Central Pain Mechanisms Research Articles

Effects of Repetitive Transcranial Magnetic Stimulation Applied over the Primary Motor Cortex on the Offset Analgesia Phenomenon

In this study, we investigate the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) applied over the left upper limb primary motor cortex (M1) on the offset analgesia (OA) phenomenon, a measure of endogenous pain modulation. In particular, we aim to determine whether rTMS influences OA differently in the forearm region, corresponding to the stimulated cortical area, compared to the trigeminal region. Twenty-two healthy volunteers underwent three experimental sessions: a baseline session without stimulation, an active rTMS session, and a sham rTMS session. Quantitative sensory testing (QST) paradigms, including warm and cold detection thresholds, heat pain threshold corresponding to a visual analogue scale (VAS) score of approximately 50–60 out of 100 (Pain50–60), and constant and offset trials, were assessed in both the forearm and trigeminal regions. The results revealed that active rTMS significantly enhanced the OA phenomenon in the forearm during the late phase, while no significant effects were observed in the trigeminal region. These findings suggest that rTMS may modulate central pain mechanisms in a body region-specific manner, potentially linked to the somatotopic organization of M1. This study points to possible mechanisms of action of rTMS for pain relief, highlighting the importance of region-specific effects in chronic pain treatment. Further research is needed to investigate the underlying mechanisms and clinical applicability of rTMS in patients with chronic pain conditions, especially when OA is compromised.

Safety and Preliminary Efficacy of Transcutaneous Auricular Vagus Nerve Stimulation on Chronic Knee Pain: A Pilot Trial

ObjectiveTranscutaneous auricular vagus nerve stimulation (tVNS) may be an innovative treatment for symptoms of knee osteoarthritis (OA) due to possible shared pathological mechanisms between diminished parasympathetic function, central pain mechanisms, and knee pain. Thus, we sought to test the safety and preliminary efficacy of tVNS in people with knee OA. DesignA pilot trial in which participants received a 60-minute tVNS was conducted. At baseline, immediately after, and 15 minutes after tVNS, we assessed knee pain, pressure pain threshold (PPT), temporal summation (TS), conditioned pain modulation (CPM), and high-frequency power of heart rate variability (HF). We examined the extent to which these outcome measures changed after tVNS using linear mixed models. Results30 participants with knee OA were included, and all completed the intervention without any major side effects. Compared to baseline, knee pain was reduced by 1.27 (95% CI, -1.74, -0.80) immediately after and by 1.87 (-2.33, -1.40) 15 minutes after tVNS; CPM improved by 0.11 (0.04, 0.19) and 0.07 (-0.01, 0.15); and HF improved by 213.29 (-0.38, 426.96) and 234.17 (20.49, 447.84). PPT and TS were not changed after tVNS. ConclusionsOur preliminary data demonstrated that tVNS may be a safe pain-relieving treatment for people with knee OA. Our findings suggest that improvement of knee pain might be derived from improvement of parasympathetic function and central pain mechanisms as no local therapy was applied. A large study is needed to confirm that tVNS is a novel intervention to ameliorate knee pain in people with knee OA. Clinical Trial #ClinicalTrials.gov (NCT05625178)

Central Neuropathic Pain.

This article provides an approach to the assessment, diagnosis, and treatment of central neuropathic pain. Recent studies of the pathophysiology of central neuropathic pain, including evidence of changes in the expression of voltage-gated sodium channels and N-methyl-d-aspartate (NMDA) receptors, may provide the basis for new therapies. Other areas of current research include the role of cannabinoid-receptor activity and microglial cell activation in various animal models of central neuropathic pain. New observations regarding changes in primary afferent neuronal activity in central neuropathic pain and the preliminary observation that peripheral nerve blocks may relieve pain due to central neuropathic etiologies provide new insights into both the mechanism and treatment of central neuropathic pain. In the patient populations treated by neurologists, central neuropathic pain develops most frequently following spinal cord injury, multiple sclerosis, or stroke. A multimodal, individualized approach to the management of central neuropathic pain is necessary to optimize pain relief and may require multiple treatment trials to achieve the best outcome.

Psychophysical changes after total sleep deprivation and experimental muscle pain.

Sleep disturbances exacerbate chronic pain, increase psychological load, and increase inflammation. Delayed onset muscle soreness (DOMS) mimics aspects of chronic pain, predominantly affecting peripheral pain mechanisms, while experimental sleep provocations have been shown to impact central pain mechanisms. This study aimed to combine a DOMS model with total sleep deprivation (TSD) to create a novel model affecting both peripheral and central pain mechanisms. A total of 30 healthy participants attended two sessions (baseline and follow-up) separated by 24 h of TSD and a home rating after 48 h. Assessments of interleukin 6 (IL-6) levels, sleep quality, pain catastrophising, affect, and symptoms of depression and anxiety were included in the baseline and follow-up sessions. Additionally, pressure pain and tolerance thresholds, temporal summation, and conditioned pain modulation (CPM) were assessed using cuff-pressure algometry in the baseline and follow-up sessions. DOMS was induced with eccentric calf raises during the baseline session followed by 24 h of TSD. At follow-up pain tolerance (p = 0.012) was significantly reduced, and CPM (p = 0.036) was significantly impaired compared to baseline. Psychological changes included decreases in pain catastrophising (p = 0.027), positive affect (p < 0.001), negative affect (p = 0.003), and anxiety (p = 0.012). Explorative regression models predicted 58% and 68% of DOMS pain intensity after 24 and 48 h, respectively, based on baseline body mass index, pain thresholds, psychological measures, and IL-6 (p < 0.01). Combining DOMS with 1 night of TSD induced pain hypersensitivity, impaired CPM, and altered psychological states. A combination of baseline inflammation, psychological measures, and pain sensitivity significantly predicted DOMS pain intensity after 24 and 48 h.

Limited content overlap between commonly used self-report instruments for central (pain) sensitization in rheumatology.

Central pain mechanisms may be prominent in a considerable subset of rheumatology patients with persistent pain. Several self-report instruments have been used in previous research to infer the presence and severity of central sensitization (CS) that stem from different definitions or approaches of CS. The current study aimed to evaluate and quantify the overlap of actual symptoms measured among self-report measures of CS in rheumatology. We used Fried's (2017) comprehensive systematic approach to analyse the content of five commonly used or typical self-report measures (Generalized Pain Questionnaire, Pain Sensitivity Questionnaire, Central Sensitization Inventory, Central Aspects of Pain in the Knee scale and the painDETECT) used in rheumatology research and to visualize and quantify the overlap in symptoms measured. The five instruments together measured 39 different symptoms, most of which could be grouped into nociplastic pain manifestations (7 symptoms), neuropathic pain qualities (5 symptoms), and psychosomatic symptoms and emotional distress (25 symptoms). Most symptoms (74.4%) were unique to a single instrument. Thermal allodynia was the most frequently measured symptom across the different instruments, assessed in four of the measures. Average content overlap was very low and ranged from no overlap at all to moderate overlap (Jaccard index = 0.43) between pairs of instruments. There is high heterogeneity and limited overlap in the content of self-report measures used to infer central pain sensitization. This may lead to results that are specific to the particular instrument and may limit the generalizability and comparability of study findings in rheumatology research.

Characterization of sleep disturbance in established rheumatoid arthritis patients: exploring the relationship with central nervous system pain regulation

BackgroundTo characterize sleep disturbance in patients with established rheumatoid arthritis (RA) and explore the relationship between sleep and mechanisms of central nervous system pain regulation.MethodsForty-eight RA participants completed wrist-worn actigraphy monitoring and daily sleep diaries for 14 days to assess sleep-wake parameters. Participants underwent quantitative sensory testing to assess pressure pain thresholds, temporal summation, and conditioned pain modulation. Data were analyzed using descriptive statistics, Spearman’s correlation, and multivariable median regression analyses.ResultsMedian actigraphy and sleep diary derived sleep duration was 7.6 h (interquartile range (IQR) 7.0, 8.2) and 7.1 h (IQR 6.7, 7.6), respectively. Actigraphy based sleep fragmentation (rho = 0.34), wake after sleep onset (rho = 0.36), and sleep efficiency (rho = -0.32) were each related to higher temporal summation values in unadjusted analyses, but these relationships did not persist after controlling for age, body mass index, disease duration, and swollen joint count. No significant relationships were observed between sleep with pressure pain thresholds and conditioned pain modulation.ConclusionActigraphy and sleep diary monitoring are well tolerated in established RA patients. Future investigations should include both subjective and objective assessments, as they may provide information relating to different components and mechanisms.

The effect of intra spinal administration of cerium oxide nanoparticles on central pain mechanism: An experimental study.

This study investigated Cerium oxide nanoparticles (CeONPs) effect on central neuropathic pain (CNP). The compressive method of spinal cord injury (SCI) model was used for pain induction. Three groups were formed by a random allocation of 24 rats. In the treatment group, CeONPs were injected above and below the lesion site immediately after inducing SCI. pain symptoms were evaluated using acetone, Radian Heat, and Von Frey tests weekly for six weeks. Finally, we counted fibroblasts using H&E staining. We evaluated the expression of Cx43, GAD65 and HDAC2 proteins using the western blot method. The analysis of results was done by PRISM software. At the end of the study, we found that CeONPs reduced pain symptoms to levels similar to those observed in normal animals. CeONPs also increased the expression of GAD65 and Cx43 proteins but did not affect HDAC2 inhibition. CeONPs probably have a pain-relieving effect on chronic pain by potentially preserving GAD65 and Cx43 protein expression and hindering fibroblast infiltration.

Platelet-derived Growth Factor Receptor-α Induces Contraction Knots and Inflammatory Pain-like Behavior in a Rat Model of Myofascial Trigger Points.

Myofascial trigger points (MTrPs) are the primary etiological characteristics of chronic myofascial pain syndrome. Receptor tyrosine kinases (RTKs) are associated with signal transduction in the central mechanisms of chronic pain, but the role of RTKs in the peripheral mechanisms of MTrPs remains unclear. The current study aimed to identify RTKs expression in MTrPs and elucidate the molecular mechanisms through which platelet-derived growth factor receptor-α (PDGFR-α) induces contraction knots and inflammatory pain-like behavior in a rat model of myofascial trigger points. MTrPs tissue samples were obtained from the trapezius muscles of patients with myofascial pain syndrome through needle biopsy, and PDGFR-α activation was analyzed by microarray, enzyme-linked immunosorbent assay, and histological staining. Sprague-Dawley rats (male and female) were used to investigate PDGFR-α signaling, assessing pain-like behaviors with Randall-Selitto and nest-building tests. Muscle fiber and sarcomere morphologies were observed using histology and electron microscopy. The PDGFR-α binding protein was identified by coimmunoprecipitation, liquid chromatograph mass spectrometer, and molecular docking. PDGFR-α-related protein or gene levels, muscle contraction, and inflammatory markers were determined by Western blot and reverse-transcription quantitative polymerase chain reaction. PDGFR-α phosphorylation levels were elevated in the MTrPs tissues of individuals with trapezius muscle pain and were positively correlated with pain intensity. In rats, PDGFR-α activation caused pain-like behaviors and muscle contraction via the Janus kinase 2/signal transducer and activator of transcription-3 (JAK2/STAT3) pathway. JAK2/STAT3 inhibitors reversed the pain-like behaviors and muscle contraction induced by PDGFR-α activation. Collagen type I α 1 (COL1A1) binds to PDGFR-α and promotes its phosphorylation, which contributed to pain-like behaviors and muscle contraction. COL1A1-induced phosphorylation of PDGFR-α and the subsequent activation of the JAK2/STAT3 pathway may induce dysfunctional muscle contraction and increased nociception at MTrPs.

(039) DIVERSITY OF CAUSES OF DYSPAREUNIA IN REAL CLINICAL PRACTICE IN THE OUTPATIENT GYNECOLOGY DEPARTMENT

Abstract Introduction Dyspareunia is a women's sexual health problem that still often goes undiagnosed, despite its high prevalence and negative impact on sexual, marital and psychological well-being. Genito-pelvic pain/penetration disorder (GPPPD) refers to significant pain and difficulty with penetrative sex that lasts for at least six months and might be caused by various diseases alone and their combinations. Objective Thus, the purpose of this study is to determine the contribution of different conditions to the total number of patients who applied for a primary appointment for GPPPD. Methods Women who agreed to participate in the study were presenting complaints on painful intercourse or inability to have intercourse for more than 6 months. Patients underwent a gynecological examination consisted of inspection, Q-tip testing, pelvic floor muscle testing and bimanual palpation in the lithotomy position (if it was possible). Diagnoses were documented according to the International Classification of Diseases Tenth Revision World Health Organization guidelines. Pain was assessed via the McGill Pain Questionnaire and a visual analogue scale. Assessment of pelvic floor muscle dysfunction was based on an International Continence Society report on the terminology for pelvic floor muscle assessment. Vulvar pain conditions were classified based on the consensus vulvar pain terminology committee of the International Society for the Study of Vulvovaginal Disease, the International Society for the Study of Women's Sexual Health, and International Pelvic Pain Society. Statistical analyses were performed by SPSS Statistics. Results The average age of the examined women was 30,63±0,69 years. As a cause of GPPPD vaginismus and dyspareunia were diagnosed in 19.31 and 80.69 % respectively. Predominant cause of dyspareunia was pelvic floor muscles dysfunction (66,19%) which was combined with other pathologies (scar deformity of the perineum, endometriosis and chronic pelvic pain, candidiasis, etc.) in 20 cases. The percentage of women diagnosed with endometriosis without the formation of central pain mechanisms was 11.36%. The overlapping chronic pain conditions such as migraine, interstitial cystitis/bladder pain syndrome, irritable bowel syndrome, endometriosis and vulvodynia were diagnosed in 21.13% patients with dyspareunia. Dyspareunia due to vaginal atrophy associated with lactation, combined oral contraception use and menopause was diagnosed in 4 patients (2.82%, 1.41% and 1.41%, respectively). Scar changes of the perineum due to traumatic delivery or episiotomy amounted to 4.23%. Lichen planus was diagnosed in one patient (1.41%). Vulvodynia was diagnosed in 8 patients with dyspareunia (11.26%) and was associated with pelvic floor tension myalgia and pelvic floor myofascial pain syndrome in 75% of cases. Conclusions GPPPD can be caused by various conditions with significant involvement of the pelvic floor muscles in the process of pain formation. Taking into account the risk of overlapping chronic pain conditions, a multidisciplinary approach is required in the treatment of this group of patients. Disclosure No.

Analgesic Activity Combination of Dry Extract of Meniran Leaves (Phyllanthus niruri L.) and Moringa Leaves (Moringa oleifera L.) Using the Chemical Induction Method: Invivo Study

Analgesics are drugs that selectively reduce pain in the central nervous system or peripheral pain mechanisms without significantly changing consciousness. This study aims to determine the analgesic activity of a combination of dry extracts of meniran leaves (Phyllanthus niruri l.) and moringa leaves (Moringa oleifera l.) against Swiss Webster rats with chemical induction methods. This research proves the presence of secondary metabolite content in the dry extract of meniran leaves and moringa leaves which have analgesic activity. The research used 30 male Swiss Webster rats divided into 5 groups. Group 1 is the negative control (CMC-Na 0.5%), group 2 is the positive control (diclofenac Na), group 3 (Dry extract of meniran leaves), group 4 (Dry extract of moringa leaves) and Group 5 (Combination of dry extracts). meniran and moringa leaves). Each was given 1 mL of 1% acetic acid induction chemical stimulation, then the writhing response was observed and recorded at 5-minute intervals for 30 minutes. The results showed that the K3 group combined dry extract of meniran leaves (Phyllanthus niruri L.) and moringa leaves (Moringa oleifera L) is not statistically significantly different from the positive control diclofenac sodium, p-value = 0.183. In conclusion, dry extract of meniran leaves (Phyllanthus niruri L.) and Moringa leaves (Moringa oleifera L.) has been proven to contain secondary metabolites of flavonoids, alkaloids, tannins, and saponins which have analgesic activity.

Cross-cultural adaption, validity, and reliability of the Japanese version of the Central Aspects of Pain in the Knee (CAP-Knee-J) questionnaire in patients with knee pain: a validation study

BackgroundKnee pain is a prominent concern among older individuals, influenced by the central nervous system. This study aimed to translate the Central Aspects of Pain in the Knee (CAP-Knee) questionnaire into Japanese and investigate its reliability and validity in older Japanese individuals with knee pain.MethodsUsing a forward–backward method, CAP-Knee was translated into Japanese, and data from 110 patients at an orthopedic clinic were analyzed. The Japanese version (CAP-Knee-J) was evaluated regarding pain intensity during walking, central sensitization inventory, and pain catastrophizing scale. Statistical analyses confirmed internal validity and test–retest reliability. Concurrent validity was assessed through a single correlation analysis between CAP-Knee-J and the aforementioned measures. Exploratory factor analysis was employed on each CAP-Knee-J item to examine structural validity.ResultsCAP-Knee-J showed good internal consistency (Cronbach’s α = 0.86) and excellent test–retest reliability (intraclass correlation coefficient = 0.77). It correlated significantly with pain intensity while walking, central sensitization inventory scores, and pain catastrophizing scale scores. Exploratory factor analysis produced a three-factor model.ConclusionsCAP-Knee-J is a reliable and valid questionnaire for assessing central pain mechanisms specific to knee pain in older Japanese individuals, with moderate correlations with the CSI and weak with the PCS, thus indicating construct validity. This study supports the development of effective knee pain treatments and prognosis predictions.

Therapeutic Patient Education as Part of the Physiotherapy Management of Adults with Headache: A Scoping Review.

Physiotherapy interventions for headache mostly include exercise and manual therapy. Yet, the complex nature of headache, sometimes characterized by symptoms of facilitated central pain mechanisms, demands an individualized approach in which therapeutic patient education could be supportive. This scoping review aimed to summarize the position of therapeutic patient education within the physiotherapy management of adults with headache. PubMed, EMBASE, Web of Science, and Scopus were searched. The search-query comprised terminology relating to "headache", "education", and "physiotherapy". Eligibility criteria were: adults with headache, interventions including education within the domain of physiotherapy, reviews, clinical trials, cohort, case report, case-control studies. Eleven publications were included from the 281 retrieved publications. These publications were clinical trials (n = 4), reviews (n = 4), case-reports (n = 2), and a guideline (n = 1). Type of headaches studied were migraine (n = 3), post-traumatic headache (n = 2), tension-type headache (n = 2), cervicogenic headache (n = 1), primary headaches (n = 1), chronic daily headache (n = 1), and mixed migraine-cervicogenic headache (n = 1). Education seems an umbrella-term for postural education, lifestyle advice, and pain education. Three themes emerged across the publications: handling headache triggers (migraine, post-traumatic headache), promoting active lifestyle (post-traumatic headache, chronic daily headache, migraine), evaluating posture (post-traumatic headache, chronic daily headache, tension-type headache, cervicogenic headache). All publications recommended education in the management of headache. Only one (of the 11 included) publication described the educational program and determined its efficacy. Based on this scoping review, therapeutic patient education seems supported within physiotherapy management of headache. However, it is unclear how such education is tailored to the specific needs of the individual, the headache subtype, or when it should be added to physiotherapy management of headache.

Causal interactions in brain networks predict pain levels in trigeminal neuralgia

Trigeminal neuralgia (TN) is a highly debilitating facial pain condition. Magnetic resonance imaging (MRI) is the main method for generating insights into the central mechanisms of TN pain in humans. Studies have found both structural and functional abnormalities in various brain structures in TN patients as compared with healthy controls. Whereas studies have also examined aberrations in brain networks in TN, no studies have to date investigated causal interactions in these brain networks and related these causal interactions to the levels of TN pain. We recorded fMRI data from 39 TN patients who either rested comfortably in the scanner during the resting state session or tracked their pain levels during the pain tracking session. Applying Granger causality to analyze the data and requiring consistent findings across the two scanning sessions, we found 5 causal interactions, including: (1) Thalamus → dACC, (2) Caudate → Inferior temporal gyrus, (3) Precentral gyrus → Inferior temporal gyrus, (4) Supramarginal gyrus → Inferior temporal gyrus, and (5) Bankssts → Inferior temporal gyrus, that were consistently associated with the levels of pain experienced by the patients. Utilizing these 5 causal interactions as predictor variables and the pain score as the predicted variable in a linear multiple regression model, we found that in both pain tracking and resting state sessions, the model was able to explain ∼36 % of the variance in pain levels, and importantly, the model trained on the 5 causal interaction values from one session was able to predict pain levels using the 5 causal interaction values from the other session, thereby cross-validating the models. These results, obtained by applying novel analytical methods to neuroimaging data, provide important insights into the pathophysiology of TN and could inform future studies aimed at developing innovative therapies for treating TN.

Efficacy of Rehabilitative Techniques on Pain Relief in Patients With Vulvodynia: A Systematic Review and Meta-Analysis.

Vulvodynia is a chronic clinical condition characterized by provoked or non-provoked vulvar pain for at least 3months of unknown etiology. The onset of vulvodynia involves a complex interplay of peripheral and central pain mechanisms, such as pelvic floor muscle and autonomic dysfunction, and interpersonal factors. A stepwise approach of pelvic floor physical therapy as medical management is suggested. In this scenario, by this meta-analysis of randomized controlled trials, we aimed to evaluate the efficacy of rehabilitation interventions in patients with vulvodynia. On October 13, 2022, PubMed, Scopus, and Web of Science were systematically searched for randomized controlled trials that assessed the efficacy of the rehabilitative approach to pain during intercourse in patients with vulvodynia. The quality assessment was performed with the Cochrane risk-of-bias tool for randomized trials. The trial registration number is CRD42021257449. At the end of the search, 9 studies were included for a total of 332 patients. A pairwise meta-analysis was performed to highlight the efficacy of rehabilitative approaches for reducing pain during intercourse, as measured with a visual analog scale or a numerical rating scale. Meta-analysis showed that all these rehabilitative approaches had an overall effect size of -1.43 (95% CI = -2.69to -0.17) in decreasing vulvodynia pain in terms of the visual analog scale. In the subgroup analysis, a significant effect size in acupuncture (effect size = -2.36; 95% CI = -3.83 to -0.89) and extracorporeal shockwave therapy (effect size = -2.94; 95% CI = -4.31 to -1.57; I2= 58%) was observed. According to the Cochrane risk-of-bias tool, a low risk of bias for outcome selection in 89% of studies. Findings from this meta-analysis suggested that the physical agent modalities and complementary medicine techniques in people with vulvodynia appear to be more effective than placebo, sham, or waiting list. Further evidence on physical agent modalities and complementary therapies are warranted in the future. This was the first systematic review and meta-analysis of randomized controlled trials to provide evidence on the efficacy of rehabilitation interventions in patients with vulvodynia.

Research on the multidimensional brain remodeling mechanisms at the level of brain regions, circuits, and networks in patients with chronic lower back pain caused by lumbar disk herniation.

Chronic lower back pain (cLBP), frequently attributed to lumbar disk herniation (LDH), imposes substantial limitations on daily activities. Despite its prevalence, the neural mechanisms underlying lower back pain remain incompletely elucidated. Functional magnetic resonance imaging (fMRI) emerges as a non-invasive modality extensively employed for investigating neuroplastic changes in neuroscience. In this study, task-based and resting-state fMRI methodologies are employed to probe the central mechanisms of lower back pain. The study included 71 chronic lower back pain patients (cLBP group) due to LDH and 80 age, gender, and education-matched healthy volunteers (HC group). The subjects are mainly middle-aged and elderly individuals. Visual Analog Scale (VAS), Oswestry Disability Index (ODI), and Japanese Orthopedic Association Scores (JOA) were recorded. Resting-state and task-based fMRI data were collected. No significant differences were observed in age, gender, and education level between the two groups. In the cLBP group during task execution, there was diffuse and reduced activation observed in the primary motor cortex and supplementary motor area. Additionally, during resting states, notable changes were detected in brain regions, particularly in the frontal lobe, primary sensory area, primary motor cortex, precuneus, and caudate nucleus, accompanied by alterations in Amplitude of Low Frequency Fluctuation, Regional Homogeneity, Degree Centrality, and functional connectivity. These findings suggest that chronic lower back pain may entail reduced excitability in sensory-motor areas during tasks and heightened activity in the sensory-motor network during resting states, along with modified functional connectivity in various brain regions.

Inhibition of aquaporin-4 and its subcellular localization attenuates below-level central neuropathic pain by regulating astrocyte activation in a rat spinal cord injury model

The mechanisms of central neuropathic pain (CNP) caused by spinal cord injury have not been sufficiently studied. We have found that the upregulation of astrocytic aquaporin-4 (AQP4) aggravated peripheral neuropathic pain after spinal nerve ligation in rats. Using a T13 spinal cord hemisection model, we showed that spinal AQP4 was markedly upregulated after SCI and mainly expressed in astrocytes in the spinal dorsal horn (SDH). Inhibition of AQP4 with TGN020 suppressed astrocyte activation, attenuated the development and maintenance of below-level CNP and promoted motor function recovery in vivo. In primary astrocyte cultures, TGN020 also changed cell morphology, diminished cell proliferation and suppressed astrocyte activation. Moreover, T13 spinal cord hemisection induced cell-surface abundance of the AQP4 channel and perivascular localization in the SDH. Targeted inhibition of AQP4 subcellular localization with trifluoperazine effectively diminished astrocyte activation in vitro and further ablated astrocyte activation, attenuated the development and maintenance of below-level CNP, and accelerated functional recovery in vivo. Together, these results provide mechanistic insights into the roles of AQP4 in the development and maintenance of below-level CNP. Intervening with AQP4, including targeting AQP4 subcellular localization, might emerge as a promising agent to prevent chronic CNP after SCI.

The interrater and test-retest reliability of 3 modalities of quantitative sensory testing in healthy adults and people with chronic low back pain or rheumatoid arthritis.

Quantitative Sensory Testing (QST) modalities used to assess central pain mechanisms require different protocols in people with different musculoskeletal conditions. We aimed to explore the possible effects of musculoskeletal diagnosis and test site on QST interrater and test-retest reliability. The study included participants with rheumatoid arthritis (RA, n = 18; QST conducted on lower leg) and low back pain (LBP, n = 25; QST conducted on forearm), plus 45 healthy control participants (n = 20 QST on lower leg and n = 25 QST on forearm). Test-retest reliability was assessed from QST conducted 1 to 3 weeks apart. Quantitative sensory testing modalities used were pressure pain detection threshold (PPT) at a site distant to tissue pathology, temporal summation (TS), and conditioned pain modulation (CPM). Temporal summation was calculated as difference or ratio of single and repeated punctate stimuli and unconditioned thresholds for CPM used single or mean of multiple PPTs. Intraclass correlation coefficients (ICCs) were compared between different subgroups. High to very high reliability was found for all assessments of PPT and TS across anatomical sites (lower leg and forearm) and participants (healthy, RA, and LBP) (ICC ≥ 0.77 for PPT and ICC ≥ 0.76 for TS). Reliability was higher when TS was calculated as a difference rather than a ratio. Conditioned pain modulation showed no to moderate reliability (ICC = 0.01-0.64) that was similar between leg or forearm, and between healthy people and those with RA or LBP. PPT and TS are transferable tools to quantify pain sensitivity at different testing sites in different musculoskeletal diagnoses. Low apparent reliability of CPM protocols might indicate minute-to-minute dynamic pain modulation.

Gut-Brain Crosstalk and the Central Mechanisms of Orofacial Pain.

Accumulated evidence has demonstrated that the gut microbiome can contribute to pain modulation through the microbiome-gut-brain axis. Various relevant microbiome metabolites in the gut are involved in the regulation of pain signaling in the central nervous system. In this review, we summarize recent advances in gut-brain interactions by which the microbiome metabolites modulate pain, with a focus on orofacial pain, and we further discuss the role of gut-brain crosstalk in the central mechanisms of orofacial pain whereby the gut microbiome modulates orofacial pain via the vagus nerve-mediated direct pathway and the gut metabolites/molecules-mediated indirect pathway. The direct and indirect pathways both contribute to the central regulation of orofacial pain through different brain structures (such as the nucleus tractus solitarius and the parabrachial nucleus) and signaling transmission across the blood-brain barrier, respectively. Understanding the gut microbiome-regulated pain mechanisms in the brain could help us to develop non-opioid novel therapies for orofacial pain.

Converging circuits between pain and depression: the ventral tegmental area as a therapeutic hub.

Chronic pain and depression are highly prevalent pathologies and cause a major socioeconomic burden to society. Chronic pain affects the emotional state of the individuals suffering from it, while depression worsens the prognosis of chronic pain patients and may diminish the effectiveness of pain treatments. There is a high comorbidity rate between both pathologies, which might share overlapping mechanisms. This review explores the evidence pinpointing a role for the ventral tegmental area (VTA) as a hub where both pain and emotional processing might converge. In addition, the feasibility of using the VTA as a possible therapeutic target is discussed. The role of the VTA, and the dopaminergic system in general, is highly studied in mood disorders, especially in deficits in reward-processing and motivation. Conversely, the VTA is less regarded where it concerns the study of central mechanisms of pain and its mood-associated consequences. Here, we first outline the brain circuits involving central processing of pain and mood disorders, focusing on the often-understudied role of the dopaminergic system and the VTA. Next, we highlight the state-of-the-art findings supporting the emergence of the VTA as a link where both pathways converge. Thus, we envision a promising part for the VTA as a putative target for innovative therapeutic approaches to treat chronic pain and its effects on mood. Finally, we emphasize the urge to develop and use animal models where both pain and depression-like symptoms are considered in conjunction.

Associations of Muscle Strength with Central Aspects of Pain: Data from the Knee Pain and Related Health in the Community (KPIC) Cohort.

Knee pain is associated with lower muscle strength, and both contribute to disability. Peripheral and central neurological mechanisms contribute to OA pain. Understanding the relative contributions of pain mechanisms to muscle strength might help future treatments. The Knee Pain and related health In the Community (KPIC) cohort provided baseline and year 1 data from people with early knee pain (n = 219) for longitudinal analyses. A cross-sectional analysis was performed with baseline data from people with established knee pain (n = 103) and comparative data from people without knee pain (n = 98). Quadriceps and handgrip strength indicated local and general muscle weakness, respectively. The indices of peripheral nociceptive drive were knee radiographic and ultrasound scores. The indices associated with central pain mechanisms were Pressure Pain detection Threshold (PPT) distal to the knee, and a validated self-report Central Aspects of Pain Factor (CAPF). The associations were explored using correlation and multivariable regression. Weaker quadriceps strength was associated with both high CAPF and low PPT at baseline. Year 1 quadriceps weakness was predicted by higher baseline CAPF (β = -0.28 (95% CI: -0.55, -0.01), p = 0.040). Weaker baseline and year 1 handgrip strength was also associated with higher baseline CAPF. Weaker baseline quadriceps strength was associated with radiographic scores in bivariate but not adjusted analyses. Quadriceps strength was not significantly associated with total ultrasound scores. Central pain mechanisms might contribute to muscle weakness, both locally and remote from the knee.