databases and the software of Citespace, VOSviewer1.6.18 and the Online Analysis Platform of Literature Metrology (https://bibliometric.com/) were used to conduct bibliometric analysis. Results The study provided an overview of research in the field and identified the most productive countries, institutions and authors. By analyzing the timelines of co-cited reference clusters and the citation bursts of co-cited references and keywords, it is evident that glia-neuron interaction and extracellular matrix mediated synaptic plasticity in neuropathic pain. Additionally, the up-to-date research trend and the constantly being discovered neurotransmitter and receptors were worth more attention. Two recent focal points in this field include microglia-related neuroinflammation and the central nucleus of the amygdala (CeA) plasticity in pain related emotional distress. Conclusions The study provides a comprehensive overview of the research on neuropathic pain and synaptic plasticity through bibliometrics and knowledge-map analyses. It aims to offer an updated perspective and suggest future directions for scientific researchers in further investigations.

Chronic pain has been proven to be an independent disease, other than an accompanying symptom of certain diseases. Interleukin-18 (IL-18), a pro-inflammatory cytokine with pleiotropic biological effects, participates in immune modulation, inflammatory response, tumor growth, as well as the process of chronic pain. Compelling evidence suggests that IL-18 is upregulated in the occurrence of chronic pain. Antagonism or inhibition of IL-18 expression can alleviate the occurrence and development of chronic pain. And IL-18 is located in microglia, while IL-18R is mostly located in astrocytes in the spinal cord. This indicates that the interaction between microglia and astrocytes mediated by the IL-18/IL-18R axis is involved in the occurrence of chronic pain. In this review, we described the role and mechanism of IL-18 in different types of chronic pain. This review provides strong evidence that IL-18 is a potential therapeutic target in pain management.

BACKGROUND:Morphine tolerance has been a challenging medical issue. Neuroinflammation is considered as a critical mechanism for the development of morphine tolerance. Bromodomain-containing protein 4 (BRD4), a key regulator in cell damage and inflammation, participates in the development of chronic pain. However, whether BRD4 is involved in morphine tolerance and the underlying mechanisms remain unknown.METHODS:The morphine-tolerant rat model was established by intrathecal administration of morphine twice daily for 7 days. Behavior test was assessed by a tail-flick latency test. The roles of BRD4, pyroptosis, microglia polarization and related signaling pathways in morphine tolerance were elucidated by Western blot, real-time quantitative polymerase chain reaction, and immunofluorescence.RESULTS:Repeated morphine administration upregulated BRD4 level, induced pyroptosis, and promoted microglia M1-polarization in spinal cord, accompanied by the release of proinflammatory cytokines, such as TNF-α and IL-1β. JQ-1, a BRD4 antagonist, alleviated the development of morphine tolerance, diminished pyroptosis and induced the switch of microglia from M1 to M2 phenotype. Mechanistically, stimulator of interferon gene (STING)- interferon regulatory factor 3 (IRF3) pathway was activated and the protective effect of JQ-1 against morphine tolerance was at least partially mediated by inhibition of STING-IRF3 pathway.CONCLUSION:This study demonstrated for the first time that spinal BRD4 contributes to pyroptosis and switch of microglia polarization via STING-IRF3 signaling pathway during the development of morphine tolerance, which extend the understanding of the neuroinflammation mechanism of morphine tolerance and provide an alternative strategy for the precaution against of this medical condition.

Background Diabetes mellitus (DM) increases the risk of developing tuberculosis (TB), and optimal glycemic control has been shown to reduce the risk of complications and improve the TB treatment outcomes in patients with DM. Objective This study aims to investigate the role of glycemic control in improving TB treatment outcomes among patients with DM. Methods MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases were searched for randomized controlled trials (RCTs) assessing the impact of oral glycemic control in patients with TB who have DM. Outcomes of interest were radiological findings, treatment success, sputum positivity, and mortality. Evaluations were reported as risk ratios (RRs) with 95% CIs using weighted random-effects models. Results The analysis included 6919 patients from 7 observational studies. Our meta-analysis showed significant differences between patients with optimal glycemic control and those with poor glycemic control with regard to improved treatment outcomes (RR 1.13, 95% CI 1.02-1.25; P=.02; I²=65%), reduced sputum positivity (RR 0.23, 95% CI 0.09-0.61; P=.003; I²=66%), and fewer cavitary lesions (RR 0.59, 95% CI 0.51-0.68; P<.001; I²=0%) in radiological findings. There was no significant difference between the 2 groups in terms of mortality (RR 0.57, 95% CI 0.22-1.49; P=.25; I²=0%), multilobar involvement (RR 0.57, 95% CI 0.22-1.49; P=.25; I²=0%) on radiologic examination, and upper lobe (RR 0.94, 95% CI 0.76-1.17; P=.58; I²=0%) and lower lobe (RR 1.05, 95% CI 0.48-2.30; P=.91; I²=75%) involvement on radiologic examination. Conclusions We concluded that optimal glycemic control is crucial for reducing susceptibility, minimizing complications, and improving treatment outcomes in patients with TB with DM. Emphasizing effective health management and health care strategies are essential in achieving this control. Integrating comprehensive care among patients with TB with DM will enhance patient outcomes and alleviate the burden of disease in this population. Trial Registration PROSPERO CRD42023427362; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=427362