Pain Mechanisms Research Articles

A novel animal model of symptomatic neuroma for assessing neuropathic pain

IntroductionFollowing amputation, peripheral nerves lack distal targets for regeneration, often resulting in symptomatic neuromas and debilitating neuropathic pain. Animal models can establish a practical method for symptomatic neuroma formation for better understanding of neuropathic pain pathophysiology through behavioral and histological assessments. We created a clinically translatable animal model of symptomatic neuroma to mimic neuropathic pain in patients and assess sexual differences in pain behaviors. MethodsTwenty-two male and female rats were randomly assigned to one of two experimental groups: (1) neuroma surgery, or (2) sham surgery. For the neuroma experimental group, the tibial nerve was transected in the thigh, and the proximal segment was placed under the skin for mechanical testing at the site of neuroma. For the sham surgery, rats underwent tibial nerve isolation without transection. Behavioral testing consisted of neuroma-site pain, mechanical allodynia, cold allodynia, and thermal hyperalgesia at baseline, and then weekly over 8 weeks. ResultsMale and female neuroma rats demonstrated significantly higher neuroma-site pain response compared to sham groups starting at weeks 3 and 4, indicating symptomatic neuroma formation. Weekly assessment of mechanical and cold allodynia among neuroma groups showed a significant difference in pain behavior compared to sham groups (p < 0.001). Overall, males and females did not display significant differences in their pain responses. Histology revealed a characteristic neuroma bulb at week 8, including disorganized axons, fibrotic tissue, Schwann cell displacement, and immune cell infiltration. ConclusionThis novel animal model is a useful tool to investigate underlying mechanisms of neuroma formation and neuropathic pain.

Mechanism of IRF5-regulated CXCL13/CXCR5 Signaling Axis in CCI-induced Neuropathic Pain in Rats.

Neuropathic pain is chronic and affects the patient's life. Studies have shown that IRF5 and CXCL13/CXCR5 are involved in neuropathic pain; however, their interactions are unknown. In this study, a rat neuropathic pain model was constructed by inducing chronic compression injury (CCI). IRF5 recombinant lentiviral vector and CXCL13 neutralizing antibody were administered to investigate their action mechanisms in neuropathic pain. Consequently, the new strategies for disease treatment could be evolved. The CCI rats were intrathecally injected with recombinant lentivirus plasmid LV-IRF5 (overexpression), LV-SH-IRF5 (silencing), and CXCL13 neutralizing antibody. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured. The tumor necrosis factor (TNF)-alpha, interleukin (IL)-1β, and IL-6 levels were recorded via the enzyme-linked immunosorbent assay (ELISA). The spinal cord was stained using hematoxylin-eosin (HE). The binding of IRF5 to CXCL13 was analyzed by chromatin immunoprecipitation (ChIP) and dual luciferase reporter assay. The IRF5, neuronal nuclei (NeuN), CXCL13, and CXCR5 expressions were detected through quantitative real-time polymerase chain reaction and Western blot. The MWT and TWL values in the CCI group were lower than in the Sham group. The expressions of CXCL13, CXCR5, and IRF5 in CCI rats were gradually increased with the modeling time. IRF5 silencing suppressed the expression of NeuN and lumbar enlargement in CCI rats and promoted MWT and TWL. Moreover, IRF5 silencing inhibited the expressions of CXCR5 and CXCL13 genes and down-regulated the expression levels of inflammatory factors. IRF5 was directly and specifically bound with the endogenous CXCL13 promoter and thus regulated it. IRF5 overexpression exacerbated the disease phenotype of CCI-induced neuropathic pain in rats. Administration of CXCL13 neutralizing antibodies reversed the IRF5 overexpression effects. The IRF5 silencing alleviated neuropathic pain in CCI rats by downregulating the pain threshold, inflammatory cytokine levels, and CXCL13/CXCR5 signaling. IRF5 overexpression exacerbated the disease parameters of CCI-induced neuropathic pain in rats; however, they were reversed by neutralizing antibodies against CXCL13.

Sodium channels Nav1.7, Nav1.8 and pain; two distinct mechanisms for Nav1.7 null analgesia

Genetic deletion and pharmacological inhibition are distinct approaches to unravelling pain mechanisms, identifying targets and developing new analgesics. Both approaches have been applied to the voltage-gated sodium channels Nav1.7 and Nav1.8. Genetic deletion of Nav1.8 in mice leads to a loss of pain and antagonists are effective analgesics. The situation with Nav1.7 is more complex. Complete embryonic loss of Nav1.7 in humans or in mouse sensory neurons leads to anosmia as well as profound analgesia as a result of diminished neurotransmitter release. This is mediated by enhanced endogenous opioid signaling in humans and mice. In contrast, anosmia is opioid-independent. Sensory neuron excitability and autonomic function appear to be normal.Adult deletion of Nav1.7 in sensory neurons also leads to analgesia, but through diminished sensory and autonomic neuron excitability. There is no opioid component of analgesia or anosmia as shown by a lack of effect of naloxone. Pharmacological inhibition of Nav1.7 in mice and humans leads both to analgesia and dramatic side-effects on the autonomic nervous system with no therapeutic window. These data demonstrate that specific Nav1.7 channel blockers will fail as analgesic drugs. The viability of embryonic null mutants suggests that there are compensatory changes to replace the lost Nav1.7 channel. Here we show that sensory neuron sodium channels Nav1.1, Nav1.2 and β4 subunits detected by Mass Spectrometry are upregulated in Nav1.7 embryonic null neurons and, together with other proteome changes, potentially compensate for the loss of Nav1.7. Interestingly, many of the upregulated proteins are known to interact with Nav1.7.

The Impact of Obesity as a Peripheral Disruptor of Brain Inhibitory Mechanisms in Fibromyalgia: A Cross-Sectional Study.

Background/Objective: Obesity, characterized by chronic inflammation, may serve as a surrogate marker for more dysfunctional peripheral inflammation, potentially exacerbating FM symptomatology. Given this premise, this study aimed to investigate the effects of obesity as an effect modifier on neural and clinical variables, specifically those indexing pain-compensatory mechanisms in FM symptoms. Methods: A cross-sectional study was conducted with 108 participants who underwent a standardized TMS protocol assessment to measure resting motor threshold (MT), intracortical facilitation (ICF), and intracortical inhibition (ICI). Clinical data were collected using Beck's Depression Index (BDI), PROMIS, the Brief Pain Inventory (BPI), and conditioned pain modulation (CPM). Linear regression models were used to explore the relationship between these variables while examining Body Mass Index (BMI) as a potential effect modifier. If it was found to be a modifier, we stratified the sample into two groups with a BMI cutoff of 30 and performed another regression model within the subgroups. Results: BMI was identified as an effect modifier in the relationships between ICI and BDI, PROMIS fatigue, and CPM and in MT versus CPM. After stratification, non-obese fibromyalgia subjects demonstrated significant correlations between clinical symptoms and CPM and ICI activity. However, these correlations were absent in the obese group, suggesting obesity disrupts pain mechanisms and their compensatory effects. Higher MT values were associated with weaker endogenous pain control, particularly evident in the obese group. Conclusions: Obesity appears to be a significant effect modifier and delineates two patient groups across multiple clinical and neural assessments of fibromyalgia. Additionally, it suggests a role for obesity in exacerbating fibromyalgia symptoms and disrupting physiological pain-inhibitory mechanisms.

Body image, sex, gender, and pain: towards an improved understanding of pain mechanisms.

Body image, sex, gender, and pain: towards an improved understanding of pain mechanisms.

Pain Related Quality of Life in Neurofibromatosis Type 1: A Narrative Review.

The purpose of this narrative review is to summarize pain symptomatology and mechanisms in neurofibromatosis type 1 (NF1), discuss the pain related quality of life impacts of NF1, and discuss the literature exploring interventions to improve quality of life. Chronic pain in NF1 is described as headache and non-headache pain. The literature describes mechanisms contributing to neuronal hyperexcitability in the setting of reduced neurofibromin as key contributors to pain in NF1. Pain in NF1 negatively impacts quality of life with pain interference, depression, anxiety, and cognitive functioning acting as important mediators. Mitogen-activated protein kinase (MEK) inhibitors are pharmacologic agents that interfere with pain mechanisms. Mind-body interventions improve coping skills to improve quality of life. Chronic pain in NF1 is heterogeneous with negative impacts on quality of life. New developments in pharmacological and non-pharmacological interventions offer promising approaches to pain management and quality of life improvement. Additional research is necessary to validate the use of MEK inhibitors and mind-body interventions in the treatment of NF1.

Chronic Low Back Pain: History, Symptoms, Pain Mechanisms, and Treatment.

Chronic low back pain (cLBP) is the most frequently reported cause of years lived with disability. Identifying the anatomical structures or dysfunction contributing to patients' symptoms is critical to guiding treatment. The etiology of back pain and differential diagnosis is often broad, ranging from non-degenerative cLBP (trauma, tumor, inflammation, infection, etc.) to degenerative (also described as nonspecific) cLBP. After eliminating suspicion for more insidious causes of cLBP, a thorough investigation can be conducted in an attempt to identify a source of degenerative cLBP. Degenerative cLBP can originate from many sources, and a detailed understanding of the structures potentially involved is invaluable for an accurate diagnosis. This review article aims to provide a broad overview of the utility of clinical history, physical exam findings, imaging findings, and diagnostic procedures in identifying the cause of patients' cLBP. We provide a framework to help guide clinicians by dividing the structures into groups as follows: anterior vertebral column, posterior vertebral column, and extra-vertebral pain. For each condition listed, we touch on the treatment options that can be considered.

Unravelling relationships between obesity, diabetes, and factors related to somatosensory functioning in knee osteoarthritis patients.

This study explores the association between obesity, diabetes, and somatosensory functioning in patients with knee osteoarthritis (OA), aiming to understand how metabolic conditions are related to pain mechanisms in this patient population. We hypothesized that higher body mass index (BMI), fat mass, and glycated hemoglobin levels (HbA1c) are associated with signs of altered somatosensory functioning. A cross-sectional analysis was conducted as part of a larger multicentre prospective cohort study. Data were collected from patients awaiting total knee arthroplasty in Belgium and the Netherlands. Associations between BMI, fat mass, HbA1c, and various pain-related variables were examined employing Pearson and Spearman correlation analyses which were further analyzed with linear regression techniques. The study included 223 participants. Analysis revealed a significant although weak negative correlation between fat mass and pressure pain thresholds (PPT) at multiple locations, suggesting a link between higher fat mass and increased mechanical hyperalgesia. There were no significant correlations between BMI and pain-related outcomes. HbA1c levels showed very weak positive correlations with pain measures but did not withstand correction for multiple testing. The findings indicate that fat mass may be closely associated with altered somatosensory functioning in patients with knee OA. However, no significant correlations were found between BMI or HbA1c levels and pain-related outcomes. Future research should focus on longitudinal studies to elucidate the causal relationships and further explore the impact of metabolic factors on pain mechanisms in this patient population. Key Points • The findings indicate that fat mass may be closely associated with altered somatosensory functioning in patients with knee OA.

Mouse models of non-dystrophic and dystrophic myotonia exhibit nociplastic pain-like behaviors.

Pain is a prominent and debilitating symptom in myotonic disorders, yet its physiological mechanisms remain poorly understood. This study assessed preclinical pain-like behavior in murine models of pharmacologically induced myotonia and myotonic dystrophy type 1 (DM1). In both myotonia congenita and DM1, impairment of the CLCN1 gene, which encodes skeletal muscle voltage-gated CLC-1 chloride channels, reduces chloride ion conductance in skeletal muscle cells, leading to prolonged muscle excitability and delayed relaxation after contraction. We used the CLC-1 antagonist anthracene-9-carboxylic acid (9-AC) at intraperitoneal doses of 30 or 60 mg/kg and HSA LR20b DM1 mice to model CLC-1-induced myotonia. Our experimental approach included in vivo pain behavioral testing, ex vivo calcium imaging, and whole-cell current-clamp electrophysiology in mouse dorsal root ganglion (DRG) neurons. A single injection of 9-AC induced myotonia in mice, which persisted for several hours and resulted in long-lasting allodynic pain-like behavior. Similarly, HSA LR20b mice exhibited both allodynia and hyperalgesia. Despite these pain-like behaviors, DRG neurons did not show signs of hyperexcitability in either myotonic model. These findings suggest that myotonia induces nociplastic pain-like behavior in preclinical rodents, likely through central sensitization mechanisms rather than peripheral sensitization. This study provides insights into the pathophysiology of pain in myotonic disorders and highlights the potential of using myotonic mouse models to explore pain mechanisms and assess novel analgesics. Future research should focus on the central mechanisms involved in myotonia-induced pain and develop targeted therapies to alleviate this significant clinical burden.

Current advances in the pain treatment and mechanisms of Traditional Chinese Medicine.

Traditional Chinese Medicine (TCM), as a unique medical model in China, has been shown to be effective in the treatment of many diseases. It has been proven that TCM can increase the pain threshold, increase the level of endorphins and enkephalins in the body, and reduce the body's response to adverse stimuli. In recent years, TCM scholars have made valuable explorations in the field of pain treatment, using methods such as internal and external application of TCM and acupuncture to carry out research on pain treatment and have achieved more satisfactory results. TCM treats pain in a variety of ways, and with the discovery of a variety of potential bioactive substances for pain treatment. With the new progress in the research of other TCM treatment methods for pain, TCM will have greater potential in the clinical application of pain.

Development and validation of a mouse model to investigate post surgical pain after laparotomy

BackgroundPostoperative pain following abdominal surgery is a significant obstacle to patient recovery, often necessitating high analgesic doses associated with adverse effects like cognitive impairment and cardiorespiratory depression. Reliable animal models are crucial for understanding the pathophysiology of post surgical pain and developing more effective pain-relieving strategies. MethodsWe developed a mouse model to replicate peritoneal trauma induced by abdominal surgery. 30 C57BL/6 mice underwent laparotomy, with half undergoing standardised peritoneal abrasion and the rest serving as controls. Mouse recovery was assessed using two validated scoring systems of surgical recovery: Post surgery Severity Assessment (PSSA) and Mouse Grimace Score (MGS). Blood samples were taken for cytokine analysis. Adhesions were evaluated on day 6, and peritoneal tissue was examined for healing markers. ResultsAfter laparotomy, all mice exhibited expected pain profiles. Mice with peritoneal abrasion had significantly higher PSSA (7.2 ± 1.2 vs 4.68 ± 0.82, p ≤ 0.001) and MGS scores (3.62 ± 0.74 vs 0.82 ± 0.40, p ≤ 0.05) with slower recovery. Serum inflammatory cytokine levels were significantly elevated in the abraded group, and adhesion formation was higher in this group. Immunohistochemical analysis showed significantly increased expression of α-SMA, CD31, CD68, and F4/80 in peritoneal tissue in the abraded group. DiscussionA mouse model involving laparotomy and standardised peritoneal abrasion replicates the expected pathophysiological changes following abdominal surgery. It will be a useful model for better understanding the mechanisms of post surgical pain and developing improved pain-relief strategies. It also has utility for the study of intra-abdominal adhesion formation. Key messageTo understand the intricate relationship between peritoneal trauma-induced pain, cytokine response, and post-operative adhesion formation in mouse models for advancing therapeutic interventions and enhancing post-operative recovery outcomes.

MDB-39. HOW DO TUMOUR DERIVED EXTRACELLULAR VESICLES INTERACT WITH THE DEVELOPING NERVOUS SYSTEM AND LEAD TO ALTERED PAIN PROCESSING IN CANCER SURVIVORS?

Abstract BACKGROUND Childhood cancer-related pain and its treatment lack sufficient clinical attention due to limited understanding of the underlying mechanisms. While chemotherapy-induced peripheral neuropathic pain (CIPN) mechanisms in adults have been extensively studied, those in early life remain unexplored. In the CIPN literature there is a growing body of evidence for tumour derived factors altering pain processing. Our study aims to understand how tumour derived extracellular vesicles (EVs) interact with the developing nervous system and impact pain processing in childhood brain tumour survivors. METHODS We determined dose-response curves and IC50 values for several medulloblastoma (MB) cell lines using standard-of-care chemotherapy drugs: vincristine, etoposide, cisplatin, and lomustine. EVs were isolated via size exclusion chromatography and characterised through western blotting, flow cytometry and electron microscopy. We quantified the effects of chemotherapy on EV release using ZetaView analysis. We then tested whether EVs from relevant MB cell lines could influence axon development in primary mouse embryonic day 16.5 dorsal root ganglion (DRG) neurons in vitro after pre-treatment with chemotherapy-treated EVs. RESULTS EVs from chemotherapy-treated and untreated cells exhibited similar size and shape. However, a combination of vincristine, etoposide, and cisplatin at low concentrations significantly increased EV secretion by MB cell lines. Moreover, 24-hours following treatment with chemotherapeutic exposed EVs there was complete cell death of embryonic DRG neurons compared to the PBS or control EV treated neurons. CONCLUSION Standard chemotherapy drugs substantially enhanced EV release from MB cells, and co-culture of embryonic DRG neurons with chemotherapy exposed EVs resulted in neuronal death. Our next step is to investigate whether administering these selected EVs in healthy animals alters pain responses and pain maturation. We also aim to study the biodistribution of these EVs within the nervous system and body, after infusion into the cerebrospinal fluid as well as how EV cargo is altered by chemotherapeutics.

(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.

A Narrative Review of the Dorsal Root Ganglia and Spinal Cord Mechanisms of Action of Neuromodulation Therapies in Neuropathic Pain.

Neuropathic pain arises from injuries to the nervous system in diseases such as diabetes, infections, toxicity, and traumas. The underlying mechanism of neuropathic pain involves peripheral and central pathological modifications. Peripheral mechanisms entail nerve damage, leading to neuronal hypersensitivity and ectopic action potentials. Central sensitization involves a neuropathological process with increased responsiveness of the nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold input due to persistent stimuli, leading to sustained electrical discharge, synaptic plasticity, and aberrant processing in the CNS. Current treatments, both pharmacological and non-pharmacological, aim to alleviate symptoms but often face challenges due to the complexity of neuropathic pain. Neuromodulation is emerging as an important therapeutic approach for the treatment of neuropathic pain in patients unresponsive to common therapies, by promoting the normalization of neuronal and/or glial activity and by targeting cerebral cortical regions, spinal cord, dorsal root ganglia, and nerve endings. Having a better understanding of the efficacy, adverse events and applicability of neuromodulation through pre-clinical studies is of great importance. Unveiling the mechanisms and characteristics of neuromodulation to manage neuropathic pain is essential to understand how to use it. In the present article, we review the current understanding supporting dorsal root ganglia and spinal cord neuromodulation as a therapeutic approach for neuropathic pain.

Validity of central pain processing biomarkers for predicting the occurrence of oncological chronic pain: a study protocol

BackgroundDespite recent improvements in cancer detection and survival rates, managing cancer-related pain remains a significant challenge. Compared to neuropathic and inflammatory pain conditions, cancer pain mechanisms are poorly understood, despite pain being one of the most feared symptoms by cancer patients and significantly impairing their quality of life, daily activities, and social interactions. The objective of this work was to select a panel of biomarkers of central pain processing and modulation and assess their ability to predict chronic pain in patients with cancer using predictive artificial intelligence (AI) algorithms.MethodsWe will perform a prospective longitudinal cohort, multicentric study involving 450 patients with a recent cancer diagnosis. These patients will undergo an in-person assessment at three different time points: pretreatment, 6 months, and 12 months after the first visit. All patients will be assessed through demographic and clinical questionnaires and self-report measures, quantitative sensory testing (QST), and electroencephalography (EEG) evaluations. We will select the variables that best predict the future occurrence of pain using a comprehensive approach that includes clinical, psychosocial, and neurophysiological variables.DiscussionThis study aimed to provide evidence regarding the links between poor pain modulation mechanisms at precancer treatment in patients who will later develop chronic pain and to clarify the role of treatment modality (modulated by age, sex and type of cancer) on pain. As a final output, we expect to develop a predictive tool based on AI that can contribute to the anticipation of the future occurrence of pain and help in therapeutic decision making.

Modulating Neural Circuits of Pain in Preclinical Models: Recent Insights for Future Therapeutics.

Chronic pain is a pathological state defined as daily pain sensation over three consecutive months. It affects up to 30% of the general population. Although significant research efforts have been made in the past 30 years, only a few and relatively low effective molecules have emerged to treat chronic pain, with a considerable translational failure rate. Most preclinical models have focused on sensory neurotransmission, with particular emphasis on the dorsal horn of the spinal cord as the first relay of nociceptive information. Beyond impaired nociceptive transmission, chronic pain is also accompanied by numerous comorbidities, such as anxiety-depressive disorders, anhedonia and motor and cognitive deficits gathered under the term "pain matrix". The emergence of cutting-edge techniques assessing specific neuronal circuits allow in-depth studies of the connections between "pain matrix" circuits and behavioural outputs. Pain behaviours are assessed not only by reflex-induced responses but also by various or more complex behaviours in order to obtain the most complete picture of an animal's pain state. This review summarises the latest findings on pain modulation by brain component of the pain matrix and proposes new opportunities to unravel the mechanisms of chronic pain.

Longitudinal multisite study of the chronobiological control of chronic pain: the CircaHealth CircaPain study protocol

IntroductionOne in five Canadians lives with chronic pain. Evidence shows that some individuals experience pain that fluctuates in intensity following a circadian (24-hour) rhythm. Endogenous molecular rhythms regulate the function...

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.

Effects of Pain Relief Through Minimal Exercise Intervention in a Rat Model of Neuropathic Pain.

We aimed to minimize the frequency of exercise intervention and test the efficacy of pain relief. We also investigated the mechanism of neuropathic pain to determine the best frequency of pain relief for neuropathic pain. The chronic constriction injury (CCI) rat model was randomly divided into three groups: exercise (Ex), No-Ex, and normal. The treadmill exercise intervention was administered, and the 50% withdrawal threshold was assessed using the Von Frey Test. Ionized calcium-binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), C-C chemokine receptor type 2 (CCR2), and tumor necrosis factor receptor-associated factor 6 (TRAF6) activation was determined through immunohistochemistry. In the brain, we examined the increased expression of β-endorphin/met-enkephalin in the gray matter of the midbrain aqueduct. Co-expression of CCR2, IBA1, and Neu-N was observed in the spinal cord dorsal horn by immunofluorescence staining. The 50% pain response threshold was significantly lower in the Ex group than in the No-Ex group at five weeks post-CCI, indicating a high analgesic effect. In the dorsal horn of the spinal cord, IBA1 and GFAP were significantly decreased in the Ex group than in the No-Ex group at five weeks post-CCI. However, no significant difference in activation of BDNF, CCR2, and TRAF6 was observed. In the midbrain, the Ex group showed a significant increase compared to the No-Ex group. In summary, our results suggest that in minimal-exercise intervention, neuropathic pain relief is achieved by activation of the descending pain inhibitory system in the midbrain.

Cross-sectional experimental assessment of pain modulation as part of multidimensional profiling of people with cervicogenic headache: protocol for a feasibility study

BackgroundAn endogenous pain modulation profile, reflecting antinociceptive and pronociceptive mechanisms, may help to direct management by targeting the involved pain mechanism. For individuals with cervicogenic headache (CeH), the characteristics of...