Peripheral and central pathogenesis of postherpetic neuralgia.

BACKGROUND: Postherpetic neuralgia (PHN) is a classic chronic condition with multiple signs of peripheral and central neuropathy. Unfortunately, the pathogenesis of PHN is not well defined, limiting clinical treatment and disease management. OBJECTIVE: To describe the peripheral and central pathological axes of PHN, including peripheral nerve injury, inflammation induction, central nervous system sensitization, and brain functional and structural network activity. METHODS: A bibliographic survey was carried out, selecting relevant articles that evaluated the characterization of the pathogenesis of PHN, including peripheral and central pathological axes. RESULTS: Currently, due to the complexity of the pathophysiological mechanisms of PHN and the incomplete understanding of the exact mechanism of neuralgia. CONCLUSION: It is essential to conduct in-depth research to clarify the origins of PHN pathogenesis and explore effective and comprehensive therapies for PHN.

Central sensitization-related symptoms and their relationship to disability in prevalent chronic musculoskeletal pain: A cross-sectional study.

BACKGROUND: Central sensitization (CS) has an important role in chronic musculoskeletal (MSK) pain, which is one of the leading causes of disability worldwide. OBJECTIVES: To investigate the relationship between CS-related symptoms and disability in chronic MSK pain. DESIGN: Multi-center cross-sectional survey. METHODS: Demographic and clinical variables including location, duration, and severity of pain were recorded. In the examination of disability, Istanbul Low Back Pain Disability Index for low back pain, Neck Pain and Disability Scale for neck pain, Quick Disability of the Arm, Shoulder, and Hand for shoulder/upper extremity pain, and Knee Injury and Osteoarthritis Outcome Score for knee pain were used. CS-related symptoms were investigated via the central sensitization inventory (CSI). Based on CSI scores, patient data were compared using the T test and an ANOVA. The association between CSI and selected variables was investigated using Pearson correlation and multivariate regression analysis. RESULTS: The mean CSI score of five hundred participants was 40.46 (SD: 15.87). Patients with CSI≥40 were found to have higher levels of pain and disability and a poorer quality of life (p < 0.05). In ANOVA, significant differences between groups were observed in CS severity levels for VAS, symptom duration, and all clinical scores (p < 0.01). In the multivariate regression analysis, CSI and VAS scores were found to be related to disability in all pain groups, while pain duration was effective only in the change of knee disability. CONCLUSION: CS-related symptoms, which are related to increased pain and disability, should be closely monitored in patients with chronic MSK pain.

Pain with orgasm in endometriosis: potential etiologic factors and clinical correlates.

BACKGROUND: Pelvic pain worsened by orgasm is a poorly understood symptom in patients with endometriosis. AIM: To assess the prevalence of pelvic pain worsened by orgasm in patients with endometriosis and explore its association with potential etiologic factors, including pelvic floor myalgia, uterine tenderness and adenomyosis, and central nervous system sensitization. METHODS: An analysis was done of a prospective data registry based at a tertiary referral center for endometriosis. Eligible participants were patients aged 18 to 50 years who were referred between January 1, 2018, and December 31, 2019, diagnosed with endometriosis, and subsequently underwent surgery at the center. Clinical features were compared between participants reporting worsening pelvic pain with orgasm and those without worsening pain with orgasm, including patient-reported variables, physical examination findings, and anatomic phenotyping at the time of surgery. Pelvic floor myalgia and uterine tenderness were assessed by palpation on pelvic examination, adenomyosis by ultrasound, and central nervous system sensitization via the Central Sensitization Inventory (range, 0-100). OUTCOMES: Outcomes included pelvic or lower abdominal pain in the last 3 months that worsened with orgasm (yes/no). RESULTS: Among 358 participants with endometriosis, 14% (49/358) reported pain worsened by orgasm while 86% (309/358) did not. Pain with orgasm was significantly associated with pelvic floor myalgia (55% [27/49] vs 35% [109/309]; Cohen's h = 0.40, P = .01) and higher scores on the Central Sensitization Inventory (mean ± SD, 53.3 ± 17.0 vs 42.7 ± 18.2; Cohen's d = 0.60, P < .001) but not with uterine tenderness or adenomyosis. Other clinical features associated with pain with orgasm were poorer sexual health (higher scores: deep dyspareunia, Cohen's h = 0.60; superficial dyspareunia, Cohen's h = 0.34; and Female Sexual Distress Scale-Revised, Cohen's d = 0.68; all P < .05) and poorer mental health (higher scores: Patient Health Questionnaire-9, 12.9 ± 6.7 vs 9.1 ± 6.3, Cohen's d = 0.59, P < .001; Generalized Anxiety Disorder-7, 9.4 ± 5.6 vs 6.8 ± 5.5, Cohen's d = 0.48, P = .002). Anatomic findings at the time of surgery did not significantly differ between the groups. CLINICAL IMPLICATIONS: Interventions targeting pelvic floor myalgia and central nervous system sensitization may help alleviate pain worsened by orgasm in patients with endometriosis. STRENGTHS AND LIMITATIONS: A strength is that pain worsened by orgasm was differentiated from dyspareunia. However, pain with orgasm was assessed by only a binary question (yes/no). Also, the study is limited to a single center, and there were limited data on sexual function. CONCLUSION: Pelvic pain exacerbated by orgasm in people with endometriosis may be related to concurrent pelvic floor myalgia and central sensitization.

Association between central sensitivity syndrome and psychophysical factors in patients with masticatory myofascial pain.

PURPOSE: This study explored the relationship between central sensitization symptoms, assessed using the Central Sensitization Inventory (CSI), and psychophysical factors in patients with chronic masticatory myofascial pain (MMP) transitioning from the acute to chronic stages. METHODS: In this study, 23 patients with MMP and 22 healthy volunteers were assessed using psychophysical tests, including measurements of pressure pain threshold (PPT) and temporal summation of pain (TSP). Additionally, CSI scores were recorded to evaluate central sensitization symptoms. RESULTS: Patients with chronic MMP showed significantly lower PPT in all masticatory muscles and extratrigeminal areas compared with controls. However, there was no significant correlation between CSI scores and psychophysical test results in patients with MMP. CONCLUSION: The significant enhancement of TSP in patients with subchronic MMP suggests a potential role in the onset of myofascial pain. The main finding suggests that sub-chronic symptom patients show higher CSI scores despite no sensory testing changes, indicating that central sensitization possibly precedes observable symptoms.

Establishing central sensitization inventory cut-off values in Dutch-speaking patients with chronic low back pain by unsupervised machine learning.

BACKGROUND: Human Assumed Central Sensitization (HACS) is involved in the development and maintenance of chronic low back pain (CLBP). The Central Sensitization Inventory (CSI) was developed to evaluate the presence of HACS, with a cut-off value of 40/100. However, various factors including pain conditions (e.g., CLBP), contexts, and gender may influence this cut-off value. Unsupervised clustering approaches can address these complexities by considering diverse factors and exploring possible HACS-related subgroups. Therefore, this study aimed to determine the cut-off values for a Dutch-speaking population with CLBP based on unsupervised machine learning. METHODS: Questionnaire data covering pain, physical, and psychological aspects were collected from patients with CLBP and aged-matched healthy controls (HC). Four clustering approaches were applied to identify HACS-related subgroups based on the questionnaire data and gender. The clustering performance was assessed using internal and external indicators. Subsequently, receiver operating characteristic (ROC) analysis was conducted on the best clustering results to determine the optimal cut-off values. RESULTS: The study included 63 HCs and 88 patients with CLBP. Hierarchical clustering yielded the best results, identifying three clusters: healthy group, CLBP with low HACS level, and CLBP with high HACS level groups. The cut-off value for the overall groups were 35 (sensitivity 0.76, specificity 0.76). CONCLUSION: This study found distinct patient subgroups. An overall CSI cut-off value of 35 was suggested. This study may provide new insights into identifying HACS-related patterns and contributes to establishing accurate cut-off values.

Evaluation of the segmental distribution of pain sensitivity among patients with central sensitization associated with chronic subacromial pain syndrome: A cross-sectional study.

INTRODUCTION: Pain sensitivity is the main finding of central sensitization (CS) and can occur in patients with chronic shoulder pain. However, there is limited evidence concerning the distribution of pain sensitivity in shoulders, forearms, and legs in patients with CS associated with chronic shoulder pain. The present study aimed to determine the distribution of pain sensitivity in patients with CS associated with chronic subacromial pain syndrome (SPS). METHOD: This cross-sectional study included 58 patients with chronic SPS and CS (patient group) and 58 healthy participants (control group). The presence of CS was determined using the Central Sensitization Inventory (CSI). To determine the distribution of pain sensitivity, pressure pain threshold (PPT) measurements were performed from the shoulders, forearms, and legs. RESULTS: There was no significant difference between the two groups in terms of sociodemographic data (p > 0.05). The patient group had a significantly higher CSI score (p < 0.001) and lower PPTs in all regions (p < 0.05) than the control group. Unlike the control group, the patient group had lower PPTs on the affected side for the shoulder [mean difference (MD) 95% confidence interval (CI): 1.2 (-1.7 to -0.6)], forearm [MD 95% CI: 1.1 (-1.7 to -0.6)], and leg [MD 95% CI: 0.9 (-1.4 to -0.3)] compared with the contralateral side (p < 0.001). CONCLUSION: Pain sensitivity is more pronounced in the affected shoulder and the forearm and leg located on this side than in those on the contralateral side in patients with CS associated with chronic SPS.

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.

Evaluation of Central Sensitisation in Bladder Pain Syndrome: A Systematic Review.

INTRODUCTION AND HYPOTHESIS: Bladder pain syndrome (BPS) is a debilitating condition characterised by exaggerated bladder sensations and altered bladder function. It is still unknown whether the condition is a peripheral sensory problem or due to abnormal central sensory processing as seen in central sensitisation. This systematic review, which followed a published and Prospective Register of Systematic Reviews-registered protocol (CRD42021229962), is aimed at establishing the scope of central sensitisation in patients with BPS to aid optimal management and treatment. METHODS: Four databases were searched, and appraisal of the identified studies was conducted by two independent reviewers based on eligibility criteria: patients with BPS being investigated for central sensitisation with or without comparison of controls, English-language articles, full text and publication in a peer-reviewed journal. The Methodological Index for non-Randomised Studies was used to determine study quality. We identified 763 papers in total, with 15 studies included in the final analysis. All studies were observational and had a low risk of bias. Measures included in the evaluation of CS were questionnaires, urodynamics, and quantitative sensory testing methods. RESULTS: There was evidence of central sensitisation in patients with BPS in all papers evaluated (15 out of 15). In addition, more significant central sensitisation correlated with severe disease presentation (3 out of 3 papers) and concomitant chronic pain conditions (5 out of 5 papers). CONCLUSIONS: Central sensitisation plays an integral role in BPS patient pathology. Many secondary measures are used to evaluate this condition. Stratification of patients based on their pathology (peripheral, central or a combination of the two) will aid in implementing an individualised management strategy.

Temporal relationships between pain, functioning, and human assumed central sensitization in patients with chronic low back pain; a single-case design.

BACKGROUND: Interdisciplinary pain rehabilitation (IPR) aims to improve functioning in people with chronic low back pain (CLBP), and is not primary aimed at pain reduction. Many patients however also report a decrease in pain. An explanation could be that IPR results in a decrease in Central Sensitization (CS). As CS is not directly assessable in humans the term Human Assumed Central Sensitization (HACS) is used in this study. It is unknown whether a decrease in HACS precedes a decrease in pain and improved functioning or vice versa. OBJECTIVES: This study aimed to gain understanding into the temporal relationships between changes in pain, functioning, and HACS in patients with CLBP during IPR. DESIGN: Longitudinal observational small-N-study. METHOD: Twelve patients filled in frequently repeated self-reports 1 week before, during the 12-week IPR program, and 2 weeks after IPR. Pain was assessed by Visual Analogue Scale for pain (daily), functioning by Pain Disability Index (weekly) and Work Ability Score (daily), and HACS by Central Sensitization Inventory part A (bi-weekly). Analyses were performed by visual inspection and time series cross-correlation analyses. RESULTS: Visual inspection showed large fluctuations within and between individual participants in patterns over time. Cross-correlation analyses showed that in most participants, relationships between pain, functioning, and HACS were strongest when analyzed at the same time (55% of comparisons). Strength and direction of (strongest) correlations showed high interindividual variability (neg: 0.33-0.97; pos: 0.22-0.99). CONCLUSION: Overall, relationships between pain, functioning, and HACS did not show consistent temporality in patients with CLBP.

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.

The Complexity of Neuropathic Pain and Central Sensitization: Exploring Mechanisms and Therapeutic Prospects.

Neuropathic pain is a common pain syndrome, which seriously affects the quality of life of patients. The mechanism of neuropathic pain is complex. Peripheral tissue injury can trigger peripheral sensitization; however, what really plays a key role is the sensitization of the central nervous system. Central sensitization is a key factor in the perception of chronic pain. Central sensitization refers to the increased sensitivity of the central nervous system to pain treatment, which is related to the change of the functional connection mode of the neural network. The current study aims to reveal the basic molecular mechanisms of central sensitization, including the involvement of P2 purine X4 receptor and brain-derived neurotrophic factor. In terms of treatment, although there are drugs and physical therapy, the accuracy of targeting is limited and the efficacy needs to be further improved. Future therapeutic strategies may involve the development of new drugs designed to specifically inhibit the central sensitization process. This article focuses on the effector molecules involved in central sensitization, aiming to elucidate the pathogenesis of neuropathic pain and provide a basis for the development of more effective treatment models.

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.

Top-down attention does not modulate mechanical hypersensitivity consecutive to central sensitization: insights from an experimental analysis.

ABSTRACT: According to the neurocognitive model of attention to pain, when the attentional resources invested in a task unrelated to pain are high, limited cognitive resources can be directed toward the pain. This is supported by experimental studies showing that diverting people's attention away from acute pain leads to experiencing less pain. Theoretical work has suggested that this phenomenon may present a top-down modulatory mechanism for persistent pain as well. However, conclusive empirical evidence is lacking. To fill this gap, we used a preregistered, double-blind, between-subject study design to investigate whether performing a tailored, demanding, and engaging working memory task unrelated to pain (difficult) vs a task that requires less mental effort to be performed (easy), could lead to lower development of secondary hypersensitivity-a hallmark of central sensitization. Eighty-five healthy volunteers, randomly assigned to one of the 2 conditions, performed a visual task with a different cognitive load (difficult vs easy), while secondary hypersensitivity was induced on their nondominant forearm using high-frequency stimulation. To assess the development of secondary hypersensitivity, sensitivity to mechanical stimuli was measured 3 times: T0, for baseline and 20 (T1) and 40 (T2) minutes after the procedure. We did not observe any significant difference in the development of secondary hypersensitivity between the 2 groups, neither in terms of the intensity of mechanical sensitivity nor its spatial extent. Our results suggest that a top-down modulation through attention might not be sufficient to affect pain sensitization and the development of secondary hypersensitivity.

Evaluating Sensitization-associated, Neuropathic-like Symptoms and Psychological Factors in Patients With Interstitial Lung Disease.

The aims of this study were to phenotype pain in patients with interstitial lung disease (ILD) by investigating the association between sensitization-associated symptoms with quality of life, anxiety/depression, pain catastrophizing, and kinesiophobia levels and identifying those risk factors explaining the variance of quality of life in individuals with ILD and pain. One hundred and thirty-two (38.6% women, mean age: 70, standard deviation: 10.5 years) patients with ILD completed clinical (age, sex, height, weight), psychological (Hospital Anxiety and Depression Scale [HADS] and the Pittsburgh Sleep Quality Index), and health-related quality of life (EQ-5D-5L) variables, as well as the Central Sensitization Inventory (CSI), the Self-Report Leeds Assessment of Neuropathic Symptoms (S-LANSS), Pain Catastrophizing Scale, and Tampa Scale for Kinesiophobia (TSK-11) questionnaires. The prevalence of sensitization-associated symptomatology (CSI), neuropathic-like features (S-LANSS), anxiety symptoms, depressive symptoms, or poor sleep was 20.5%, 23.5%, 23.6%, 22.9%, or 51.6%. Significant associations between CSI, S-LANSS, HADS-A, HADS-D, Pain Catastrophizing Scale, TSK-11, and EQ-5D-5L (.220 < r < .716) were found. The regression analysis revealed that CSI, TSK-11, and HADS-D explained 44.8% of the variance of EQ-5D-5L (r2 adjusted: .448). This study found the presence of sensitization-associated and neuropathic-like symptoms as well as other central nervous system-derived symptoms, such as anxiety, depression, poor sleep, pain catastrophizing, and kinesiophobia in 25% of ILD patients with pain. Sensitization-associated symptoms, depression, and kinesiophobia were associated with a worse quality of life. These findings would support that individuals with ILD can exhibit different pain phenotypes, including nociplastic-like pain phenotype based on self-reported measurements. PERSPECTIVE: Pain in patients with ILD can fulfill features of different phenotypes, including nociplastic pain, when sensory, emotional, and cognitive mechanisms are involved at the same time.

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.

Local Magnesium Sulfate Administration Ameliorates Nociception, Peripheral Inflammation, and Spinal Sensitization in a Rat Model of Incisional Pain.

OBJECTIVE: Postoperative pain remains one of the most common complaints after surgery, and appropriate treatments are limited. METHODS: We therefore investigated the effect of the anti-nociceptive properties of magnesium sulfate (MgSO4), an N-methyl-D-aspartate (NMDA) receptor antagonist, on incision-induced postoperative pain and peripheral and central nervous system inflammation. RESULTS: We found that local MgSO4 administration dose-dependently increases paw withdrawal latency, indicating reduced peripheral postoperative pain. Furthermore, MgSO4 inhibited the expression of interleukin-1ß (IL-1ß) and inducible nitric oxide synthase (iNOS) and phosphorylation of the NMDA receptor NR1 subunit in injured paw tissue and significantly attenuated microglial and astrocytic activation in the ipsilateral lumbar spinal cord dorsal horn. CONCLUSION: Locally administered MgSO4 has potential for development as an adjunctive therapy for preventing central nociceptive sensitization.

Elevated pain sensitivity is associated with reduced rapid eye movement (REM) sleep in females with comorbid temporomandibular disorder and insomnia.

OBJECTIVE: Patients with chronic pain disorders, including Temporomandibular Disorders (TMDs) endorse high levels of sleep disturbances, frequently reporting reduced sleep quality. Despite this, little is known about the effect that daytime pain has on the microstructure and macro-architecture of sleep. Therefore, we aimed to examine the extent to which daytime pain sensitivity, measured using quantitative sensory testing (QST), is associated with objective sleep parameters the following night, including sleep architecture and power spectral density, in women with TMD. METHODS: 144 females with myalgia and arthralgia by examination using the Diagnostic criteria for TMD completed a comprehensive QST battery consisting of General Pain Sensitivity, Central Sensitization Index, and Masseter Pressure Pain Threshold assessments. Polysomnography was collected the same night to measure sleep architecture and calculate relative power in delta, theta, alpha, sigma, and beta power bands. RESULTS: Central Sensitization (B = -3.069, P = .009), General Pain Sensitivity Indices (B = -3.069, P = .007), and Masseter Pain Pressure Threshold (B = 0.030, P = .008) were significantly associated with lower REM% both before and after controlling for covariates. Pain sensitivity measures were not significantly associated with relative power in any of the spectral bands nor with any other sleep architectural stages. CONCLUSIONS: Our findings demonstrate that higher generalized pain sensitivity, masseter pain pressure threshold, as well as central sensitization were associated with a lower percentage of REM in participants with myofascial pain and arthralgia of the masticatory system. These findings provide an important step toward understanding the mechanistic underpinnings of how chronic pain interacts with sleep physiology.

Pain mechanisms for the practicing rheumatologist.

Pain in rheumatic diseases transcends the traditional nociceptive paradigm, incorporating complex interactions between nociceptive, neuropathic, and nociplastic mechanisms, as well as significant psychosocial factors. Advances in understanding chronic pain highlight the role of peripheral and central sensitization, and the emergence of nociplastic pain-a result of altered central nervous system processing. This modern perspective acknowledges the influence of mood disorders, environmental stressors, and cognitive patterns like catastrophizing, revealing the intricate interplay between biological, psychological, and social determinants of pain. Research emphasizes the brain's pivotal role in pain perception, underscoring the importance of comprehensive approaches that integrate medical, psychological, and social interventions to address the multifaceted nature of chronic pain in rheumatic diseases effectively.

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.

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.