Neuropathic pain and mood disorders in earthquake survivors with peripheral nerve injuries.

Background and purpose:

        Natural disasters, such as earthquakes, frequently result in mood disorders among affected individuals. It is established that neuropathic pain arising from traumatic neuropathies is also linked to mood disorders. This study investigates the influence of neuropathic pain on the development of mood disorders in earthquake survivors with peripheral nerve injuries, following the earthquake centered in Kahramanmaras on February 6, 2023. Additionally, we aim to assess the electro­physiological aspects of neuropathic injuries in these survivors.

The study comprised 46 earth-quake survivors with electrophysiologically confirmed peripheral nerve injuries, with 39 trauma-free survivors serving as the control group. Neuropathic pain, anxiety and depression were assessed using the Douleur Neuropathique 4 (DN4) questionnaire and the Hospital Anxiety and Depression Scale (HADS).

Our findings revealed that the ulnar and peroneal nerves were the most commonly injured structures. Among the survivors with peripheral nerve injury, 31 out of 46 (67%) were found to experience neuropathic pain. Furthermore, plexopathy and multiple extremity injuries were associated with more severe neuropathic pain. However, there was no significant difference in anxiety and depression scores between the two groups and neuropathic pain was found to have no independent effect.

The study indicates that the intensity of neuropathic pain varies based on the localization and distribution of peripheral nerve injuries. However, the presence of peripheral nerve damage or neuropathic pain was not directly associated with HADS scores, suggesting that mood disorders following disasters may have multifactorial causes beyond physical trauma.

Stigmasterol alleviates neuropathic pain by reducing Schwann cell-macrophage cascade in DRG by modulating IL-34/CSF1R.

AIMS: This study aimed to investigate the potential therapeutic applications of stigmasterol for treating neuropathic pain. METHODS: Related mechanisms were investigated by DRG single-cell sequencing analysis and the use of specific inhibitors in cellular experiments. In animal experiments, 32 male Sprague-Dawley rats were randomly divided into the sham operation group, CCI group, ibuprofen group, and stigmasterol group. We performed behavioral tests, ELISA, H&E staining and immunohistochemistry, and western blotting. RESULTS: Cell communication analysis by single-cell sequencing reveals that after peripheral nerve injury, Schwann cells secrete IL-34 to act on CSF1R in macrophages. After peripheral nerve injury, the mRNA expression levels of CSF1R pathway and NLRP3 inflammasome in macrophages were increased in DRG. In vitro studies demonstrated that stigmasterol can reduce the secretion of IL-34 in LPS-induced RSC96 Schwann cells; stigmasterol treatment of LPS-induced Schwann cell-conditioned medium (L-S-CM) does not induce the proliferation and migration of RAW264.7 macrophages; L-S-CM reduces CSF1R signaling pathway (CSF1R, P38MAPK, and NFκB) activation, NLRP3 inflammasome activation, and ROS production. In vivo experiments have verified that stigmasterol can reduce thermal and cold hyperalgesia in rat chronic compressive nerve injury (CCI) model; stigmasterol can reduce IL-1ß, IL-6, TNF-α, CCL2, SP, and PGE2 in serum of CCI rats; immunohistochemistry and western blot confirmed that stigmasterol can reduce the levels of IL-34/CSF1R signaling pathway and NLRP3 inflammasome in DRG of CCI rats. CONCLUSION: Stigmasterol alleviates neuropathic pain by reducing Schwann cell-macrophage cascade in DRG by modulating IL-34/CSF1R axis.

Regenerative Peripheral Nerve Interface: Surgical Protocol for a Randomized Controlled Trial in Postamputation Pain.

Surgical procedures, including nerve reconstruction and end-organ muscle reinnervation, have become more prominent in the prosthetic field over the past decade. Primarily developed to increase the functionality of prosthetic limbs, these surgical procedures have also been found to reduce postamputation neuropathic pain. Today, some of these procedures are performed more frequently for the management and prevention of postamputation pain than for prosthetic fitting, indicating a significant need for effective solutions to postamputation pain. One notable emerging procedure in this context is the Regenerative Peripheral Nerve Interface (RPNI). RPNI surgery involves an operative approach that entails splitting the nerve end longitudinally into its main fascicles and implanting these fascicles within free denervated and devascularized muscle grafts. The RPNI procedure takes a proactive stance in addressing freshly cut nerve endings, facilitating painful neuroma prevention and treatment by enabling the nerve to regenerate and innervate an end organ, i.e., the free muscle graft. Retrospective studies have shown RPNI's effectiveness in alleviating postamputation pain and preventing the formation of painful neuromas. The increasing frequency of utilization of this approach has also given rise to variations in the technique. This article aims to provide a step-by-step description of the RPNI procedure, which will serve as the standardized procedure employed in an international, randomized controlled trial (ClinicalTrials.gov, NCT05009394). In this trial, RPNI is compared to two other surgical procedures for postamputation pain management, specifically, Targeted Muscle Reinnervation (TMR) and neuroma excision coupled with intra-muscular transposition and burying.

Peripheral nerve stimulation (PNS): A valid and definitive therapeutical option for a case of anterior cutaneous nerve entrapment syndrome (ACNES).

Anterior cutaneous nerve entrapment syndrome (ACNES) is a cause of moderate to severe chronic pain, hyperesthesia/hypoesthesia, and altered perception of heat/cold in a specific region of the anterior abdominal wall, referable to the territory of innervation of one or more anterior branches of the intercostal nerves. None of the therapeutic options currently available has proved to be effective in the long term or decisive. In recent years, we have begun to treat purely sensory neuropathies, such as this, with the implantation of wireless peripheral nerve stimulators (PNS), achieving the safety of modular and personalized analgesia. We report the case of a 41-year-old man suffering from ACNES of the 8th intercostal nerve for two years. We first performed two consecutive ultrasound-guided diagnostic blocks of the anterior cutaneous branch of the 8th intercostal right nerve and then elected the patient for ultrasound-guided nerve decompression followed by neuromodulation and pulsed-radiofrequency (PRF). Taking into account full employment, young age, and the likelihood of having to repeat the treatment several times, we considered him for Peripheral Nerve Stimulation (PNS) implantation under ultrasound guidance, and we implanted the wireless lead at the anterior branch of the right 8th intercostal nerve, and programmed tonic stimulation 100 Hz PW 200 ms. The patient reported immediate pain relief and never took medication for this problem again, at two years follow-up. PNS has had an increasing role in the management of chronic neuropathic pain, especially in merely sensitive neuropathies like ACNES. We support future research on this theme.

Pain type and neuropathic pain components in acute herpes zoster.

OBJECTIVES: The aim of this study was to investigate the pain type (nociceptive or neuropathic) and neuropathic pain components in patients with acute herpes zoster (HZ). METHODS: Patients with acute HZ referred to the outpatient Dermatology and Venereology clinic between January 2021 and January 2022 were retrospectively detected. The demographic data including gender and age, rash localization, pain severity, and neuropathic pain components were recorded. Pain severity and neuropathic pain components were evaluated using a Visual Analog Scale (VAS) and Douleur Neuropathique 4 (DN4), respectively. RESULTS: The study included a total of 58 patients, comprising 33 females and 25 males. Of these patients, 35 (60.3%) were found to have neuropathic pain. Itching, burning, pins and needles, and tingling were the most frequently reported neuropathic pain signs and symptoms. The proportion of female patients with neuropathic pain was found to be significantly higher than that of male patients (p=0.021). No significant differences were observed in the distribution of pain across different body sites or in the age of patients with neuropathic pain (p>0.05). Itching was significantly more common in younger patients (p=0.02). CONCLUSION: In conclusion, the study found that over half of the patients with acute HZ experienced neuropathic pain, and this was more frequently observed in female patients. Analysis of different components of neuropathic pain showed significant differences in age, gender, and site distribution. The findings of this study may have important implications for the manage-ment and treatment of acute HZ.

Cluster Headache, SUNCT, and SUNA.

OBJECTIVE: This article reviews the epidemiology, clinical features, differential diagnosis, pathophysiology, and management of three types of trigeminal autonomic cephalalgias: cluster headache (the most common), short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). LATEST DEVELOPMENTS: The first-line treatments for trigeminal autonomic cephalalgias have not changed in recent years: cluster headache is managed with oxygen, triptans, and verapamil, and SUNCT and SUNA are managed with lamotrigine. However, new successful clinical trials of high-dose prednisone, high-dose galcanezumab, and occipital nerve stimulation provide additional options for patients with cluster headache. Furthermore, new genetic and imaging tests in patients with cluster headache hold promise for a better understanding of its pathophysiology. ESSENTIAL POINTS: The trigeminal autonomic cephalalgias are a group of diseases that appear similar to each other and other headache disorders but have important differences. Proper diagnosis is crucial for proper treatment.

Cranial Neuralgias.

OBJECTIVE: The cranial neuralgias are relatively rare, but recognizing these syndromes and distinguishing among them is critical to reducing unnecessary pain and disability for affected patients. Despite their distinctive features, cranial neuralgias may go undiagnosed or misdiagnosed for several years. A notable proportion of cranial neuralgia presentations are due to secondary causes and require targeted treatment. The purpose of this article is to review the diagnosis and management of cranial neuralgias encountered in clinical practice. LATEST DEVELOPMENTS: In 2020, the International Classification of Orofacial Pain was released for the first time. Modeled after the International Classification of Headache Disorders, it includes updated terminology for cranial neuralgias. The underlying pathophysiology of the cranial neuralgias is currently believed to be rooted in both peripheral and central nociceptive systems. In addition, a growing number of familial cases are being identified. Recent therapeutic advancements include a better understanding of how to utilize older therapies and procedures more effectively as well as the development of newer approaches. ESSENTIAL POINTS: Cranial neuralgia syndromes are rare but important to recognize due to their debilitating nature and greater likelihood of having potentially treatable underlying causes. While management options have remained somewhat limited, scientific inquiry is continually advancing the understanding of these syndromes and how best to address them.

Pain in the Context of Sensory Deafferentation.

Pain that accompanies deafferentation is one of the most mysterious and misunderstood medical conditions. Prevalence rates for the assorted conditions vary considerably but the most reliable estimates are greater than 50% for strokes involving the somatosensory system, brachial plexus avulsions, spinal cord injury, and limb amputation, with controversy surrounding the mechanistic contributions of deafferentation to ensuing neuropathic pain syndromes. Deafferentation pain has also been described for loss of other body parts (e.g., eyes and breasts) and may contribute to between 10% and upwards of 30% of neuropathic symptoms in peripheral neuropathies. There is no pathognomonic test or sign to identify deafferentation pain, and part of the controversy surrounding it stems from the prodigious challenges in differentiating cause and effect. For example, it is unknown whether cortical reorganization causes pain or is a byproduct of pathoanatomical changes accompanying injury, including pain. Similarly, ascertaining whether deafferentation contributes to neuropathic pain, or whether concomitant injury to nerve fibers transmitting pain and touch sensation leads to a deafferentation-like phenotype can be clinically difficult, although a detailed neurologic examination, functional imaging, and psychophysical tests may provide clues. Due in part to the concurrent morbidities, the physical, psychologic, and by extension socioeconomic costs of disorders associated with deafferentation are higher than for other chronic pain conditions. Treatment is symptom-based, with evidence supporting first-line antineuropathic medications such as gabapentinoids and antidepressants. Studies examining noninvasive neuromodulation and virtual reality have yielded mixed results.

Neuropathic pain after surgery - A clinical validation study and assessment of accuracy measures of the 5-item NeuPPS scale.

OBJECTIVE: The aim of this study was to validate the Neuropathic Pain for Post-Surgical Patients (NeuPPS) scale against clinically verified neuropathic pain (NP) by quantitative sensory testing (QST) as well as evaluation of other psychometric properties. The NeuPPS is a validated 5-item scale designed to evaluate NP in surgical populations. METHODS: Data from 537 women aged >18 years scheduled for primary breast cancer surgery enrolled in a previous study for assessing risk factors for persistent pain after breast cancer treatment were used. Exclusion criteria were any other breast surgery or relevant comorbidity. A total of 448 eligible questionnaires were available at 6 months and 455 at 12 months. At 12 months, 290 patients completed a clinical examination and QST. NeuPPS and PainDETECT were analyzed against patients with and without clinically verified NP. NP was assessed using a standardized QST protocol including a clinical assessment. Furthermore, the NeuPPS and PainDETECT scores were psychometrically tested with an item response theory method, the Rasch analysis, to assess construct validity. Primary outcomes were the diagnostic accuracy measures for the NeuPPS, and secondary measures were psychometric analyses of the NeuPPS after 6 and 12 months. PainDETECT was also compared to clinically verified NP as well as NeuPPS comparing the stability of the estimates. RESULTS: Comparing the NeuPPS scores with verified NP using a receiver operating characteristic curve, the NeuPPS had an area under the curve of 0.80. Using a cutoff of 1, the NeuPPS had a sensitivity of 88% and a specificity of 59%, and using a cutoff of 3, the values were 35 and 96%, respectively. Analysis of the PainDETECT indicated that the used cutoffs may be inappropriate in a surgical population. CONCLUSION: The present study supports the validity of the NeuPPS as a screening tool for NP in a surgical population.

Alteration of serotonin release response in the central nucleus of the amygdala to noxious and non-noxious mechanical stimulation in a neuropathic pain model rat.

Previously, we found that serotonin (5-HT) release in the central nucleus of the amygdala (CeA) of anesthetized rats decreases in response to innocuous stroking of the skin, irrespective of stimulus laterality, but increases in response to noxious pinching applied to a hindlimb contralateral to the 5-HT measurement site. The aim of the present study was to determine whether intra-CeA 5-HT release responses to cutaneous stimulation were altered in an animal model of neuropathic pain induced by ligation of the left L5 spinal nerve. In anesthetized neuropathic pain model rats, stroking of the left hindlimb increased 5-HT release in the CeA, whereas stroking of the right hindlimb decreased it. Meanwhile, pinching of the left hindlimb increased intra-CeA 5-HT release irrespective of stimulus laterality. In conclusion, the present study demonstrated that intra-CeA 5-HT release responses to cutaneous stimulation are altered in an animal model of neuropathic pain.

Spinal microglial M1 polarization contributes paclitaxel-induced neuropathic pain by triggering cells necroptosis.

Paclitaxel (PTX) is a chemotherapeutic agent that is widely used for the treatment of several types of tumors. However, PTX-induced peripheral neuropathy (PIPN) is an adverse effect generally induced by long-term PTX use that significantly impairs the quality of life. Necroptosis has been implicated in various neurodegenerative disorders. Necroptosis of dorsal root ganglion neurons triggers the pathogenesis of PIPN. Therefore, the present study aims to investigate the role of spinal neuronal necroptosis in PIPN. It also explores the potential role of microglial polarization in necroptosis. We established rat models of PIPN via quartic PTX administration on alternate days (accumulated dose: 8 mg/kg). PTX induced obvious neuronal necroptosis and upregulated the expression of receptor-interacting protein kinase (RIP3) and mixed lineage kinase domain-like protein (MLKL) in the spinal dorsal horn. These effects were inhibited with a necroptosis pathway inhibitor, necrostatin-1 (Nec-1). The effect of microglial polarization on the regulation of spinal necroptosis was elucidated by administering minocycline to inhibit PTX-induced M1 polarization of spinal microglia caused by PTX. We observed a significant inhibitory effect of minocycline on PTX-induced necroptosis in spinal cord cells, based on the downregulation of RIP3 and MLKL expression, and suppression of tumor necrosis factor-α and IL-ß synthesis. Additionally, minocycline improved hyperalgesia symptoms in PIPN rats. Overall, this study suggests that PTX-induced polarization of spinal microglia leads to RIP3/MLKL-regulated necroptosis, resulting in PIPN. These findings suggest a potential target for the prevention and treatment of neuropathic pain.

Targeting TRP channels for pain relief: A review of current evidence from bench to bedside.

Several decades of research support the involvement of transient receptor potential (TRP) channels in nociception. Despite the disappointments of early TRPV1 antagonist programs, the TRP family remains a promising therapeutic target in pain disorders. High-dose capsaicin patches are already in clinical use to relieve neuropathic pain. At present, localized injections of the side-directed TRPV1 agonist capsaicin and resiniferatoxin are undergoing clinical trials in patients with osteoarthritis and bone cancer pain. TRPA1, TRPM3, and TRPC5 channels are also of significant interest. This review discusses the role of TRP channels in human pain conditions.

Ketogenic Diet Alleviates Mechanical Allodynia in the Models of Inflammatory and Neuropathic Pain in Male Mice.

Inflammation is involved in the induction of chronic inflammatory and neuropathic pain. Moreover, the ketogenic diet, a high-fat, low-carbohydrate, and adequate protein diet, has an anti-inflammatory effect. Thus, we hypothesized that a ketogenic diet has a therapeutic effect on both types of chronic pain. In the present study, we investigated the effect of a ketogenic diet on mechanical allodynia, a chronic pain symptom, in formalin-induced chronic inflammatory pain and nerve injury-induced neuropathic pain models using adult male mice. Formalin injection into the hind paw induced mechanical allodynia in both the injected and intact hind paws, and the ketogenic diet alleviated mechanical allodynia in both hind paws. In addition, the ketogenic diet prevented formalin-induced edema. Furthermore, the diet alleviated mechanical allodynia induced by peripheral nerve injury. Thus, these findings indicate that a ketogenic diet has a therapeutic effect on chronic pain induced by inflammation and nerve injury.

A novel microglia-targeting strategy based on nanoparticle-mediated delivery of miR-26a-5p for long-lasting analgesia in chronic pain.

Accumulating evidence supports the notion that microglia play versatile roles in different chronic pain conditions. However, therapeutic strategies of chronic pain by targeting microglia remain largely overlooked. This study seeks to develop a miRNA-loaded nano-delivery system by targeting microglia, which could provide a decent and long-lasting analgesia for chronic pain. Surface aminated mesoporous silica nanoparticles were adopted to load miR-26a-5p, a potent analgesic miRNA, by electrostatic adsorption, which can avoid miR-26a-5p is rapidly released and degraded. Then, targeting peptide MG1 was modified on the surface of aminated mesoporous silica particles for microglia targeting. In peripheral nerve injury induced neuropathic pain model, a satisfactory anti-allodynia effect with about 6 weeks pain-relief duration were achieved through targeting microglia strategy, which decreased microglia activation and inflammation by Wnt5a, a non-canonical Wnt pathway. In inflammatory pain and chemotherapy induced peripheral neuropathic pain, microglia targeting strategy also exhibited more efficient analgesia and longer pain-relief duration than others. Overall, we developed a microglia-targeting nano-delivery system, which facilitates precisely miR-26a-5p delivery to enhance analgesic effect and duration for several chronic pain conditions.

Ursolic acid alleviates paclitaxel-induced peripheral neuropathy through PPARγ activation.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) reduces the overall quality of life and leads to interruption of chemotherapy. Ursolic acid, a triterpenoid naturally which presents in fruit peels and in many herbs and spices, can function as a peroxisome proliferator-activated receptor γ (PPARγ) agonist, and has been widely used as an herbal medicine with a wide spectrum of pharmacological activities, including anti-cancer, anti-inflammatory and neuroprotective effect. METHODS: We used a phenotypic drug screening approach to identify ursolic acid as a potential neuroprotective drug in vitro and in vivo and carried out additional biochemical experiments to identify its mechanism of action. RESULTS: Our study demonstrated that ursolic acid reduced neurotoxicity and cell apoptosis induced by pacilitaxel, resulting in an improvement of CIPN. Moreover, we explored the potential mechanisms of ursolic acid on CIPN. As a result, ursolic acid inhibited CHOP (C/EBP Homologous Protein) expression, indicating the endoplasmic reticulum (ER) stress suppression, and regulating CHOP related apoptosis regulator (the Bcl2 family) to reverse pacilitaxel induced apoptosis. Moreover, we showed that the therapeutic effect of ursolic acid on the pacilitaxel-induced peripheral neuropathy is PPARγ dependent. CONCLUSIONS: Taken together, the present study suggests ursolic acid has potential as a new PPARγ agonist targeting ER stress-related apoptotic pathways to ameliorate pacilitaxel-induced peripheral neuropathic pain and nerve injury, providing new clinical therapeutic method for CIPN.

Effects of the elongated needling combined with routine acupuncture therapy in the patients with post-stroke hemiplegia and central pain： a randomized controlled trial. / èŠ’é’ˆé€åˆºè”åˆä½“é’ˆæ²»ç–—å¯¹ä¸­é£ŽåŽåç˜«ä¼´ä¸­æž¢æ€§ç–¼ç—›æ‚£è€ çš„ä¸´åºŠç–—æ•ˆè§‚å¯Ÿï¼šéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To investigate the effects of the elongated needling at the points of hand and foot yang meridians and the Governor Vessel combined with the routine acupuncture therapy on pain, balance function and muscle strength of the patients with post-stroke hemiplegia and central post-stroke pain (CPSP), and to investigate whether its therapeutic mechanism is related to antioxidant damage. METHODS: Ninety-four patients with post-stroke hemiplegia and CPSP admitted from March 2020 to September 2021 were divided into a trial group (47 cases, 1 cases dropped out) and a control group (47 cases 3 cases dropped out). In the control group, the rehabilitation exercise combined with routine acupuncture therapy was used, and in the trial group, on the base of the treatment as the control group, the elongated needling at the points of hand and foot yang meridians and the Governor Vessel was supplemented. In the two groups, the treatment was given once daily, and 1 course of treatment was composed of 14 days, a total of 6 courses were required in the trial. Separately, before treatment, and 1, 2 and 3 months after treatment, between two groups, the score of visual analogue scale (VAS) and that of Berg balance scale (BBS), as well as muscle strength were compared；the neural function was evaluated using the national institutes of health stroke scale (NIHSS) and the serum contents of nitricoxide synthase (NOS), superoxide dismutase (SOD) and malondialdehyde (MDA) were detected by ELISA in the patients. RESULTS: Compared with those before treatment, VAS score and NIHSS score were all decreased (P<0.05) in the trial and the control group after 1 month, 2 months and 3 months of treatment, and BBS score was increased (P<0.05)；and the case proportion of muscle strength grade 4 and 5 was higher (P<0.05) in the trial group. In the control group, the proportion of grade 4 increased after treatment for 2 months (P<0.05), and that of grade 4 and 5 increased after treatment for 3 months (P<0.05). The serum contents of NOS and SOD were increased (P<0.05), and MDA was decreased (P<0.05) after 3 months of treatment in the two groups. In comparison with the control group at the same time point, VAS score and NIHSS score were lower (P<0.05), BBS score higher (P<0.05) and the muscle strength grade was improved (P<0.05, P<0.01) after 1, 2 and 3 months of treatment, respectively；and the serum contents of NOS and SOD increased (P<0.05), and MDA decreased (P<0.05) after 3 months of treatment in the trial group. CONCLUSIONS: The elongated needling at the points of hand and foot yang meridians and the Governor Vessel, combined with the routine acupuncture therapy alleviates CPSP, improves balance and muscle strength and promotes the recovery of neural function in the patients with post-stroke hemiplegia, the mechanism may be related to antioxidant damage.

Post-treatment with maropitant reduces oxidative stress, endoplasmic reticulum stress and neuroinflammation on peripheral nerve injury in rats.

OBJECTIVE: To determine the effective dose and therapeutic potential of maropitant using through expression of mediators of oxidative stress, inflammatory and of the unfolded protein response (UPR) (bio) markers on spinal cord using a model of neuropathic pain induced through chronic constriction injury (CCI) in rats. STUDY DESIGN: Randomized, blinded, prospective experimental study. ANIMALS: 98 male Wistar rats. METHODS: Rats were anesthetized with sevoflurane and after CCI, they were randomly assigned to the following groups that received: vehicle, 3, 6, 15, 30 e 50 mg/kg/24q of maropitant. The effect on inflammatory mediators (IL10, TNFα), oxidative stress (GPx, CAT, SOD), microglial (IBA-1) and neuronal (NeuN, TACR1) markers was evaluated though immunohistochemistry and expression levels of markers of hypoxia (HIF1α, Nrf2), antioxidant enzymes (Catalse, Sod1 and GPx1), and endoplasmic reticulum stress mediators (GRP78, CHOP and PERK) through qRT-PCR. RESULTS: Intraperitoneal injection (IP) of maropitant inhibited nociception with ID50 values of 4,1 mg/kg (5,85-19,36) in a neuropathic pain model through CCI. A dose of 30 mg/kg/24q was significantly effective in reducing mechanical allodynia 1 to 4h after treatment with nociception inhibition (145,83%). A reduction in the expression of hypoxia factors (HIF1α, Nrf2) was observed, along with an increase in antioxidant activity (CAT, SOD and GPX). Additionally, there was a reduction in inflammatory markes (IL10, TNFα), microglial (IBA-1), and neuronal markers (NeuN, TACR1). CONCLUSION AND CLINICAL RELEVANCE: These findings demonstrate that the determined dose, administered daily for seven days, had an antinociceptive effect, as well as anti-inflammatory and antioxidant activity.

Electroacupuncture suppresses neuronal ferroptosis to relieve chronic neuropathic pain.

Growing evidence supports the analgesic efficacy of electroacupuncture (EA) in managing chronic neuropathic pain (NP) in both patients and NP models induced by peripheral nerve injury. However, the underlying mechanisms remain incompletely understood. Ferroptosis, a novel form of programmed cell death, has been found to be activated during NP development, while EA has shown potential in promoting neurological recovery following acute cerebral injury by targeting ferroptosis. In this study, to investigate the detailed mechanism underlying EA intervention on NP, male Sprague-Dawley rats with chronic constriction injury (CCI)-induced NP model received EA treatment at acupoints ST36 and GV20 for 14 days. Results demonstrated that EA effectively attenuated CCI-induced pain hypersensitivity and mitigated neuron damage and loss in the spinal cord of NP rats. Moreover, EA reversed the oxidative stress-mediated spinal ferroptosis phenotype by upregulating reduced expression of xCT, glutathione peroxidase 4 (GPX4), ferritin heavy chain (FTH1) and superoxide dismutase (SOD) levels, and downregulating increased expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), malondialdehyde levels and iron overload. Furthermore, EA increased the immunofluorescence co-staining of GPX4 in neurons cells of the spinal cord of CCI rats. Mechanistic analysis unveiled that the inhibition of antioxidant pathway of Nrf2 signalling via its specific inhibitor, ML385, significantly countered EA's protective effect against neuronal ferroptosis in NP rats while marginally diminishing its analgesic effect. These findings suggest that EA treatment at acupoints ST36 and GV20 may protect against NP by inhibiting neuronal ferroptosis in the spinal cord, partially through the activation of Nrf2 signalling.

Intra-articular injection of gold micro-particles with hyaluronic acid for painful knee osteoarthritis.

BACKGROUND: Recently, in an open pilot study, we found up to two years, a potential pain-relieving effect of intra-articular gold micro-particles using the patient's synovial fluid for patients with knee osteoarthritis (KOA). During the study the excluded group of patients, due to multisite pain, co-morbidities, and other exclusion criteria., received intra-articular gold micro-particles using hyaluronic acid,. We aimed to identify if pre-treatment characteristics influence the global outcome two years after intra-articular treatment for painful KOA with gold microparticles using hyaluronic acid. METHODS: Using hyaluronic acid as the carrier, 136 patients with KOA received intraarticular injections with 20 mg gold microparticles (72.000 particles, 20-40 µm in diameter). In the analysis, we included the Global Rating of Change Scale, Pain Detect Questionnaire (PDQ), Body Mass Index (BMI), and Kellgren & Lawrence score at the inclusion, Western Ontario, and McMaster Universities Osteoarthritis Index (WOMAC) sub-scores for pain, stiffness, and function at inclusion and two years. RESULTS: On the Global Rating Change Scale, 69.1% of patients reported a positive effect, 28.7% no effect, and 2.2% worse. PDQ and the three WOMAC subscores all improved at two years of follow-up. PDQ ≥ 13 (P = 0.028), BMI (P = 0.022) and Kellgren & Lawrence grade 4 (P = 0.028) at inclusion reduced the effect with a minor odds ratio compared to the baseline effect of treatment (P = 0.025). WOMAC subscores at inclusion did not influence the outcome (P > 0.5). CONCLUSIONS: Severe osteoarthritis, obesity, and neuropathic pain, reduced the effect of intra-articular gold microparticles for knee OA. TRIAL REGISTRATION: The study followed the principles of the Declaration of Helsinki and was approved by the local ethics committee of the North Denmark Region by 27/07/2016 (N-20,160,045). The regional data protection agency approved the project by 06/07/2016 (2008-58-0028, ID 2016 - 116) and registered in ClinicalTrial.Gov by 04/01/2018 (NCT03389906).

Low-Level miR-199 Contribute to Neuropathic Low Back Pain via TRPV1 by Regulating the Production of Pro-Inflammatory Cytokines on Macrophage.

AIM: To explore the post-translational regulation of TRPV1, which plays an important role in neuropathic low back pain (NLBP). MATERIAL AND METHODS: qPCR was used to examine the gene mRNA levels. Western blot was used to examine the protein level. NLBP rat model was established for confirming what we observed in clinical samples. Dual-luciferase assay was used to verify the miR-199 targets on the 3'UTR of TRPV1. Cell coculture was used to explore the interaction between macrophages and nerve cells. RESULTS: We found the mRNA level of TRVP1 decreased in the sinuvertebral nerve biopsy of NLBP. With bioinformatics prediction, miR199 would involve the post-transcription regulation of TRPV1. As the prediction, the miR199 level decreased in the clinical samples. Correlation regression analysis showed a negative correlation between miR-199 and TRPV1. The same phenomenon was confirmed in the rat NLBP model. With dual-luciferase assay, we confirmed that miR199 directly binds to the 3'UTR of TRPV1. Through co-culture of macrophage (THP1) and sNF96.2, we found that up or down-regulates miR-199 in macrophage and sNF96.2 could relieve or aggravate the injury of nerve cells strain. CONCLUSION: These results suggest that the occurrence of NLBP may be caused by the lower expression of miR-199 in macrophages and nerve via TRPV1.