Environmental enrichment alleviates hyperalgesia by modulating central sensitization in a nitroglycerin-induced chronic migraine model of mice.

BACKGROUND: Chronic migraine (CM) is a debilitating neurofunctional disorder primarily affecting females, characterized by central sensitization. Central sensitization refers to the enhanced response to sensory stimulation, which involves changes in neuronal excitability, synaptic plasticity, and neurotransmitter release. Environmental enrichment (EE) can increase the movement, exploration, socialization and other behaviors of mice. EE has shown promising effects in various neurological disorders, but its impact on CM and the underlying mechanism remains poorly understood. Therefore, the purpose of this study was to determine whether EE has the potential to serve as a cost-effective intervention strategy for CM. METHODS: A mouse CM model was successfully established by repeated administration of nitroglycerin (NTG). We selected adult female mice around 8 weeks old, exposed them to EE for 2 months, and then induced the CM model. Nociceptive threshold tests were measured using Von Frey filaments and a hot plate. The expression of c-Fos, calcitonin gene-related peptide (CGRP) and inflammatory response were measured using WB and immunofluorescence to evaluate central sensitization. RNA sequencing was used to find differentially expressed genes and signaling pathways. Finally, the expression of the target differential gene was investigated. RESULTS: Repeated administration of NTG can induce hyperalgesia in female mice and increase the expression of c-Fos and CGRP in the trigeminal nucleus caudalis (TNC). Early exposure of mice to EE reduced NTG-induced hyperalgesia in CM mice. WB and immunofluorescence revealed that EE inhibited the overexpression of c-Fos and CGRP in the TNC of CM mice and alleviated the inflammatory response of microglia activation. RNA sequencing analysis identified that several central sensitization-related signaling pathways were altered by EE. VGluT1, a key gene involved in behavior, internal stimulus response, and ion channel activity, was found to be downregulated in mice exposed to EE. CONCLUSION: EE can significantly ameliorate hyperalgesia in the NTG-induced CM model. The mechanisms may be to modulate central sensitization by reducing the expression of CGRP, attenuating the inflammatory response, and downregulating the expression of VGluT1, etc., suggesting that EE can serve as an effective preventive strategy for CM.

Central sensitization significantly deteriorates functionality and the interpretation of self-reported disease activity in primary Sjögren's syndrome.

BACKGROUND: Central sensitization has a major role in health-related parameters in musculoskeletal conditions. There is still a lack of understanding regarding the impact of central sensitization on the interpretation of disease activity and functional disability in primary Sjögren's syndrome (pSS). METHODS: The Central Sensitization Inventory (CSI) was used to screen for central sensitization. Disease-related parameters, including objective tests, medication use, the EULAR SS Patient Reported Index (ESSPRI), and the EULAR SS Disease Activity Index (ESSDAI), were assessed. Functionality, quality of life, sleep, and mental health were evaluated by the Health Assessment Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), Jenkins Sleep Evaluation Scale (JSS), and Hospital Anxiety and Depression Scale (HADS), respectively. The effect of central sensitization on functionality and disease activity measures was assessed by regression analyses. RESULTS: The frequency of central sensitization was 65% in patients with pSS (n = 60). Patients with central sensitization had higher HAQ-DI, ESSPRI, HADS, and JSS and lower SF-36 subdomain scores (p < 0.05 for all). A significant positive correlation was observed between the CSI score and the ESSPRI, JSS, HAQ-DI, and HADS scores (Spearman's rho ranging from 0.342 to 0.739). The multiple regression analysis indicated that CSI was independently associated with HAQ-DI (adjusted R2 = 0.19, B = 0.01) and ESSPRI (adjusted R2 = 0.45, B = 0.08) (p < 0.001 for all). CONCLUSION: This study confirms that central sensitization has a major impact on functionality and the interpretation of self-reported disease activity in pSS. When devising strategies for the management of patients with pSS, it is crucial to consider these close relationships. Key Points • The frequency of central sensitization accompanying primary Sjögren's syndrome is considerable. • Central sensitization was independently associated with functionality and self-reported disease activity assessment. • This close association leads to challenges in functionality, evaluating treatment response, and planning or switching between therapies in primary Sjögren's syndrome.

Electroacupuncture improves allodynia and central sensitization via modulation of microglial activation associated P2X4R and inflammation in a rat model of migraine.

Background: Recent studies have demonstrated that activated microglia were involved in the pathogenesis of central sensitization characterized by cutaneous allodynia in migraine. Activation of microglia is accompanied by increased expression of its receptors and release of inflammatory mediators. Acupuncture and its developed electroacupuncture (EA) have been recommended as an alternative therapy for migraine and are widely used for relieving migraine-associated pain. However, it remains rare studies that show whether EA exerts anti-migraine effects via inhibiting microglial activation related to a release of microglial receptors and the inflammatory pathway. Therefore, this study aimed to investigate EA' ability to ameliorate central sensitization via modulation of microglial activation, microglial receptor, and inflammatory response using a rat model of migraine induced by repeated epidural chemical stimulation. Methods: In the present study, a rat model of migraine was established by epidural repeated inflammatory soup (IS) stimulation and treated with EA at Fengchi (GB20) and Yanglingquan (GB34) and acupuncture at sham-acupoints. Pain hypersensitivity was further determined by measuring the mechanical withdrawal threshold using the von-Frey filament. The changes in c-Fos and ionized calcium binding adaptor molecule 1 (Ibal-1) labeled microglia in the trigeminal nucleus caudalis (TNC) were examined by immunflurescence to assess the central sensitization and whether accompanied with microglia activation. In addition, the expression of Ibal-1, microglial purinoceptor P2X4, and its associated inflammatory signaling pathway mediators, including interleukin (IL)-1ß, NOD-like receptor protein 3 (NLRP3), and Caspase-1 in the TNC were investigated by western blot and real-time polymerase chain reaction analysis. Results: Allodynia increased of c-Fos, and activated microglia were observed after repeated IS stimulation. EA alleviated the decrease in mechanical withdrawal thresholds, reduced the activation of c-Fos and microglia labeled with Ibal-1, downregulated the level of microglial purinoceptor P2X4, and limited the inflammatory response (NLRP3/Caspase-1/IL-1ß signaling pathway) in the TNC of migraine rat model. Conclusions: Our results indicate that the anti-hyperalgesia effects of EA ameliorate central sensitization in IS-induced migraine by regulating microglial activation related to P2X4R and NLRP3/IL-1ß inflammatory pathway.

Is the Central Sensitization Inventory (CSI) associated with quantitative sensory testing (QST)? A systematic review and meta-analysis.

Central sensitization (CS) involves an amplification of neural processing within the central nervous system that can result in widespread pain patterns and hypersensitivity to stimuli. The Central Sensitization Inventory (CSI) and various quantitative sensory testing (QST) methods purport to assess clinical markers of CS. The purpose of this systematic review and meta-analysis was to summarize and quantify the associations between total CSI scores and QST measures from previous studies. A systematic search identified 39 unique studies that were deemed eligible for the systematic review and 33 studies for meta-analyses (with 3314 subjects and 154 effect sizes), including five QST modalities: conditioned pain modulation, temporal summation, pressure pain threshold, heat pain threshold, and cold pain threshold. The meta-analysis yielded statistically significant CSI-QST correlations in total subject samples for all five QST modalities. The strongest associations were identified between CSI scores and pain threshold testing, especially pressure pain threshold, in which 51% of effects sizes, from 29 studies and 3071 subjects, were determined to be in a medium to large range.

The effect of joint position sense therapy on chronic shoulder pain with central sensitization.

BACKGROUND: Chronic shoulder pain is a common musculoskeletal problem associated with unreleased pain and functional dysfunction that can evolve into central sensitization. Some forms of manual therapy may exacerbate pain and central sensitization. This study investigated the impact of joint position sense therapy (JPST), a moderate joint proprioception training technique, on central sensitization, shoulder functional dysfunction, and pain in patients with chronic shoulder pain compared with more intense exercises or aggressive manual therapies. METHODS: We assessed the pressure pain threshold (PPT) in 30 patients with and 30 patients without chronic shoulder pain. The assessment focused on 4 muscle sites: deltoid, upper trapezius, brachioradialis, and tibialis anterior. Thirty patients with chronic shoulder pain were randomly divided into the JPST and control groups. The JPST group underwent additional shoulder joint position-sense training. The efficiency outcomes were the disabilities of the arm, shoulder, and hand questionnaire, visual analog scale (VAS), and PPT, evaluated at baseline and after the intervention. RESULTS: Significant differences were observed in the PPT values at the brachioradialis (P < .05), deltoid (P < .01), and trapezius (P < .001) among the non-chronic and chronic groups, but not in the tibialis anterior muscle (P > .05). Although both control and JPST interventions effectively improved the disabilities of the arm, shoulder, and hand questionnaire score, pain intensity, and PPT values in the upper limb, the outcomes in the JPST group were significantly different from those in the control group. CONCLUSIONS: Generalized hyperalgesia changes limited to the upper limbs were observed in patients with chronic shoulder pain. JPST has beneficial effects on pain control and functional dysfunction in patients with chronic shoulder pain.

Central sensitivity syndrome affects the disease activity index and treatment satisfaction in patients with rheumatoid arthritis.

AIM: Many rheumatoid arthritis (RA) patients prioritize pain improvement in treatment. As pain can result from various causes, including noninflammatory factors such as central sensitivity syndrome (CSS), we hypothesized that CSS might impact treatment satisfaction. In this cross-sectional study, we assessed the CSS effects on clinical disease activity and treatment satisfaction in RA patients. METHODS: In total, 220 consecutive RA patients receiving long-term follow-up were evaluated for clinical disease activity and treatment satisfaction. CSS was evaluated using the Central Sensitization Inventory (CSI). An overall score of ≥40 indicates the presence of CSS. We queried "How satisfied are you with your treatment?"; answers included (a) very satisfied, (b) satisfied, (c) not satisfied, or (d) very dissatisfied. For univariate analysis, we condensed these answers into "dissatisfied" or "satisfied." We also evaluated treatment satisfaction using the visual analog scale (VAS), with scores ranging from 0 mm (very dissatisfied) to 100 mm (very satisfied). RESULTS: Of the 220 patients, 17 (7.7%) were classified as having CSS. CSI score was significantly correlated with the clinical disease activity index (CDAI; r = .322, p < .01) and treatment satisfaction (r = -.336, p < .01). Regarding treatment satisfaction, univariate analysis revealed that patient global assessment (PtGA), pain VAS, Health Assessment Questionnaire-Disability Index (HAQ-DI), Disease Activity Score in 28 joints with C-reactive protein, CDAI, and CSI scores of patients who were satisfied with treatment differed significantly from those of dissatisfied patients. Multivariate analysis revealed that CSI, PtGA, and HAQ-DI scores were associated with treatment satisfaction. CONCLUSION: In RA patients, CSS may affect the disease activity index and reduce treatment satisfaction.

AMPK activation attenuates central sensitization in a recurrent nitroglycerin-induced chronic migraine mouse model by promoting microglial M2-type polarization.

BACKGROUND: Energy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM. METHODS: Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention. RESULTS: Repeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1ß, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway. CONCLUSIONS: AMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine.

Curcumin analogue NL04 inhibits spinal cord central sensitization in rats with bone cancer pain by inhibiting NLRP3 inflammasome activation and reducing IL-1ß production.

The management and therapy of bone cancer pain (BCP) remain formidable clinical challenges. Curcumin and its analogues have been shown to have anti-inflammatory and analgesic properties. In the present study, we investigated the efficacy of curcumin analogue NL04 (NL04) in modulating inflammation in spinal dorsal horn (SDH), thereby exploring its potential to reduce central sensitization of BCP in a rat model. Differing doses of NL04 and curcumin were administered intrathecally either once (on day 12 of BCP) or over seven consecutive days (from day 6-12 of BCP). Results indicated that the ED50 for NL04 and curcumin ameliorating BCP-induced mechanical hyperalgesia is 49.08 µg/kg and 489.6 µg/kg, respectively. The analgesic effects at various doses of NL04 lasted between 4 and 8 h, with sustained administration over a week maintaining pain relief for 1-4 days, while also ameliorating locomotor gait via gait analysis and reducing depressive and anxiety-like behaviors via open-field and light-dark transition tests. The analgesic effects at various doses of curcumin lasted 4 h, with sustained administration over a week maintaining pain relief for 0-2 days. ELISA, Western blotting, qPCR, and immunofluorescence assays substantiated that intrathecal administration of NL04 on days 6-12 of BCP dose-dependently lowered spinal IL-1ß and IL-18 levels and significantly reduced the expression of IKKß genes and proteins, as well as the downstream cleavage of the trans-Golgi network (TGN). Whole-cell patch-clamp results demonstrated that NL04 inhibits potassium ion efflux in rat primary spinal neurons. Thus, NL04 exhibits significant analgesic effects in a BCP rat model by downregulating IKKß expression and inhibiting neuronal potassium ion efflux, which, in turn, suppresses the activation of NLRP3 inflammasomes and reduces IL-1ß production, potentially ameliorating pain management in BCP.

The effect of balance exercises on central sensitization in patients with knee osteoarthritis.

The aim of this study was to evaluate the effectiveness of balance exercises on functional status, pain, balance, and central sensitization in patients with knee osteoarthritis (OA). Patients diagnosed with bilateral Kellgren-Lawrence grade ≥ 2 primary knee OA and associated central sensitization were included in the study. Patients were randomized into two groups. Both groups were provided with verbal and written information on knee OA. In addition, the intervention group received a supervised balance exercise program for 6 weeks, 3 days a week on alternating days. The outcome measures were the changes in the Central Sensitization Inventory (CSI), Visual Analog Scale (VAS) pain, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Berg Balance Scale, and Y Balance Test. Evaluations were performed at baseline, immediately after treatment (6th week) and at 12th week. The study included 40 patients, 20 patients in each group. At the end of the treatment period (6th week), the improvement in CSI score, WOMAC pain, WOMAC physical function, WOMAC total score, Y Balance Test scores, and VAS pain during activity was significantly greater in the intervention group than that in the control group (p < 0.001). Regarding the changes from baseline to the 12th week, the intervention group experienced greater improvement in most of the outcome measures. Yet, the change in WOMAC pain score, Berg Balance Scale score, and VAS pain at rest was similar between the study groups (p = 0.05, p = 0.257, and p = 0.385, respectively). A two-model multiple linear regression analysis revealed that the changes in VAS pain (during activity) after the treatment and at follow-up [(p = 0.004, adjusted R2: 0.346) and (p = 0.002, adjusted R2: 0.391), respectively], as well as changes in WOMAC pain from baseline to follow-up (p = 0.020, ΔR2 = 0.245) significantly affected central sensitization. However, changes in Y Balance Test and WOMAC total scores did not appear to have a significant impact on the improvement in central sensitization (p > 0.05). Balance exercises may provide improvement in central sensitization, functional status, and dynamic balance among patients with knee OA. The improvement in central sensitization depends mostly on the pain relief effect of balance exercises.

Psychometric properties of the Turkish version of Central Sensitization Inventory-9 in patients with chronic musculoskeletal pain.

The aim of the study was to assess the psychometric properties of the Turkish version of Central Sensitization Inventory-9 (CSI-9) in patients with chronic musculoskeletal pain. The methodological study included 92 patients with chronic musculoskeletal pain. The original version of the CSI-9 was translated and culturally adapted into Turkish. The internal consistency and test-retest reliability were evaluated with Cronbach's α and the intraclass correlation coefficient (ICC), respectively. The assessment of reproducibility was conducted with the standard error of measurement (SEM) and minimal detectable difference (MDD) values. Convergent validity was explored by correlation analysis between the CSI-9 and Central Sensitization Inventory (CSI-25), Brief Pain Inventory (BPI), and European Quality of Life Survey-5 Dimensions (EQ-5D). The structural validity was assessed with factor analysis. Floor and ceiling effects were also analyzed. We found a very good internal consistency (Cronbach's α of 0.83) and excellent test-retest reliability (ICC of 0.96) of the Turkish CSI-9. The SEM demonstrated a range between 0.19 and 1.12, and the MDD was observed to vary from 1.17 to 1.35. The CSI-9 correlated significantly with the CSI-25 ( r  = 0.77, P  < 0.001), the pain severity subscale of the BPI ( r  = 0.41 to 0.53, P  < 0.001), the pain interference subscale of the BPI ( r  = 0.21 to 0.58, P  = 0.02 to P  < 0.001), the EQ-5D ( r  = 0.24 to 0.48, P  < 0.05), and the EQ-5D visual analog scale ( r  = -0.41, P  < 0.001). One factor was identified within the CSI-9. Our data suggest that the Turkish CSI-9 is reliable and valid outcome measure for assessing CS in patients with chronic musculoskeletal pain.

Characterizing clinical progression in patients with musculoskeletal pain by pain severity and central sensitization-related symptoms.

Central sensitization-related symptoms (CSS) are associated with the severity and progression of pain. The relationship between the severity of pain/CSS and clinical progresses remains unclear. This multicenter, collaborative, longitudinal study aimed to characterize the clinical outcomes of patients with musculoskeletal pain by classifying subgroups based on the severity of pain/CSS and examining changes in subgroups over time. We measured the pain intensity, CSS, catastrophic thinking, and body perception disturbance in 435 patients with musculoskeletal pain. Reevaluation of patients after one month included 166 patients for pain intensity outcome and 110 for both pain intensity and CSS outcome analysis. We classified the patients into four groups (mild pain/CSS, severe pain/mild CSS, severe pain/CSS, and mild pain/severe CSS groups) and performed multiple comparison analyses to reveal the differences between the CSS severity groups. Additionally, we performed the adjusted residual chi-square to identify the number of patients with pain improvement, group transition, changing pain, and CSS pattern groups at baseline. The most characteristic result was that the mild and severe CSS groups showed worsening pain. Moreover, many of the group transitions were to the same group, with a few transitioning to a group with mild pain/CSS. Our findings suggest that the severity and improvement of CSS influence pain prognosis.

5-HT3a receptor contributes to neuropathic pain by regulating central sensitization in a rat with brachial plexus avulsion.

PURPOSE: As a frequently occurring complication resulting from brachial plexus avulsion (BPA), neuropathic pain significantly impacts the quality of life of patients and places a substantial burden on their families. Recent reports have suggested that the 5-HT3a receptor may play a role in the development and regulation of neuropathic pain. The current study aimed to explore the involvement of the 5-HT3a receptor in neuropathic pain resulting from BPA in rats. METHODS: A rat model of neuropathic pain was induced through brachial plexus avulsion (BPA). The pain thresholds of the rats were measured after BPA. The spinal dorsal horn (SDH) of rats was collected at day 14 after surgery, and the expression and distribution of the 5-HT3a receptor were analyzed using immunohistochemistry and western blotting. The expression levels of various factors related to central sensitization were measured by western blot, including c-Fos, GFAP, IBA-1, IL-1ß and TNF-α. The effects of 5-HT3a receptor antagonists on hyperalgesia were assessed through behavioral tests after intrathecal administration of ondansetron. Additionally, at 120 min postinjection, the SDH of rats was acquired, and the change of expression levels of protiens related to central sensitization were measured by western blot. RESULTS: BPA induced mechanical and cold hypersensitivity in rats. The 5-HT3a receptor was increased and mainly distributed on neurons and microglia in the SDH after BPA, and the level of central sensitization and expression of inflammatory factors, such as c-Fos, GFAP, IBA-1, IL-1ß and TNF-α, were also increased markedly. Ondansetron, which is a selective 5-HT3a receptor antagonist, reversed the behavioral changes caused by BPA. The antagonist also decreased the expression of central sensitization markers and inflammatory factors. CONCLUSION: The results suggested that the 5-HT3a receptor is involved in neuropathic pain by regulating central nervous system sensitization in a rat brachial plexus avulsion model. Targeting the 5-HT3a receptor may be a promising approach for treating neuropathic pain after brachial plexus avulsion.

Frequency of idiopathic intracranial hypertension with ultrasound in patients with fibromyalgia: Relation with function, central sensitization, and neuropathic pain.

OBJECTIVE: The purpose of this study was to evaluate the prevalence of idiopathic intracranial hypertension (IIH) in fibromyalgia (FMS) patients by utilizing ultrasound to measure the optic nerve sheath diameter (ONSD), a marker of elevated intracranial pressure and also to investigate the relationship with function, fatigue, quality of life (QOL), central sensitization (CS) and neuropathic pain. METHODS: The study encompassed 80 female FMS patients and 75 healthy controls. Ultrasound was employed to measure the average ONSD in both groups. Conditions potentially elevating intracranial pressure were ruled out following neurological assessments. Pain (via visual analog scale, VAS), function (revised Fibromyalgia Impact Questionnaire, r-FIQ), QOL (Short Form-36, SF-36), fatigue (fatigue severity scale, FACIT), CS (Central Sensitization Scale), and neuropathic pain (Douleur Neuropathique-4) were evaluated. RESULTS: The average ONSD was significantly higher in the patient group than the control group. Patients with ONSD >5.5 mm consistent with IIH were categorized as Group 1 (n = 54, 67.5%), while those with a diameter of 5.5 mm and below-formed Group 2. VAS pain (p = .033) and FIQ-R scores (p = .033) were significantly higher in Group 1 than Group 2. Headache was found more common in Group 1. CONCLUSION: This study unveils a substantial occurrence (67.5%) of IIH in FMS patients, suggesting shared pathophysiological mechanisms contributing to symptoms like fatigue, headache, and cognitive dysfunction. Additionally, these findings implicate heightened functional impairment, CS, headache, and fatigue in FMS patients with IIH.

Central Sensitisation Syndrome: A Frequent Finding in Women with Pelvic Floor Symptoms Without Evident Urogenital Prolapse.

INTRODUCTION AND HYPOTHESIS: Women with central sensitisation syndrome (CSS) experience poorer subjective post-operative outcomes even after successful pelvic floor reconstruction. This study tests the hypothesis that women with pelvic floor symptoms (PFS) without relevant pelvic organ prolapse (POP), are more likely to have CSS. METHODS: A questionnaire was sent to women who participated in the POP-UP study in 2017. The POP-UP study evaluated POP in 247 women 16 years after laparoscopic or vaginal hysterectomy. POP-Q data and Pelvic Floor Distress Inventory (PFDI-20) results were used and supplemented with CSS-specific questionnaires. A Central Sensitisation Inventory (CSI) score above 40 implicates CSS. Women were divided into groups based on POP beyond the hymen in relation to the PFDI-20 score. Outcomes of women with PFS and without POP (called 'group 1') were compared with the rest of the cohort (groups 2-4; women without PFS and/or with POP). RESULTS: A total of 136 women were included in the analysis. A CSI score above 40 was present in 16 out of 42 women of group 1 (37%) versus 11 out of 93 women of groups 2-4 (12%), p < 0.0001. Passive coping was more prevalent in group 1 (p = 0.039), and more deviations in somatisation, depression, anxiety and distress were found in group 1 (p values of < 0.0001, 0.018, 0.003 and 0.002 respectively). CONCLUSIONS: This study suggests that CSS might be more prevalent in women with PFS without relevant POP. More awareness of CSS and valid individual counselling may overcome unnecessary surgery for POP and help in setting realistic expectations.

Microglia TREM1-mediated neuroinflammation contributes to central sensitization via the NF-κB pathway in a chronic migraine model.

BACKGROUND: Neuroinflammation, mediated by the activation of microglia, contributes to central sensitization, which is associated with the development of chronic migraine (CM). TREM1 receptors amplify the inflammatory response. However, their relationship to CM is unclear. Thus, this study endeavoured to elucidate the exact role of TREM1 in CM. METHODS: Nitroglycerin (NTG) was repeatedly administered intraperitoneally to establish the CM model. Mechanical and thermal sensitivities were assessed using von Frey filaments and hot plate assays. Using Western blotting, TREM1, NF-κB pathway, NLRP3 inflammasome components, and proinflammatory cytokines were all detected. Immunofluorescence was used to examine the cellular distribution of TREM1 and NLRP3, the number of microglia, immunoreactivity, and morphological changes. We examined the effects of TREM1 antagonists (LR12) and NF-κB inhibitors (PDTC) on pain behaviour, as well as the production of c-fos and CGRP. Additionally, we investigated whether LR12 and PDTC affect the activation of microglia and the NLRP3 inflammasome. We synthesized siRNA and TREM1-overexpressing plasmids to transfect BV2 cells treated with LPS and normal BV2 cells and treated TREM1-overexpressing BV2 cells with PDTC. The NF-κB pathway, NLRP3 inflammasome components, and proinflammatory cytokines were quantified using Western blotting. RESULTS: Following NTG administration, the expression of TREM1 was significantly upregulated and exclusively localized in microglia in the TNC, and was well co-localized with NLRP3. Furthermore, activation of the classical NF-κB pathway was observed. Pre-treatment with LR12 and PDTC effectively attenuated mechanical hypersensitivity, suppressed the expression of c-fos and CGRP, and inhibited NF-κB activity in CM mice. Additionally, inhibition of TREM1 and NF-κB activity mitigated NTG-induced microglia and NLRP3 activation, as well as proinflammatory cytokines production. In vitro, knockdown of TREM1 resulted in attenuated activation of the NF-κB pathway following lipopolysaccharide (LPS) treatment and reduced expression of NLRP3 inflammasome components as well as proinflammatory cytokines. After TREM1 overexpression, the NF-κB pathway was activated, NLRP3 inflammasome components and proinflammatory cytokines were upregulated, and PDTC reversed this phenomenon. CONCLUSIONS: Our findings suggest that TREM1 regulates microglia and NLRP3 activation via the NF-κB pathway, thereby contributing to central sensitization and implicating its involvement in chronic migraine pathogenesis.

The Effect of Central Sensitization on Postoperative Neurocognitive Dysfunction in Hospitalized Elderly Patients: A Prospective Cohort Clinical Trial.

OBJECTIVE: To investigate whether central sensitization (CS) in elderly patients was a predictive risk factor for postoperative neurocognitive dysfunction (PNCD). METHODS: One hundred and thirty-three aged patients undergoing total knee arthroplasty (TKA) who received femoral nerve block and general anesthesia were recruited in this research and prospectively assigned into two groups according to the Central Sensitization Inventory (CSI) score: group C (n = 106, CSI score less than 40) and group CS (n = 27, CSI score higher than 40). Scores of Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Confusion Assessment Method (CAM), Numerical Rating Scale (NRS) and Quality of recovery-40 (QoR-40) questionnaires were assessed. Basic information and clinical records of all participants were also collected. RESULTS: PNCD occurred in 24 (22.6%) of patients in group C and 16 (59.3%) in group CS (p < .05). Multivariate logistic regression analysis revealed that patients with CSI score ≥40 before surgery exhibited higher risk of PNCD after adjustment for other risk factors (p < .05). Compared to group C, the pre- and post-operative NRS scores, pain duration, the WOMAC score, and propofol consumptions for anesthesia induction were significantly increased in group CS (p < .05). CONCLUSION: Hospitalized elderly patients with clinical symptoms of CS scores may have increased risk of PNCD following TKA.

Black box in overactive bladder: Central sensitization and its relationship with urinary symptom severity and quality of life.

AIM: To examine central sensitization (CS), and to investigate the relationship between CS, and urinary symptom severity, and quality of life (QoL) in women with overactive bladder (OAB). MATERIALS AND METHODS: A total of 144 women with OAB included the study. CS with the Central Sensitization Inventory (CSI), urinary symptom with the Overactive Bladder Questionnaire-Version 8 (OAB-V8), bladder diary and Patients' Perception of Intensity of Urgency Scale (PPIUS) and QoL with the King's Health Questionnaire (KHQ) were assessed. RESULTS: It was found that 47.9% (n = 69) of women with OAB had CS. It was observed that the CSI score was related to the OAB-V8 score (ρ = 0.327; p < 0.001) and the average number of voids/day (ρ = 0.291; p < 0.001). Additionally, urgency severity was higher in women with OAB with CS than in women with OAB without CS (p = 0.006). There was a relationship between the CSI score and KHQ-incontinence impact (ρ = 0.250; p = 0.012), KHQ-personal relationship (ρ = 0.253; p = 0.002), KHQ-sleep/energy (ρ = 0.180; p = 0.031), KHQ-emotional state (ρ = 0.310; p < 0.001) and KHQ-severity measurement scores (ρ = 0.391; p < 0.001). CONCLUSION: In this study, it was observed that the majority of women with OAB had CS. It was found that more severe symptoms of CS were associated with worse urinary symptom severity and QoL in these patients. It may be beneficial to evaluate CS in the management of OAB and to consider CS when determining treatment strategies.