Central Neuropathic Pain Research Articles

Generalisation of EEG-Based Pain Biomarker Classification for Predicting Central Neuropathic Pain in Subacute Spinal Cord Injury.

Background: The objective was to test the generalisability of electroencephalography (EEG) markers of future pain using two independent datasets. Methods: Datasets, A [N = 20] and B [N = 35], were collected from participants with subacute spinal cord injury who did not have neuropathic pain at the time of recording. In both datasets, some participants developed pain within six months, (PDP) will others did not (PNP). EEG features were extracted based on either band power or Higuchi fractal dimension (HFD). Three levels of generalisability were tested: (1) classification PDP vs. PNP in datasets A and B separately; (2) classification between groups in datasets A and B together; and (3) classification where one dataset (A or B) was used for training and testing, and the other for validation. A novel normalisation method was applied to HFD features. Results: Training and testing of individual datasets achieved classification accuracies of >80% using either feature set, and classification of joint datasets (A and B) achieved a maximum accuracy of 86.4% (HFD, support vector machine (SVM)). With normalisation and feature reduction (principal components), the validation accuracy was 66.6%. Conclusions: An SVM classifier with HFD features showed the best robustness, and normalisation improved the accuracy of predicting future neuropathic pain well above the chance level.

Classifying Low Back Pain Through Pain Mechanisms: A Scoping Review for Physiotherapy Practice.

Background: Low back pain (LBP) is a leading cause of disability worldwide, often driven by distinct pain mechanisms: nociceptive, neuropathic, and central sensitization. Accurate classification of these mechanisms is critical for guiding effective, targeted treatments. Methods: A scoping review was conducted following the Joanna Briggs Institute methodology and reported according to PRISMA-ScR guidelines. A comprehensive literature search was performed in MEDLINE, Cochrane CENTRAL, Scopus, PEDro, and Web of Science. Eligible studies included adults with LBP and focused on clinical criteria for classifying pain mechanisms. Data on study methods, population characteristics, and outcomes were extracted and synthesized. Results: Nine studies met the inclusion criteria. Nociceptive pain was characterized by localized symptoms proportional to mechanical triggers, with no neurological signs. Neuropathic pain was associated with burning sensations, dysaesthesia, and a positive neurodynamic straight leg raise (SLR) test. Central sensitization featured widespread pain, hyperalgesia, and disproportionate symptoms. Tools such as painDETECT, DN4, and the Central Sensitisation Inventory (CSI) were validated for neuropathic and central sensitization pain. Central sensitization and neuropathic pain were linked to greater disability and psychological distress compared to nociceptive pain. Conclusions: This review aims to provide a historical perspective on pain mechanism classifications and to explore how previous frameworks have influenced current diagnostic concepts in physiotherapy practice. By synthesizing key clinical criteria used to differentiate between nociceptive, neuropathic, and central sensitization pain, this review proposes a practical framework to improve the accuracy of pain classification in clinical settings.

Ivabradine reduces neuropathic pain after spinal cord injury by inhibiting excitatory synaptic transmission in the spinal dorsal horn.

Spinal cord injuries (SCIs) can lead to severe neuropathic pain and increased risk of myocardial infarction and heart failure; therefore, the use of analgesics against SCI-induced pain should be minimized because of their adverse effects on the cardiovascular system. Ivabradine, a blocker of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels, is used as a bradycardic agent, but recent studies focused on it as an analgesic agent for peripheral neuropathic pain. However, the analgesic effects of ivabradine on central neuropathic pain, such as SCI-induced pain, have not been examined. The aim of this study was to investigate the spinal analgesic effects of ivabradine on central neuropathic pain induced by SCI. Ivabradine induced analgesia in both spontaneous pain-related behavior and mechanical allodynia in SCI-induced pain (6-7 rats/group; p<0.01). In immunohistochemical staining analyses, ivabradine suppressed phosphorylation of extracellular signal-regulated kinases activated by SCI-induced pain in the superficial spinal dorsal horn (6 rats/group; p<0.01). In in vitro whole-cell patch-clamp analysis, ivabradine decreased the frequency of miniature excitatory postsynaptic currents in substantia gelatinosa neurons (11-12 rats/group; p<0.01). We concluded that ivabradine reduces SCI-induced pain by inhibiting excitatory synaptic transmission in the spinal dorsal horn.

Effects of multiple transcranial magnetic stimulation sessions on pain relief in patients with chronic neuropathic pain: A French cohort study in real-world clinical practice.

Current clinical trials indicate that repetitive transcranial magnetic stimulation (rTMS) is effective in reducing drug-resistant neuropathic pain (NP). However, there is a lack of studies evaluating the long-term feasibility and clinical efficacy of rTMS in large patient cohorts in real-world conditions. In this retrospective cohort study, we analysed 12 years of clinical data to assess the long-term analgesic effects of 20 Hz rTMS over the primary motor cortex in patients with NP. Subgroup analyses were conducted to identify predictive factors and assess the potential role of epidural motor cortex stimulation (eMCS) as a sustained solution. In total, 193 patients completed test period of 4 rTMS sessions and 42% of them reported a pain relief (PR) greater than 30%, with concurrent improvement in their most disabling symptom. Iterative rTMS sessions maintained analgesic effects over 10 years in certain patients identified as responders (≥10% PR) without adverse effects. Success probability was higher in patients with central NP compared to peripheral NP (OR = 2.03[1.04;4.00]), and among those with central post-stroke pain, this probability was higher in ischemic versus hemorrhagic strokes (OR = 3.36[1.17;10.05]). PR obtained with iterative rTMS sessions was an excellent predictor of eMCS efficacy. While rTMS shows promise as a therapeutic option for some patients with drug-resistant NP, it does not benefit all patients. Efficacy varies by NP aetiology, aiding patient selection. For responders, eMCS may offer a permanent solution. These findings support a tailored approach to rTMS in NP management, while recognizing both its potential and limitations across diverse patient profiles. Multiple rTMS sessions demonstrate long-term efficacy and safety in treating drug-resistant neuropathic pain. Extending session numbers for the test period can enhance responder identification, especially in patients with initial low pain relief. This identification refines patient selection for neurosurgery, reducing non-responders. Central neuropathic pain shows higher success rates than peripheral. For post-stroke central pain, patients with ischemic stroke are more likely to respond than those with hemorrhagic stroke. These results support integrating rTMS into clinical practice for managing neuropathic pain.

The relationship between changes in inflammation and locomotor function in sensory phenotypes of central neuropathic pain after spinal cord injury.

Central neuropathic pain (CNP) commonly develops in patients after spinal cord injury (SCI), causing debilitating symptoms and sensory abnormalities to mechanical and thermal stimuli. The biological variability of pain phenotypes in individuals has limited the number of positive outcomes. Thus, it is necessary to investigate the physiological processes contributing to sensory changes that develop over time. To investigate the physiological processes contributing to neuropathic pain sensory changes and locomotor impairments with sensory phenotypes that develop over time. Using the tail flick and von Frey tests, we performed hierarchical clustering to determine the subpopulation of rats that developed thermal and mechanical sensory abnormalities. To measure inflammation as a potential mediator of CNP phenotypes, we used flow cytometry and immunohistochemistry. Finally, to assess the secondary effects on locomotor recovery, up to 8 weeks after injury, we used the CatWalk test to assess multiple parameters of gait. The von Frey test showed a subpopulation of SCI rats that were hyposensitive to mechanical stimuli from 6 to 8 weeks after injury. The tail flick test showed a subpopulation of SCI rats that were hypersensitive to thermal stimuli at 1 week and 3 to 8 weeks after injury. Although there were no differences in inflammatory cells between subpopulations, we did see significant changes in locomotor recovery between rats with and without sensory abnormalities. The myeloid cell population at large is not affected by mechanical or thermal phenotypes of pain in this model; however, locomotor recovery is impaired depending on the pain phenotype present. Further investigation into acute inflammatory cells may be insightful for predicting the development of pain phenotypes.

Electroencephalography Longitudinal Markers of Central Neuropathic Pain Intensity in Spinal Cord Injury: A Home-Based Pilot Study.

It is well known from cross-sectional studies that pain intensity affects brain activity as measured by electroencephalography (EEG) in people with neuropathic pain (NP). However, quantitative characterisation is scarce. In this longitudinal study, ten people with spinal cord injury-related NP recorded their home EEG activity ten days before and after taking medications over a period of several weeks. The reduction in pain due to medications was accompanied by changes in the resting state EEG and its reactivity to eyes opening (EO) and closing (EC). There was a significant positive correlation between the frontal theta band and the intensity of pain (visual numerical scale) pre-medication (p = 0.007, Pearson R = 0.29) and theta, alpha, and lower beta (6-15 Hz) band power and the intensity of pain after post-medication over the frontal, central, and parietal cortices. Reactivity had a negative correlation with pain intensity at all locations and frequency bands and showed similar behaviour in wider frequency bands like 8-15 Hz at the occipital cortex and 2-12 Hz at the frontal cortex. EEG could be used to detect the intensity of NP to serve as a surrogate or pharmacodynamic marker.

The Use of Cannabinoids in the Treatment of Peripheral Neuropathy and Neuropathic Pain: A Systematic Review

Peripheral neuropathies are commonly occurring conditions that are chronic and debilitating for patients. Established nonsurgical treatments have yielded mixed and patient-dependent results. Although cannabinoids have demonstrated efficacy as a treatment for central neuropathic pain, the therapeutic potential of cannabis-based medications for the management of peripheral neuropathic pain caused by nerve injury, trauma, and other noncompressive etiologies has yet to be definitively established. This study aims to determine whether cannabinoids are a potentially effective treatment for pain and symptoms associated with peripheral neuropathy. A systematic search was conducted by two independent reviewers across PubMed, Cochrane, Ovid Medline, and CINAHL to identify studies in accordance with the predetermined inclusion/exclusion criteria. Information regarding study design, medication, dosage, effect on neuropathic pain, and other related outcomes was extracted. Meta-analysis of pain scores was performed for seven studies, and descriptive statistics were used to summarize other study findings as appropriate. Of the 927 studies identified, 14 randomized controlled trials were included. Thirteen of 14 studies (79%) observed a statistically significant decrease in neuropathic pain score following treatment with a cannabinoid. Meta-analysis yielded a mean difference of-0.67 [-0.89,-0.45]) on a 0-10 scale compared with placebo. Improvements in secondary outcomes such as sleep, sensory symptoms, and quality of life were observed. Our analysis of the literature shows that cannabis-based medicines may be effective in treating the pain and symptoms of peripheral neuropathy. These findings suggest the applicability of cannabis-based medicines for peripheral neuropathy. Therapeutic IV.

Discriminating fingerprints of chronic neuropathic pain following spinal cord injury using artificial neural networks and mass spectrometry analysis of female mice serum

Spinal cord injury (SCI) often leads to central neuropathic pain, a condition associated with significant morbidity and is challenging in terms of the clinical management. Despite extensive efforts, identifying effective biomarkers for neuropathic pain remains elusive. Here we propose a novel approach combining matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with artificial neural networks (ANNs) to discriminate between mass spectral profiles associated with chronic neuropathic pain induced by SCI in female mice. Functional evaluations revealed persistent chronic neuropathic pain following mild SCI as well as minor locomotor disruptions, confirming the value of collecting serum samples. Mass spectra analysis revealed distinct profiles between chronic SCI and sham controls. On applying ANNs, 100% success was achieved in distinguishing between the two groups through the intensities of m/z peaks. Additionally, the ANNs also successfully discriminated between chronic and acute SCI phases. When reflexive pain response data was integrated with mass spectra, there was no improvement in the classification. These findings offer insights into neuropathic pain pathophysiology and underscore the potential of MALDI-TOF MS coupled with ANNs as a diagnostic tool for chronic neuropathic pain, potentially guiding attempts to discover biomarkers and develop treatments.

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.

Usefulness of Mirogabalin in Central Neuropathic Pain After Stroke: Post Hoc Analysis of a Phase3 Study by Stroke Type and Location.

Central post-stroke pain (CPSP) is a common type of central neuropathic pain (CNeP) that can occur following the onset of stroke. The oral gabapentinoid mirogabalin besylate (mirogabalin) is a selective α2δ ligand that is effective for the treatment of CNeP, including CPSP. However, it is unknown whether the analgesic effect of mirogabalin on CPSP varies in patients with different background factors. This was a post hoc subgroup analysis of a multinational, open-label, long-term phase3 study of mirogabalin for the treatment of CNeP conducted between March 2019 and December 2020. Data from patients with CPSP were stratified by type of stroke (ischemic or hemorrhagic), stroke location (thalamus, putamen, brainstem, or other), presence/absence of motor weakness, median time since stroke (≥ 59 or < 59months), and median duration of CPSP (≥ 55.5 or < 55.5months). Efficacy was assessed with the short-form McGill Pain Questionnaire (SF-MPQ), and treatment-emergent adverse events (TEAEs) and adverse drug reactions (ADRs) were recorded. This subanalysis included all 94 patients with CPSP from the phase3 study; all were Japanese, and the mean age was 65.3years. The least squares mean change [95% confidence interval] in SF-MPQ visual analog scale (VAS) score from baseline at week52 (last observation carried forward) was - 17.0 [- 22.1, - 11.9] mm. Among the subgroups, least squares mean changes in SF-MPQ VAS scores were not different. Most TEAEs were mild or moderate; severe TEAEs occurred in six patients (6.4%). Somnolence (25.5%), peripheral edema (13.8%), dizziness (11.7%), and weight gain (6.4%) were the most common ADRs, and the types and frequencies of ADRs were similar among subgroups. Mirogabalin was generally effective and well tolerated in patients with CPSP, regardless of background factors such as stroke type or location, presence/absence of motor weakness, time since stroke, and duration of CPSP. Trial registration number NCT03901352.

Peripheral Neuropathic Pain.

This article synthesizes current knowledge on neuropathic pain, with a brief review of mechanisms, diagnostic approaches, and treatment strategies to help neurologists provide effective and individualized care for patients with this complex condition. The most promising developments in peripheral neuropathic pain are related to the molecular biology of the peripheral nervous system. Systematic molecular and genetic analyses of peripheral nerve terminals and dorsal root ganglia have advanced our understanding of the genetics of function and disease of peripheral nerves, as well as their physiology and clinical manifestations. Peripheral neuropathic pain, similar to central neuropathic pain, is primarily influenced by the biology and pathophysiology of the underlying structures, peripheral sensory nerves, and their central pathways. The clinical course is widely variable in sensory symptoms and intensities, natural history, and response to treatments.

The sexually dimorphic expression of glutamate transporters and their implication in pain after spinal cord injury.

JOURNAL/nrgr/04.03/01300535-202511000-00033/figure1/v/2024-12-20T164640Z/r/image-tiff In addition to the loss of motor function, ~ 60% of patients develop pain after spinal cord injury. The cellular-molecular mechanisms are not well understood, but the data suggests that plasticity within the rostral, epicenter, and caudal penumbra of the injury site initiates a cellular-molecular interplay that acts as a rewiring mechanism leading to central neuropathic pain. Sprouting can lead to the formation of new connections triggering abnormal sensory transmission. The excitatory glutamate transporters are responsible for the reuptake of extracellular glutamate which makes them a critical target to prevent neuronal hyperexcitability and excitotoxicity. Our previous studies showed a sexually dimorphic therapeutic window for spinal cord injury after treatment with the selective estrogen receptor modulator tamoxifen. In this study, we investigated the anti-allodynic effects of tamoxifen in male and female rats with spinal cord injury. We hypothesized that tamoxifen exerts anti-allodynic effects by increasing the expression of glutamate transporters, leading to reduced hyperexcitability of the secondary neuron or by decreasing aberrant sprouting. Male and female rats received a moderate contusion to the thoracic spinal cord followed by subcutaneous slow-release treatment of tamoxifen or matrix pellets as a control (placebo). We used von Frey monofilaments and the "up-down method" to evaluate mechanical allodynia. Tamoxifen treatment decreased allodynia only in female rats with spinal cord injury revealing a sex-dependent effect. The expression profile of glutamatergic transporters (excitatory amino acid transporter 1/glutamate aspartate transporter and excitatory amino acid transporter 2/glutamate transporter-1) revealed a sexual dimorphism in the rostral, epicenter, and caudal areas of the spinal cord with a pattern of expression primarily on astrocytes. Female rodents showed a significantly higher level of excitatory amino acid transporter-1 expression while male rodents showed increased excitatory amino acid transporter-2 expression compared with female rodents. Analyses of peptidergic (calcitonin gene-related peptide-α) and non-peptidergic (isolectin B4) fibers outgrowth in the dorsal horn after spinal cord injury showed an increased calcitonin gene-related peptide-α/ isolectin B4 ratio in comparison with sham, suggesting increased receptive fields in the dorsal horn. Although the behavioral assay shows decreased allodynia in tamoxifen-treated female rats, this was not associated with overexpression of glutamate transporters or alterations in the dorsal horn laminae fibers at 28 days post-injury. Our findings provide new evidence of the sexually dimorphic expression of glutamate transporters in the spinal cord. The dimorphic expression revealed in this study provides a therapeutic opportunity for treating chronic pain, an area with a critical need for treatment.

Explorative sensory profile evaluation in central neuropathic pain following spinal cord injury.

Sensory profiling in neuropathic pain using quantitative sensory testing (QST) has not been extended to central neuropathic pain due to spinal cord injury (SCI). This study aims to fill this gap by evaluating sensory profiles in patients with neuropathic SCI pain. We retrospectively analysed consecutive QST data from 62 patients with neuropathic spinal cord injury pain (SCIP), following the German Research Network on Neuropathic Pain protocol. The study included at-level and below-level SCIP due to a spinal cord lesion, and at-level SCIP following a cauda equina lesion. QST parameters were compared between diagnostic groups. QST profiles of below-level SCIP (central neuropathic pain) were manually assigned to sensory phenotypes based on literature and expert opinion. No statistical difference in QST parameters between pain diagnoses was found. For central neuropathic pain (below-level SCIP), three phenotypes were descriptively observed: loss of function (59%), thermal and mechanical hyperalgesia combination (16%), and mechanical hyperalgesia (19%). The remaining 5% of patients did not fit a common pattern. There was no statistical difference in clinical and psychological variables between phenotypes. In a subgroup analysis, the loss of function phenotype weakly correlated with older age, longer time since injury, and longer pain duration. Here, we capture sensory phenotypes of central neuropathic pain following SCI. The limited sample size, high rate of missing values, and the retrospective nature of the study mean that results should be seen as strictly exploratory. Further research should replicate these findings and explore the significance of phenotypes. The evaluation of sensory phenotypes by quantitative sensory testing in central neuropathic pain due to SCI adds a new perspective on sensory phenotypes in comparison to peripheral neuropathic pain. The described thermal and mechanical hyperalgesia combination might represent involvement of the spinothalamic tract. In addition, there was a trend towards older age and longer time since injury in patients with loss of function.

Contributions of neuroimaging in central poststroke pain: a review.

Central neuropathic poststroke pain (CNPSP) affects up to 12% of patients with stroke in general and up to 18% of patients with sensory deficits. This pain syndrome is often incapacitating and refractory to treatment. Brain computed tomography and magnetic resonance imaging (MRI) are widely used methods in the evaluation of CNPSP. The present study aims to review the role of neuroimaging methods in CNPSP. We performed a literature review of the main clinical aspects of CNPSP and the contribution of neuroimaging methods to study its pathophysiology, commonly damaged brain sites, and possible differential diagnoses. Lastly, we briefly mention how neuroimaging can contribute to the non-pharmacological CNPSP treatment. Additionally, we used a series of MRI from our institution to illustrate this review. Imaging has been used to explain CNPSP pathogenesis based on spinothalamic pathway damage and connectome dysfunction. Imaging locations associated with CNPSP include the brainstem (mainly the dorsolateral medulla), thalamus (especially the ventral posterolateral/ventral posteromedial nuclei), cortical areas such as the posterior insula and the parietal operculum, and, more recently, the thalamocortical white matter in the posterior limb of the internal capsule. Imaging also brings the prospect of helping search for new targets for non-pharmacological treatments for CNPSP. Other neuropathic pain causes identified by imaging include syringomyelia, multiple sclerosis, and herniated intervertebral disc. Imaging is a valuable tool in the complimentary evaluation of CNPSP patients in clinical and research scenarios.

Successful pain control with add-on methadone for refractory neuropathic pain due to radiation necrosis in pontine metastatic lesion: a case report

BackgroundCentral pain, characterized by neuropathic pain, can manifest due to injury to the superior spinothalamic tract. The brainstem includes sensory and motor pathways as well as nuclei of the cranial nerves, and therefore cancer metastasis in the region requires early intervention. Although stereotactic radiosurgery (SRS) is commonly employed for the treatment of brain metastasis, it poses risks of late complications like radiation necrosis (RN). RN exacerbates the progression of brain lesions within the irradiated area, and in the brainstem, it can damage multiple nerves, including the superior spinothalamic tract. Central neuropathic pain is often intractable and empirically managed with a combination of conventional drugs, such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and anticonvulsants. However, their efficacy is often limited, leading to a decline in performance status (PS) and quality of life (QOL).Case presentationWe present the case of a 53-year-old man diagnosed with stage IV lung cancer, referred to our palliative care team for managing severe central pain resulting from SRS-related RN in the pons. Despite administration of opioids, including oxycodone and hydromorphone, and adjuvant analgesics, the patient continued to require frequent use of immediate-release opioids. The addition of methadone alone proved successful in achieving optimal pain control.ConclusionsProvided that RN in the brainstem can lead to intractable neuropathic pain, it is advisable to avoid SRS for brainstem metastasis when possible. Add-on methadone should be considered as a viable pain management medication for patients experiencing unresolved central pain.

Successful spinal cord stimulation using fast-acting sub-perception therapy for postoperative neuropathic pain of syringomyelia with Chiari malformation type 1: a case report and literature review

BackgroundCentral neuropathic pain after foramen magnum decompression (FMD) for Chiari malformation type 1 (CM-1) with syringomyelia can be residual and refractory. Here we present a case of refractory central neuropathic pain after FMD in a CM-1 patient with syringomyelia who achieved improvements in pain following spinal cord stimulation (SCS) using fast-acting sub-perception therapy (FAST™).Case presentationA 76-year-old woman presented with a history of several years of bilateral upper extremity and chest-back pain. CM-1 and syringomyelia were diagnosed. The pain proved drug resistant, so FMD was performed for pain relief. After FMD, magnetic resonance imaging showed shrinkage of the syrinx. Pain was relieved, but bilateral finger, upper arm and thoracic back pain flared-up 10 months later. Due to pharmacotherapy resistance, SCS was planned for the purpose of improving pain. A percutaneous trial of SCS showed no improvement of pain with conventional SCS alone or in combination with Contour™, but the combination of FAST™ and Contour™ did improve pain. Three years after FMD, percutaneous leads and an implantable pulse generator were implanted. The program was set to FAST™ and Contour™. After implantation, pain as assessed using the McGill Pain Questionnaire and visual analog scale was relieved even after reducing dosages of analgesic. No adverse events were encountered.ConclusionPercutaneously implanted SCS using FAST™ may be effective for refractory pain after FMD for CM-1 with syringomyelia.

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.

The role of spinal neurons targeted by corticospinal neurons in central poststroke neuropathic pain.

Central poststroke pain (CPSP) is one of the primary sequelae following stroke, yet its underlying mechanisms are poorly understood. By lesioning the lateral thalamic nuclei, we first established a CPSP model that exhibits mechanical and thermal hypersensitivity. Innocuous mechanical stimuli following the thalamic lesion evoked robust neural activation in somatosensory corticospinal neurons (CSNs), as well as in the deep dorsal horn, where low threshold mechanosensory afferents terminate. In this study, we used viral-based mapping and intersectional functional manipulations to decipher the role of somatosensory CSNs and their spinal targets in the CPSP pathophysiology. We first mapped the post-synaptic spinal targets of lumbar innervating CSNs using an anterograde trans-synaptic AAV1-based strategy and showed these spinal interneurons were activated by innocuous tactile stimuli post-thalamic lesion. Functionally, tetanus toxin-based chronic inactivation of spinal neurons targeted by CSNs prevented the development of CPSP. Consistently, transient chemogenetic silencing of these neurons alleviated established mechanical pain hypersensitivity and innocuous tactile stimuli evoked aversion linked to the CPSP. In contrast, chemogenetic activation of these neurons was insufficient to induce robust mechanical allodynia typically observed in the CPSP. The CSNs and their spinal targets are required but insufficient for the establishment of CPSP hypersensitivity. Our study provided novel insights into the neural mechanisms underlying CPSP and potential therapeutic interventions to treat refractory central neuropathic pain conditions.

Associations between pain intensity, pain sensitivity, demographics, psychological factors, disability, physical activity, pain phenotype and COVID-19 history in low back pain: An observational study.

Knowledge of the factors affecting pain intensity and pain sensitivity can inform treatment targets and strategies aimed at personalizing the intervention, conceivably increasing its positive impact on patients. Therefore, this study aimed to investigate the association between demographic factors (sex and age), body mass index (BMI), psychological factors (anxiety and depression, kinesiophobia and catastrophizing), self-reported physical activity, pain phenotype (symptoms of central sensitization, and nociceptive or neuropathic pain), history of COVID-19 and pain intensity and sensitivity in patients with chronic non-specific low back pain (LBP). This was a cross-sectional secondary analysis with 83 participants with chronic non-specific LBP recruited from the community between August 2021 and April 2022. BMI, pain intensity (Visual Analog Scale), pain sensitivity at the lower back and at a distant point [pressure pain threshold], catastrophizing (Pain Catastrophizing Scale), kinesiophobia (Tampa Scale for Kinesiophobia), anxiety and depression (Hospital Anxiety and Depression Scale), pain phenotype (Central Sensitization Inventory and PainDetect Questionnaire), physical activity (International Physical Activity Questionnaire), and disability (Roland Morris Disability Questionnaire) were assessed. Multiple linear regression analyses with pain intensity and sensitivity as the dependent variables were used. The model for pain intensity explained 34% of its variance (Adjusted R2=-0.343, p<0.001), with depression and anxiety (p=0.008) and disability (p=0.035) reaching statistical significance. The model for pain sensitivity at the lower back, also explained 34% of its variance (Adjusted R2=0.344, p<0.001) at the lower back with sex, BMI, and kinesiophobia reaching statistical significance (p<0.05) and 15% of the variance at a distant body site (Adjusted R2=0.148, p=0.018) with sex and BMI reaching statistical significance (p<0.05). This study found that different factors are associated with pain intensity and pain sensitivity in individuals with LBP. Increased pain intensity was associated with higher levels of anxiety and depression and disability and increased pain sensitivity was associated with being a female, higher kinesiophobia, and lower BMI.

Spinal lipocalin 2 as a factor in the development of central post-stroke pain

Central poststroke pain (CPSP) is a type of central neuropathic pain whose mechanisms remain unknown. Recently, we showed that activated astrocytes and microglial cells are present in the spinal cord of CPSP model mice. Activated glial cells exacerbate cerebral ischemic pathology by increasing the expression of inflammatory factors. However, the involvement of spinal glial cells in CPSP remains unknown. We hypothesized that spinal glial cell-derived molecules cause hyperexcitability or promoted the development of CPSP. In this study, we identified glial cell-derived factors involved in the development of CPSP using a bilateral common carotid occlusion (BCAO)-induced CPSP mouse model. Male ddY mice were subjected to BCAO for 30min. The von Frey test assessed mechanical hypersensitivity in the right hind paw of mice. BCAO mice showed hypersensitivity to mechanical stimuli and astrocyte activation in the spinal cord 3days after treatment. DNA microarray analysis revealed a significant increase in lipocalin 2 (LCN2), is known as neutrophil gelatinase-associated lipocalin, in the superficial dorsal horns of BCAO-induced CPSP model mice. LCN2 colocalized with GFAP, an astrocyte marker. Spinal GFAP-positive cells in BCAO mice co-expressed signal transducer and activator of transcription 3 (STAT3). The increase in the fluorescence intensity of LCN2 and GFAP in BCAO mice was suppressed by intrathecal injection of AG490, an inhibitor of JAK2 and downstream STAT3 activation, or anti-LCN2 antibody. Our findings indicated that LCN2 in spinal astrocytes may be a key molecule and may be partly involved in the development of CPSP.