MFG-E8 Ameliorates Nerve Injury-Induced Neuropathic Pain by Regulating Microglial Polarization and Neuroinflammation via Integrin ß3/SOCS3/STAT3 Pathway in Mice.

Spinal microglial polarization plays a crucial role in the pathological processes of neuropathic pain following peripheral nerve injury. Accumulating evidence suggests that milk fat globule epidermal growth factor-8 (MFG-E8) exhibits anti-inflammatory effect and regulates microglial polarization through the integrin ß3 receptor. However, the impact of MFG-E8 on microglial polarization in the context of neuropathic pain has not yet been investigated. In this study, we evaluated the effect of MFG-E8 on pain hypersensitivity and spinal microglial polarization following spared nerve injury (SNI) of the sciatic nerve in mice. We determined the molecular mechanisms underlying the effects of MFG-E8 on pain hypersensitivity and spinal microglial polarization using pain behavior assessment, western blot (WB) analysis, immunofluorescence (IF) staining, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and small interfering RNA (siRNA) transfection. Our findings indicate that SNI significantly increased the levels of MFG-E8 and integrin ß3 expressed in microglia within the spinal cord of mice. Additionally, we observed that intrathecal injection of recombinant human MFG-E8 (rhMFG-E8) alleviated SNI induced-mechanical allodynia and thermal hyperalgesia. Furthermore, the results suggested that rhMFG-E8 facilitated M2 microglial polarization and ameliorated neuroinflammation via integrin ß3/SOCS3/STAT3 pathway in the spinal cord of mice with SNI. Importantly, these effects were negated by integrin ß3 siRNA, or SOCS3 siRNA. These results demonstrate that MFG-E8 ameliorates peripheral nerve injury induced-mechanical allodynia and thermal hyperalgesia by driving M2 microglial polarization and mitigating neuroinflammation mediated by integrin ß3/SOCS3/STAT3 pathway in the spinal cord of mice. MFG-E8 may serve as a promising target for the treatment of neuropathic pain.

Potentiation of Imipramine-Induced Anti-hyperalgesic and Anti-Nociceptive Effects by Citicoline in the Sciatic Nerve Ligated Mice.

BACKGROUND: Peripheral neuropathic pain is a result of damage/illness of the peripheral nerves. The mechanisms caused by its pathophysiology are not completely understood. METHODS: Imipramine is a tricyclic antidepressant that is sometimes used to treat neuropathic pain. Moreover, citicoline is considered a novel adjuvant for painful disorders such as neuropathic pain. So, a possible interaction between imipramine and citicoline on pain behavior was examined in nerve-ligated mice using tail-flick and hot plate tests. RESULTS: The results indicated that induction of neuropathic pain by sciatic nerve ligation caused hyperalgesia in nerve-ligated mice. On the other hand, intraperitoneal (i.p.) administration of citicoline (50, 75, and 100 mg/kg), and imipramine (2.5 and 5 mg/kg) induced anti-hyperalgesic and anti-nociceptive effects in nerve-ligated mice. Furthermore, citicoline potentiated the anti-hyperalgesic and anti-nociceptive effects of imipramine when they were co-administrated in nerve-ligated mice. Interestingly, there was an additive effect between imipramine and citicoline upon induction of anti-hyperalgesic and anti-nociceptive effects in nerve-ligated mice. CONCLUSION: Therefore, it can be concluded that citicoline (as an adjuvant substance) enhanced the efficacy of imipramine for the modulation of pain behavior in nerve-ligated mice.

Effect of aerobic exercise program on neuropathic pain and quality of life in person with paraplegia: study protocol for a randomized controlled trial.

BACKGROUND: Individuals with spinal cord injury (SCI) often suffer from neuropathic pain which is often disabling and negatively affects function, participation, and quality of life (QoL). Pharmacological treatments lack efficacy in neuropathic pain reduction hence studying alternatives to drug treatment is necessary. Preclinical evidence of various aerobic exercises has shown positive effects on neuropathic pain but scientific studies investigating its effect in the SCI human population are limited. METHODOLOGY: This study is a double-blind, parallel, two-group, randomized controlled trial with an interventional study design that aims to evaluate the effectiveness of aerobic exercise program on neuropathic pain and quality of life (QoL) in individuals with chronic paraplegia. Thirty individuals with chronic paraplegia with the neurological level of injury from T2 to L2 will be recruited from the rehabilitation department at a super specialty hospital based on the inclusion criteria. Using a 1:1 allocation ratio, the participants will be randomly assigned to one of the two groups. The intervention group will perform high-intensity interval training (HIIT) aerobic exercise using an arm ergometer based on their peak heart rate, and the control group will perform free-hand arm aerobic exercise. In both groups, the intervention will be delivered as 30-min sessions, four times a week for 6 weeks. OUTCOME MEASURES: International Spinal Cord Injury Pain Basic Data Set Version 3.0 will be used for diagnosing and assessing neuropathic pain and its interference with day-to-day activities, mood, and sleep. The International Spinal Cord Society (ISCoS) QoL basic data set will be used to assess QoL, and 6-min push test distance will be used to assess peak heart rate and aerobic capacity. DISCUSSION: The effectiveness of the aerobic exercise program will be assessed based on the changes in neuropathic pain score and its interference with day-to-day activities, mood, sleep, QoL, and aerobic capacity after 3 weeks mid-intervention and after 6 weeks post-intervention. The trial will provide new knowledge about the effectiveness of the aerobic exercise program in improving neuropathic pain and QoL in individuals with chronic paraplegia. TRIAL REGISTRATION: Clinical Trials Registry-India CTRI/2023/08/056257. Registered on 8 August 2023.

A comprehensive review of traditional Chinese medicine in treating neuropathic pain.

Neuropathic pain (NP) is a common, intractable chronic pain caused by nerve dysfunction and primary lesion of the nervous system. The etiology and pathogenesis of NP have not yet been clarified, so there is a lack of precise and effective clinical treatments. In recent years, traditional Chinese medicine (TCM) has shown increasing advantages in alleviating NP. Our review aimed to define the therapeutic effect of TCM (including TCM prescriptions, TCM extracts and natural products from TCM) on NP and reveal the underlying mechanisms. Literature from 2018 to 2024 was collected from databases including Web of Science, PubMed, ScienceDirect, Google academic and CNKI databases. Herbal medicine, Traditional Chinese medicines (TCM), neuropathic pain, neuralgia and peripheral neuropathy were used as the search terms. The anti-NP activity of TCM is clarified to propose strategies for discovering active compounds against NP, and provide reference to screen anti-NP drugs from TCM. We concluded that TCM has the characteristics of multi-level, multi-component, multi-target and multi-pathway, which can alleviate NP through various pathways such as anti-inflammation, anti-oxidant, anti-apoptotic pathway, regulating autophagy, regulating intestinal flora, and influencing ion channels. Based on the experimental study and anti-NP mechanism of TCM, this paper can offer analytical evidence to support the effectiveness in treating NP. These references will be helpful to the research and development of innovative TCM with multiple levels and multiple targets. TCM can be an effective treatment for NP and can serve as a treasure house for new drug development.

Complex Regional Pain Syndrome: a cross-sectional study of physical symptoms, disability, and psychological health in long term.

Introduction: Knowledge about long-time residual symptoms, disabilities, and psychological health in complex regional pain syndrome (CRPS) is limited. Objectives: The aim was to evaluate outcome, focusing on physical symptoms, disability, and psychological health, in individuals with CRPS through a cross-sectional survey study. Methods: Individuals with a confirmed diagnosis of CRPS were identified through medical charts and sent validated survey forms (Disabilities of the Arm, Shoulder and Hand-Quick version, Specific Hand Surgery Questionnaire-8 questions, EuroQol 5 Dimensions 3 levels, Life Satisfaction Questionnaire-11, Hospital Anxiety and Depression Scale, Pain Catastrophizing Scale, and Sense of Coherence-29) and complementary questions. Results: Responders (response rate: 99/238, 42%; CRPS type 1: 72%; CRPS type 2: 28%; time since diagnosis median: 59 [34-94] months) reported remaining symptoms and disability (Disabilities of the Arm, Shoulder and Hand-Quick version score: 45 [20-70]) and more improvement in type 1 than in type 2. Only 9% of individuals with CRPS reported no residual pain or discomfort. Approximately 60% had problems in daily activities, 49% had sleeping problems, and 90% experienced moderate-extreme pain with 23% still on sick leave. The Hospital Anxiety and Depression Scale survey revealed significantly higher scores than a Swedish reference population. Individuals with a low Sense of Coherence and high pain catastrophizing had worse disability and were less satisfied with their lives and physical and psychological health. A lower level of education and more anxiety were associated with worsened disability over time. Conclusion: Individuals with CRPS suffer in the long term from pain, sleeping problems, and limitations in daily activities with occurrence of anxiety and depression, resulting in dissatisfaction with many aspects of their lives. A low Sense of Coherence and high pain catastrophizing are associated with a worse outcome. Biopsychosocial aspects should be addressed in clinical practice.

The dual role of TRPV1 in peripheral neuropathic pain: pain switches caused by its sensitization or desensitization.

The transient receptor potential vanilloid 1 (TRPV1) channel plays a dual role in peripheral neuropathic pain (NeuP) by acting as a "pain switch" through its sensitization and desensitization. Hyperalgesia, commonly resulting from tissue injury or inflammation, involves the sensitization of TRPV1 channels, which modulates sensory transmission from primary afferent nociceptors to spinal dorsal horn neurons. In chemotherapy-induced peripheral neuropathy (CIPN), TRPV1 is implicated in neuropathic pain mechanisms due to its interaction with ion channels, neurotransmitter signaling, and oxidative stress. Sensitization of TRPV1 in dorsal root ganglion neurons contributes to CIPN development, and inhibition of TRPV1 channels can reduce chemotherapy-induced mechanical hypersensitivity. In diabetic peripheral neuropathy (DPN), TRPV1 is involved in pain modulation through pathways including reactive oxygen species and cytokine production. TRPV1's interaction with TRPA1 channels further influences chronic pain onset and progression. Therapeutically, capsaicin, a TRPV1 agonist, can induce analgesia through receptor desensitization, while TRPV1 antagonists and siRNA targeting TRPV1 show promise in preclinical studies. Cannabinoid modulation of TRPV1 provides another potential pathway for alleviating neuropathic pain. This review summarizes recent preclinical research on TRPV1 in association with peripheral NeuP.

The endocannabinoid system as a therapeutic target in neuropathic pain: a review.

INTRODUCTION: This review highlights the critical role of the endocannabinoid system (ECS) in regulating neuropathic pain and explores the therapeutic potential of cannabinoids. Understanding the mechanisms of the ECS, including its receptors, endogenous ligands, and enzymatic routes, can lead to innovative treatments for chronic pain, offering more effective therapies for neuropathic conditions. This review bridges the gap between preclinical studies and clinical applications by emphasizing ECS modulation for better pain management outcomes. AREAS COVERED: A review mapped the existing literature on neuropathic pain and the effects of modulating the ECS using natural and synthetic cannabinoids. This analysis examined ECS components and their alterations in neuropathic pain, highlighting the peripheral, spinal, and supraspinal mechanisms. This review aimed to provide a thorough understanding of the therapeutic potential of cannabinoids in the management of neuropathic pain. EXPERT OPINION: Advances in cannabinoid research have shown significant potential for the management of chronic neuropathic pain. The study emphasizes the need for high-quality clinical trials and collaborative efforts among researchers, clinicians, and regulatory bodies to ensure safe and effective integration of cannabinoids into pain management protocols. Understanding the mechanisms and optimizing cannabinoid formulations and delivery methods are crucial for enhancing therapeutic outcomes.

A role for leucine-rich, glioma inactivated 1 in regulating pain sensitivity.

Neuronal hyperexcitability is a key driver of persistent pain states including neuropathic pain. Leucine-rich, glioma inactivated 1 (LGI1), is a secreted protein known to regulate excitability within the nervous system and is the target of autoantibodies from neuropathic pain patients. Therapies that block or reduce antibody levels are effective at relieving pain in these patients, suggesting that LGI1 has an important role in clinical pain. Here we have investigated the role of LGI1 in regulating neuronal excitability and pain-related sensitivity by studying the consequences of genetic ablation in specific neuron populations using transgenic mouse models. LGI1 has been well studied at the level of the brain, but its actions in the spinal cord and peripheral nervous system (PNS) are poorly understood. We show that LGI1 is highly expressed in DRG and spinal cord dorsal horn neurons in both mouse and human. Using transgenic muse models, we genetically ablated LGI1, either specifically in nociceptors (LGI1fl/Nav1.8+), or in both DRG and spinal neurons (LGI1fl/Hoxb8+). On acute pain assays, we find that loss of LGI1 resulted in mild thermal and mechanical pain-related hypersensitivity when compared to littermate controls. In from LGI1fl/Hoxb8+ mice, we find loss of Kv1 currents and hyperexcitability of DRG neurons. LGI1fl/Hoxb8+ mice displayed a significant increase in nocifensive behaviours in the second phase of the formalin test (not observed in LGI1fl/Nav1.8+ mice) and extracellular recordings in LGI1fl/Hoxb8+ mice revealed hyperexcitability in spinal dorsal horn neurons, including enhanced wind-up. Using the spared nerve injury model, we find that LGI1 expression is dysregulated in the spinal cord. LGI1fl/Nav1.8+ mice showed no differences in nerve injury induced mechanical hypersensitivity, brush-evoked allodynia or spontaneous pain behaviour compared to controls. However, LGI1fl/Hoxb8+ mice showed a significant exacerbation of mechanical hypersensitivity and allodynia. Our findings point to effects of LGI1 at both the level of the DRG and spinal cord, including an important impact of spinal LGI1 on pathological pain. Overall, we find a novel role for LGI1 with relevance to clinical pain.

Perspectives on Stem Cell Therapy in Diabetic Neuropathic Pain.

Diabetes mellitus-related morbidity and mortality are primarily caused by long-term complications such as retinopathy, nephropathy, cardiomyopathy, and neuropathy. Diabetic neuropathy (DN) involves the progressive degeneration of axons and nerve fibers due to chronic exposure to hyperglycemia. This metabolic disturbance leads to excessive activation of the glycolytic pathway, inducing oxidative stress and mitochondrial dysfunction, ultimately resulting in nerve damage. There is no specific treatment for painful DN, and new approaches should aim not only to relieve pain but also to prevent oxidative stress and reduce inflammation. Given that existing therapies for painful DN are not effective for diabetic patients, mesenchymal stromal cells (MSCs)-based therapy shows promise for providing immunomodulatory and paracrine regulatory functions. MSCs from various sources can improve neuronal dysfunction associated with DN. Transplantation of MSCs has led to a reduction in hyperalgesia and allodynia, along with the recovery of nerve function in diabetic rats. While the pathogenesis of diabetic neuropathic pain is complex, clinical trials have demonstrated the importance of MSCs in modulating the immune response in diabetic patients. MSCs reduce the levels of inflammatory factors and increase anti-inflammatory cytokines, thereby interfering with the progression of DM. Further investigation is necessary to ensure the safety and efficacy of MSCs in preventing or treating neuropathic pain in diabetic patients.

Analgesic effects of co-administration of mirogabalin and diclofenac sodium on neuropathic pain in rats.

Co-administration of mirogabalin besylate and nonsteroidal anti-inflammatory drugs is effective for neuropathic pain; however, mechanism of its action remains unknown. We aimed to evaluate the mechanism of this synergistic effect of the concomitant administration for neuropathic pain using chronic constriction injury model rats. Fifty male Wister rats of 7-week-old were used. Right sciatic nerve ligation was performed in 40 rats and they were sub-divided into four groups: vehicle, mirogabalin, diclofenac sodium and co-administration of them. Ten rats underwent sham surgery. Fluorogold was attached to sciatic nerve during surgery. Von Frey filament and weight bearing tests were performed on postoperative Day 6 as behavioral assessments and drug was administrated intraperitoneally. Half rats in each group underwent behavioral assessment and perfusion fixation using 4% paraformaldehyde on postoperative Day 7 and remaining on postoperative Day 14. Subsequently, dorsal root ganglion at L4 to L6 was collected and examined immunohistochemistry for calcitonin gene-related peptide, and their immunoreactivity in fluorogold-labeled neurons was measured. Spinal cord at lumbar swelling was resected, immunostained for ionized-calcium-binding adapter molecule-1 and glial fibrillary acidic protein, and immunoreactive neurons in dorsal horn of spinal cords were calculated as the occupancy of them. Mirogabalin suppresses the neuropeptide-release from presynaptic afferent neuron directly and it resulted in suppressing glia cells activation. Diclofenac sodium inhibits cyclooxygenase-2 and prostaglandin production, related to allodynia. These effects of mirogabalin and diclofenac sodium, respectively, inhibited glia cells strongly, which is presumed to be one of the mechanisms for the effectiveness of their co-administration for neuropathic pain.

Urinary kallikrein reverses neuropathic pain by inhibiting ectopic neural discharges, neural inflammation and oxidative stress.

Background: Neuropathic pain is a refractory disease and badly impacts the lives of patients. Urinary kallikrein (UK) acted as a glycoprotein has been discovered to play a pivotal role in neuroprotection. However, the regulatory impacts and correlative pathways of UK in the progression of neuropathic pain remain dimness. Methods: The chronic constriction injury (CCI) rat model was firstly established to mimic neuropathic pain. The withdrawal threshold was measured through the Von Frey test. The levels of TNF-α, IL-1ß and IL-6 were determined through ELISA. The levels of ROS, GSH, SOD and GSH-Px were examined through the commercial kits. The ectopic discharges were assessed. The protein expressions were inspected through western blot. Results: It was demonstrated that withdrawal threshold was reduced in CCI rat model, but this change was reversed after UK treatment, indicating that UK relieved mechanical allodynia. Moreover, UK alleviated the inflammatory response through reducing TNF-α, IL-1ß and IL-6 levels. It was uncovered that oxidative stress was strengthened in CCI rat model, but this impact was restrained after UK treatment. Additionally, UK suppressed ectopic discharge. At last, it was proved that UK triggered the Nrf2/ARE signaling pathway in CCI rat model. Conclusion: This study manifested that UK reversed neuropathic pain by inhibiting ectopic neural pathways, neural pathways and oxidation via the Nrf2/ARE pathway. This study may offer useful proofs the regulatory functions of UK in the cure of neuropathic pain.

Long-Term Treatment of Chronic Postamputation Pain With Bioelectric Nerve Block: Twelve-Month Results of the Randomized, Double-Blinded, Cross-Over QUEST Study.

OBJECTIVE: The multicenter, randomized, double-blinded, active-sham controlled trial (high-freQUEncy nerve block for poST amputation pain [QUEST]) was conducted to show the safety and efficacy of a novel, peripherally placed high-frequency nerve block (HFNB) system in treating chronic postamputation pain (PAP) in patients with lower limb amputations. The primary outcomes from QUEST were reported previously. This study presents the long-term, single-cross-over, secondary outcomes of on-demand HFNB treatment for chronic PAP. MATERIALS AND METHODS: After the three-month randomized period, subjects in the active-sham group were crossed over to receive therapy for 12 months. Subjects self-administered HFNB therapy as needed and reported their pain (numerical rating scale [NRS]; range, 1-10) before and 30 and 120 minutes after each treatment. Pain medication use was reported throughout the study. Pain-days per week and quality of life (QOL) were assessed using the Brief Pain Inventory (BPI). Adverse events (AEs) were recorded for all subjects implanted for 12 months. RESULTS: Of 180 subjects implanted in QUEST, 164 (91%) were included in the cross-over period, and 146 (82%) completed follow-up. By month 12, average NRS pain in the combined cohort was reduced by 2.3 ± 2.2 points (95% CI, 1.7-2.8; p < 0.0001) 30 minutes after treatment and 2.9 ± 2.4 points (95% CI, 2.2-3.6; p < 0.0001) 120 minutes after treatment. Mean pain-days per week were significantly reduced (-3.5 ± 2.7 days; p < 0.001), and subject daily opioid use was reduced by 6.7 ± 29.0 morphine equivalent dose from baseline to month 12 (p = 0.013). Mean BPI-interference scores (QOL) improved by 2.7 ± 2.7 points from baseline (p < 0.001). The incidence of nonserious AEs and serious AEs was 72% (130/180) and 42% (76/180), respectively; serious device-related AEs occurred in 15 of 180 subjects (8%). CONCLUSION: Overall, HFNB delivered directly to the damaged peripheral nerve provided sustained, on-demand relief of acute PAP exacerbations, reduced opioid utilization, and improved QOL for patients with lower limb amputations with chronic PAP.

Are combined conservative interventions effective in reducing pain, disability and/or global rating of pain in people with sciatica with known neuropathic pain mechanisms?

PURPOSE: National Clinical Guidelines recommend an integrated combination of conservative management strategies for sciatica. However, the efficacy of such combinations have not been established. The purpose of this systemic review with meta-analysis was to determine the efficacy of combined conservative (non-pharmacological) compared to single interventions for people with sciatica with a confirmed neuropathic mechanism. METHODS: The systematic review was registered on PROSPERO CRD42023464011. The databases included were the Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), Embase, PubMed, Scopus, APA PsycINFO, and grey literature sources from inception until January 2024. Inclusion criteria were randomized controlled trials that assessed the effectiveness of combined non-pharmacological interventions in comparison to a control intervention among individuals with sciatica of a neuropathic origin identified using diagnostic or clinical tests. Primary outcomes were back pain, leg pain, and disability. The secondary outcome was global rating of change. Study selection, data extraction and risk of bias assessment (using Cochrane ROB2) were assessed by two reviewers. Meta-analysis was performed with a random effects model with inverse variance weighting used for the metanalysis using SPSS v 29. RESULTS: 3,370 articles were identified, of which 6 were included. Risk of bias was high in one study and had some concerns in the remaining 5 studies for each outcome measure. There was evidence of efficacy for combined interventions for back pain in the short-and long-term (SMD - 0.56 (95% CI -0.91, -0.22, p = 0.01, I2 = 0.2; SMD - 0.44 (95% CI -0.79, -0.1, p = 0.03, I2 = 0.00), and for disability in the short term (SMD - 0.48 (95% CI -0.92, -0.04, p = 0.04, I2 = 0.72). There was no evidence of efficacy for leg pain at any time point (( short term SMD - 0.45 (95% CI -0.91, 0.02, p = 0.06, I2 = 0.65), medium term (SMD - 0.29 (95% CI -1.12, 0.54, p = 0.35, I2 = 0.82), long term (SMD - 0.40 (95% CI -1.23, 0.44, p = 0.18, I2 = 0.57).Certainty of evidence ranged from very low to moderate. CONCLUSION: There are few studies that have combined conservative (non-pharmacological) interventions for the management of sciatica with a neuropathic component pain mechanism, as recommended by National Clinical Guidelines. This review indicates that combining conservative (no-pharmacological) management strategies appeared more effective than single interventions for the outcomes of low back pain in the short and long term, and for disability in the short term, but not for leg pain at any time point. The overall low certainty of evidence, suggests that future studies with more robust methodologies are needed.

Artichoke leaf hydroethanolic extract reduces neuropathic pain in a rat model of chronic constriction injury via attenuating the sciatic nerve oxidative stress.

Neuropathic pain, a nerve damage consequence, presents symptoms such as dysesthesia, hyperalgesia, and allodynia. This study aimed to evaluate the alleviating potential of artichoke leaf extract in neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve in male rats. The hydroethanolic extract of artichoke leaf was administered via gavage at doses of 200, 400, and 800 mg/kg for 21 days. Behavioural tests were conducted on days 1, 4, 7, 14, and 21 post-surgeries. Only the dose of 800 mg/kg significantly reduced thermal hyperalgesia and allodynia from day 14 and mechanical allodynia from day 7, and the other doses did not affect behaviours. Biochemical analysis showed that artichoke extract decreased lipid peroxidation and restored antioxidant enzyme activities (SOD and GPx) in the sciatic nerve tissue. In conclusion, artichoke leaf extract administration diminishes neuropathic pain-related behaviours by enhancing antioxidant capacity and reducing oxidative stress in the rats' sciatic nerve.

Pain Interference Prior to and 1 Year After Surgery for Adult Traumatic Brachial Plexus Injury.

PURPOSE: Pain after brachial plexus injury (BPI) can be severely debilitating and is poorly understood. We hypothesized that pain interference (PI) ("the extent to which pain hinders engagement in life") would be predicted by depression, anxiety, severity of pain symptoms, and poorer preoperative muscle function. METHODS: Among patients in a prospective multicenter BPI cohort study, 37 completed Patient-Reported Outcomes Measurement Information System (PROMIS) PI questionnaires before and 1 year after surgery. At both times, participants completed anxiety and depression questionnaires and BPI-specific measures of pain symptoms, physical limitations, and emotional recovery. Surgeon-graded muscle testing, injury severity, age at the time of injury, body mass index, and time from injury to surgery were included. We performed a bivariate analysis of predictors for preoperative and 1-year PROMIS PI followed by multivariable regression modeling using stepwise selection and Bayesian Information Criterion to select covariates. RESULTS: Before surgery, the mean PROMIS PI score was 60.8 ± 11.0, with moderate correlations between PROMIS PI and depression, as well as between PROMIS PI and functional limitations. At 1 year after surgery, the mean PROMIS PI score was 59.7 ± 9.5. There was no difference in preoperative and 1-year PROMIS PI. There were strong correlations between PROMIS PI and pain symptoms, functional limitations, and emotional aspects of recovery at the 1-year follow-up that remained significant in multivariable regression. There were no notable associations between muscle testing and PI. CONCLUSIONS: Pain interference remained substantial and elevated in BPI patients 1 year after surgery. We noted strong associations between PI and pain symptoms, functional limitations, and emotional aspects of recovery. These findings demonstrate the persistence of pain as a feature throughout life after BPI and that its treatment should be considered a priority alongside efforts to improve extremity function. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognosis IV.

Examination of the antiallodynic effect of rosmarinic acid in neuropathic pain and possible mechanisms of action.

This study aimed to explore the potential antiallodynic effects of rosmarinic acid, a natural antioxidant with a demonstrated safety profile across a broad dose range. Using a chronic constriction injury-induced neuropathic pain model, the impact of rosmarinic acid on allodynia was investigated. Furthermore, the involvement of adrenergic and opioidergic mechanisms in its activity was assessed. To evaluate rosmarinic acid's efficacy, doses of 10, 20, and 40 mg/kg were administered and the electronic von Frey test was utilized along with an activity cage apparatus. % MPE values were calculated to gauge the extent of pain relief. Mechanistic insights were obtained by pretreating animals with the ß-adrenergic receptor antagonist propranolol, the α1-adrenergic receptor antagonist prazosin, α2-adrenergic receptor antagonist yohimbine, and the opioid receptor antagonist naloxone. Rosmarinic acid demonstrated a statistically significant antiallodynic effect that was independent of locomotor activity. This effect was noteworthy as it resembled both the level and duration of relief provided by pregabalin. Additionally, the %MPE value of the group treated with 40 mg/kg rosmarinic acid showed a significant difference compared to the value of the pregabalin-treated group (P<0.001). Pre-administration of the antagonists revealed that the antiallodynic activity was shown to be mediated by the stimulation of opioid and adrenergic receptors, with a primary contribution from α2-adrenergic receptor stimulation. Our findings suggest that rosmarinic acid may hold promise as a potential therapeutic agent for neuropathic pain. By elucidating the involvement of adrenergic and opioidergic mechanisms, we have provided valuable preclinical data that could inform novel treatment approaches.

Effect of repetitive transcranial magnetic stimulation on trigeminal-mediated headshaking in 17 horses.

BACKGROUND: Trigeminal-mediated headshaking is a neuropathic facial pain condition in horses. No treatment has been entirely successful. Repetitive transcranial magnetic stimulation (rTMS) is used in human medicine as a treatment for various neuropathic pain conditions, and good results have been achieved in cases of trigeminal neuralgia. OBJECTIVES: Apply rTMS to horses with trigeminal-mediated headshaking (TMHS) and to evaluate tolerability, application of the setting, and success rate. ANIMALS: Seventeen horses with nonseasonal signs of TMHS. METHODS: Other underlying causes of headshaking were ruled out. The rTMS was performed under standing sedation on 5 consecutive days applying 3 sets of 500 stimulations each, with a stimulation strength of 5 Hz. Horses were evaluated on Day 1 (t0) and Day 5 (t1) of the treatment and 2 (t2) and 4 weeks (t3) afterwards using a special scoring system. RESULTS: The rTMS was well tolerated. Headshaking signs during exercise were decreased by 70% (Day 5; t1). Four weeks after rTMS, signs were still decreased (mean reduction of 50%) during exercise. Improvement of mean resting and exercise scores was significant (P < .05) and effect sizes between pretreatment and all time points after treatment (t1, t2, t3) were large (>±0.8). CONCLUSIONS AND CLINICAL IMPORTANCE: Repetitive transcranial magnetic stimulation may be a promising treatment for neuropathic pain and headshaking in affected horses. Pain-free periods after treatment differ individually, and repeated treatment may be necessary. More studies should be performed to determine ideal settings for horses.

Treatment of Painful Diabetic Neuropathy with 10 kHz Spinal Cord Stimulation: Long-Term Improvements in Hemoglobin A1c, Weight, and Sleep Accompany Pain Relief for People with Type 2 Diabetes.

Purpose: The recent SENZA-PDN study showed that high-frequency (10kHz) spinal cord stimulation (SCS) provided significant, durable pain relief for individuals with painful diabetic neuropathy (PDN), along with secondary benefits, including improved sleep quality and HRQoL. Given that metabolic factors and chronic neuropathic pain are related, we evaluated potential secondary effects of 10kHz SCS on hemoglobin A1c (HbA1c) and weight in SENZA-PDN participants with type 2 diabetes (T2D). Patients and Methods: This analysis included 144 participants with T2D and lower limb pain due to PDN who received 10kHz SCS during the SENZA-PDN study. Changes in HbA1c, weight, pain intensity, and sleep were evaluated over 24 months, with participants stratified according to preimplantation HbA1c (>7% and >8%) and body mass index (BMI; ≥30 and ≥35 kg/m2). Results: At 24 months, participants with preimplantation HbA1c >7% and >8% achieved clinically meaningful and statistically significant mean reductions in HbA1c of 0.5% (P = 0.031) and 1.1% (P = 0.004), respectively. Additionally, we observed a significant mean weight loss of 3.1 kg (P = 0.003) across all study participants. In subgroups with BMI ≥30 and ≥35 kg/m2, weight reductions at 24 months were 4.1 kg (P = 0.001) and 5.4 kg (P = 0.005), respectively. These reductions were accompanied by a mean pain reduction of 79.8% and a mean decrease in pain interference with sleep of 65.2% at 24 months across all cohorts. Conclusion: This is the first study of SCS to demonstrate long-term, significant, and clinically meaningful reductions in HbA1c and weight in study participants with PDN and T2D, particularly among those with elevated preimplantation HbA1c and BMI. Although the mechanism for these improvements has yet to be established, the results suggest possible direct and indirect metabolic benefits with 10kHz SCS in addition to durable pain relief. Trial Registration: ClincalTrials.gov Identifier, NCT03228420.

Topical treatment of chemotherapy-induced peripheral neuropathy (CIPN) with high-concentration (179 mg) capsaicin patch in breast cancer patients - results of the QUCIP study.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) following oral or intravenous chemotherapy often results in neuropathic pain, accompanied by symptoms such tingling, burning and hypersensitivity to stimuli, with a notable decline in quality of life (QoL). Effective therapies for CIPN are lacking, with a high demand for analgesics to address this issue. The QUCIP study aimed to assess the effectiveness of high concentration (179 mg) capsaicin patch (HCCP) in alleviating neuropathic pain and associated symptoms in breast cancer patients with confirmed CIPN. Methods: QUCIP is a prospective, multi-center observational study spanning 36 weeks with up to three HCCP treatments. Initial treatment (visit V0) was followed by two telephone contacts (T1, T2) and subsequent face-to-face visits every 12 weeks or upon retreatment (visits V1-V3). 73 female patients with painful CIPN post neoadjuvant/adjuvant breast cancer therapy were enrolled. Primary endpoint was the reduction of neuropathic pain symptom score (painDETECT®). Secondary endpoints included improvements in CIPN-specific QoL (QLQ-CIPN20), reductions in pain intensity (numeric pain rating scale, NPRS), and achievement of ≥ 30% and ≥ 50% pain reduction. Results: Median age was 61 years, with 52.0% of patients experiencing peripheral neuropathic pain for > 1 year (> 2 years: 34.2%). The painDETECT® score significantly decreased from baseline (19.71 ± 4.69) to 15.80 ± 6.20 after initial treatment (p < 0.0001) and continued to decrease at follow-up visits. The NPRS indicated significant pain intensity reduction at each time point, particularly pronounced in patients receiving three HCCP treatments. Clinically significant pain relief of ≥ 30% increased from 25.0% at week 4 (T2) to 36.2%, 43.5%, and 40.0% at weeks 12 (V1), 24 (V2), and 36 (V3), respectively. The percentage of patients achieving pain relief of ≥ 50% increased from 14.7% at T2 to 15.5%, 21.7% and 32.5% at V1, V2 and V3, respectively. Patients further reported a significant improvement in their CIPN-related QoL throughout the study. Adverse drug reactions (ADRs) mainly included application site reactions. Conclusion: In this study, HCCP shows benefit in managing CIPN in real-world settings. The data demonstrate a sustained and progressive reduction in neuropathic pain and symptomatology, confirming the clinical benefit of repeated treatment observed in former clinical trials. HCCP treatment has also the potential to significantly improve the QoL associated with CIPN. The safety profile of HCCP was confirmed, supporting its use in clinical practice.

Transcriptome analysis unveils PLSCR1 associated with microglial polarization in neuropathic pain.

Neuropathic pain (NP) continues to be a significant problem that lacks effective treatment. Our study sought to explore a new promising gene target for the treatment of NP. Differential and enrichment analyses were performed on 24,197 genes and 12,088 genes from the NP microglial microarray and sequencing dataset. Candidate differentially expressed genes (DEGs), functions, and signaling pathways that are closely related to NP were identified by analyzing the bioinformatic results. For in vivo experiments, mice were divided into the sham and NP groups. The expressions of DEGs were validated to screen out the NP hub genes. For in vitro experiments, the hub genes in resting M0-BV2 and polarized M1-BV2 microglia were examined by immunofluorescence, flow cytometry, and qRT-PCR. DEGs in the NP microarray and sequencing data shared five candidate genes, CD244, MEGF9, PCGF2, PLSCR1, and NECAB2. The results of the in vivo experiment showed that the NP model group exhibited higher expression of PLSCR1 and MEGF9 compared to the sham group. The enrichment results of the DEGs revealed the biological processes of "response to lipopolysaccharide". PLSCR1 was highly expressed in the lipopolysaccharide-induced M1-BV2 microglia. PLSCR1 is a potential gene associated with microglial polarization in NP. These findings provide a new view on understanding the pathogenesis mechanism of NP.