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Abstract Background: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that acts on the activity of the cerebral cortex employing electrical currents. Aim: The objective of this project is to evaluate the effectiveness of rTMS on pain and quality of life in patients with chemotherapy-induced peripheral neuropathic pain. Method: Ten patients with chemotherapy-induced peripheral neuropathic pain received 20 sessions of rTMS, consisting of 15 minutes of treatment repeated 5 times per week for four weeks (10 Hz, 20s, 30 trains with 81% intensity). Patients were evaluated using the Brief pain inventory (BPI) and the Functional Assessment of Cancer Therapy and neurotoxicity (FACT-GOG-NTX 13). Results: There were significant differences in BPI mean severity, interference score and FACT-GOG-NTX 13 (p<0,05). Conclusion: The pilot study results suggest that rTMS is potentially beneficial for the treatment of chemotherapy-induced peripheral neuropathy. rTMS over the M1 had an important reduction in pain severity, interference with daily activities, and quality of life scores. However, results should be taken with caution due to the small sample size, absence of a control group and short period of follow-up.

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Resumen Antecedentes: La estimulación magnética transcraneal repetitiva (EMTr) es una técnica no invasiva que actúa sobre la actividad de la corteza cerebral, empleando corrientes eléctricas. Objetivo: El objetivo de este proyecto es evaluar la eficacia de la EMTr sobre el dolor y la calidad de vida en pacientes con dolor neuropático periférico inducido por quimioterapia. Métodos: Diez pacientes con dolor neuropático periférico inducido por quimioterapia recibieron 20 sesiones de EMTr que consistieron en un tratamiento de 15 minutos repetido 5 veces por semana durante cuatro semanas (10 Hz, 20 s, 30 trenes con 81 % de intensidad). Los pacientes fueron evaluados mediante el Inventario Breve de Dolor (BPI) y la Evaluación Funcional de la Terapia del Cáncer y la neurotoxicidad (FACT-GOG-NTX 13). Resultados: Hubo diferencias significativas en la severidad media del dolor del BPI, la puntuación de interferencia y el FACT-GOG-NTX 13 (p<0,05). Conclusión: Los resultados del estudio piloto sugieren que la rTMS es potencialmente beneficiosa para el tratamiento de la neuropatía periférica inducida por la quimioterapia. La rTMS sobre M1 tuvo una reducción importante de la severidad del dolor, la interferencia con las actividades diarias y las puntuaciones de calidad de vida. Sin embargo, los resultados deben tomarse con cautela debido al pequeño tamaño de la muestra, la ausencia de un grupo de control y el corto período de seguimiento.

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Chronic neuropathic pain arises from changes in the somatosensory nervous system and can lead to disability and intense physical and emotional suffering. Recognized as a painful syndrome, its causes are diverse, ranging from stroke, trauma, and diabetes mellitus to unknown origins. It tends to be more common in women, and it is estimated that the number of people affected by this condition increases every year as the population ages. Treatments are based on pharmacological and non-pharmacological interventions; however, the therapeutic plan does not always offer satisfactory relief, and learning to live with pain is, in most cases, the only option. The treatment aims to provide relief from symptoms, and alternative measures such as physiotherapy, physical exercise, and psychological support are strongly recommended. The coronavirus disease (COVID)-19 pandemic exacerbated the pain process, impacting quality of life, generating emotional problems, and potentially contributing to the increased incidence of neuropathic pain. In this context, the narrative review aimed to explore the complex panorama of chronic neuropathic pain, not only from a physiological perspective but also encompassing the psychological perspective and actions related to the pain process.

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Neuropathic pain (NP) is a heterogeneous group of conditions characterized by the experience of a number of sensory disturbances including pain, burning sensations, paroxysms of stabbing pain, dysesthesias, allodynia, and hyperalgesia. The above-mentioned sensations may occur in a specific dermatome area or other delimited region of the body. The objective of this review was to analyze the evidence for ketamine in multifactorial neuropathic pain. The research group systematically searched the databases MEDLINE (via PubMed), EMBASE, SCOPUS, the Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature (Cinahl), and the Web of Science. The findings of this review show that different forms of low doses of ketamine (LDK) do not present statistically significant changes for any of the scales included. In this study, the total symptom score [standardized mean difference (SMD) = -3.59, confidence interval (CI) = -4.16 to -3.02, and p < 0.00001], neuropathy impairment score (SMD = -1.42, CI = -3.68 to 0.84, and p = 0.22), and neuropathy symptom checklist (SMD = -0.09, CI = -0.15 to -0.02, and p = 0.01) were taken into account. For finality compared to the use of a placebo, the findings suggest that LDK does not exhibit significant differences in terms of pain reduction and functionality. Moreover, no specific dosages are identified to support the use of LDK in the reduction in NP.

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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.

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Cannabinoides , Endocannabinoides , Neuralgia , Neuralgia/tratamiento farmacológico , Neuralgia/fisiopatología , Humanos , Endocannabinoides/metabolismo , Animales , Cannabinoides/farmacología , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/fisiopatología , Analgésicos/farmacología , Terapia Molecular Dirigida , Receptores de Cannabinoides/metabolismo

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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.

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BACKGROUND: Recently, we demonstrated that nicorandil inhibits mechanical allodynia induced by paclitaxel. In the present study, we evaluated the effect induced by nicorandil in a model of neuropathic pain induced by chronic constriction injury (CCI) in mice. We also investigated putative mechanisms underlying such an effect. METHODS: CCI was induced by three ligatures of the left sciatic nerve. Mechanical allodynia was evaluated by measuring the paw withdrawal threshold with an electronic von Frey apparatus. Concentrations of cytokines and myeloperoxidase activity were determined in the paw tissue, sciatic nerve, and dorsal root ganglia (DRG). RESULTS: Oral administration of two doses of nicorandil (150 mg/kg po), but not equimolar doses of nicotinamide or nicotinic acid, attenuated mechanical allodynia induced by CCI. Nicorandil activity was reduced by previous administration of glibenclamide (40 mg/kg) or naltrexone (5 mg/kg or 10 mg/kg). Two doses of nicorandil (150 mg/kg, po) reduced tumor necrosis factor-α, interleukin-1ß and interleukin-6, but not CXCL-1, concentrations in the paw tissue of CCI mice. Two doses of nicorandil (150 mg/kg, po) reduced concentrations of all these mediators in the sciatic nerve and DRG. Two doses of nicorandil (150 mg/kg, po) also reduced the myeloperoxidase activity in the paw tissue, sciatic nerve, and DRG. CONCLUSIONS: Nicorandil exhibits antiallodynic activity in a model of neuropathic pain induced by CCI. Inhibition of cytokines production and reduction of neutrophils recruitment in paw tissue, sciatic nerve, and DRG as well as activation of ATP-dependent potassium channels and opioidergic pathways, underlie nicorandil antiallodynic activity.

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Citocinas , Modelos Animales de Enfermedad , Ganglios Espinales , Hiperalgesia , Canales KATP , Neuralgia , Nicorandil , Nervio Ciático , Animales , Nicorandil/farmacología , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Ratones , Nervio Ciático/efectos de los fármacos , Nervio Ciático/metabolismo , Masculino , Citocinas/metabolismo , Canales KATP/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Gliburida/farmacología , Naltrexona/farmacología , Naltrexona/análogos & derivados , Peroxidasa/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Analgésicos/farmacología

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Chronic neuropathic pain (CNP) remains a significant clinical challenge, with complex neurophysiological underpinnings that are not fully understood. Identifying specific neural oscillatory patterns related to pain perception and interference can enhance our understanding and management of CNP. To analyze resting electroencephalography data from individuals with chronic neuropathic pain to explore the possible neural signatures associated with pain intensity, pain interference, and specific neuropathic pain characteristics. We conducted a secondary analysis from a cross-sectional study using electroencephalography data from a previous study, and Brief Pain Inventory from 36 patients with chronic neuropathic pain. For statistical analysis, we modeled a linear or logistic regression by dependent variable for each model. As independent variables, we used electroencephalography data with such brain oscillations: as delta, theta, alpha, and beta, as well as the oscillations low alpha, high alpha, low beta, and high beta, for the central, frontal, and parietal regions. All models tested for confounding factors such as age and medication. There were no significant models for Pain interference in general activity, walking, work, relationships, sleep, and enjoyment of life. However, the model for pain intensity during the past four weeks showed decreased alpha oscillations, and increased delta and theta oscillations were associated with decreased levels of pain, especially in the central area. In terms of pain interference in mood, the model showed high oscillatory Alpha signals in the frontal and central regions correlated with mood impairment due to pain. Our models confirm recent findings proposing that lower oscillatory frequencies, likely related to subcortical pain sources, may be associated with brain compensatory mechanisms and thus may be associated with decreased pain levels. On the other hand, higher frequencies, including alpha oscillations, may disrupt top-down compensatory mechanisms.

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Objectives: Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes mellitus (DM) with symptoms like intense pain and impaired quality of life. This condition has no treatment; instead, the pain is managed with various antidepressants, including duloxetine. The aim of this study is to analyze the evidence on the efficacy of duloxetine in the management of DPN. Methods: A systematic search in different databases was conducted using the keywords "diabetic neuropathy", "duloxetine therapy", "neuropathic pain", and "Diabetes Mellitus". Finally, eight studies were included in this meta-analysis. Results: All articles comparing duloxetine at different doses vs. a placebo reported significant differences in favor of duloxetine on pain scales like 24 h Average Pain Severity (standardized mean difference [SMD] = -1.06, confidence interval [CI] = -1.09 to -1.03, and p < 0.00001) and BPI Severity (SMD = -0.70, CI = -0.72 to -0.68, and p < 0.00001), among others. A total of 75% of the meta-analyses of studies comparing duloxetine at different doses showed a tendency in favor of the 120 mg/d dose. There were significant differences in favor of duloxetine when compared to routine care on the Euro Quality of Life (SMD = -0.04, CI = -0.04 to -0.03, and p < 0.00001) and SF-36 Survey (SMD = -5.86, CI = -6.28 to -5.44, and p < 0.00001) scales. There were no significant differences on the visual analog scale (VAS) when comparing duloxetine and gabapentin. Conclusions: Duloxetine appears to be effective in the management of DPN in different pain, symptom improvement, and quality of life scales.

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Neuropathic pain is a high-intensity pain that can be caused by compression, transection, injury, nerve infiltration and drug treatment of cancer. Furthermore, drug therapy has low clinical efficacy, many adverse effects and remission of painful symptoms. In this way, natural products derived from plants constitute a promising therapeutic alternative. Therefore, the aim of this study was to evaluate the antihyperalgesic effect of γ-terpinene (γ-TPN) e γ-terpinene in ß-cyclodextrin inclusion complexes (TPN/CD) on neuropathic pain induced by tumor cells. Complexation extended the effect time for another 5 h and daily treatment for six days with γ-TPN (50 mg/kg, p.o.) and γ-TPN/ß-CD (50 mg/kg, p.o.) significantly reduced (p < 0.001) the mechanical hyperalgesia induced by the administration of 2x106 sarcoma cells 180 in the around the sciatic nerve. In addition, the Grip and Rota-rod techniques demonstrated that there was no interference on the muscle strength and motor coordination of the animals, suggesting that the compound under study does not have central nervous system depressant effects at the doses used. Molecular docking studies demonstrate favorable binding energies between γ-TPN and ß-CD, and alpha-2 adrenergic, glutamatergic, opioid and cholinergic receptors. Thus, this study demonstrates the potential of terpinene complexation in controlling neuropathic pain induced by tumor cells.

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Monoterpenos Ciclohexánicos , Hiperalgesia , Monoterpenos , Neuralgia , beta-Ciclodextrinas , Animales , beta-Ciclodextrinas/química , beta-Ciclodextrinas/administración & dosificación , Neuralgia/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Masculino , Monoterpenos/farmacología , Monoterpenos/química , Monoterpenos/administración & dosificación , Ratones , Analgésicos/farmacología , Analgésicos/química , Analgésicos/administración & dosificación , Modelos Animales de Enfermedad , Nervio Ciático/efectos de los fármacos , Nervio Ciático/lesiones , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Sarcoma 180/tratamiento farmacológico , Sarcoma 180/patología

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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.

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BACKGROUND: The activated microglia have been reported as pillar factors in neuropathic pain (NP) pathology, but the molecules driving pain-inducible microglial activation require further exploration. In this study, we investigated the effect of dorsal root ganglion (DRG)-derived exosomes (Exo) on microglial activation and the related mechanism. METHODS: A mouse model of NP was generated by spinal nerve ligation (SNL), and DRG-derived Exo were extracted. The effects of DRG-Exo on NP and microglial activation in SNL mice were evaluated using behavioral tests, HE staining, immunofluorescence, and western blot. Next, the differentially enriched microRNAs (miRNAs) in DRG-Exo-treated microglia were analyzed using microarrays. RT-qPCR, RNA pull-down, dual-luciferase reporter assay, and immunofluorescence were conducted to verify the binding relation between miR-16-5p and HECTD1. Finally, the effects of ubiquitination modification of HSP90 by HECTD1 on NP progression and microglial activation were investigated by Co-IP, western blot, immunofluorescence assays, and rescue experiments. RESULTS: DRG-Exo aggravated NP resulting from SNL in mice, promoted the activation of microglia in DRG, and increased neuroinflammation. miR-16-5p knockdown in DRG-Exo alleviated the stimulating effects of DRG-Exo on NP and microglial activation. DRG-Exo regulated the ubiquitination of HSP90 through the interaction between miR-16-5p and HECTD1. Ubiquitination alteration of HSP90 was involved in microglial activation during NP. CONCLUSIONS: miR-16-5p shuttled by DRG-Exo regulated the ubiquitination of HSP90 by interacting with HECTD1, thereby contributing to the microglial activation in NP.

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Exosomas , Ganglios Espinales , Proteínas HSP90 de Choque Térmico , MicroARNs , Microglía , Neuralgia , Animales , Masculino , Ratones , Modelos Animales de Enfermedad , Exosomas/metabolismo , Ganglios Espinales/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Ratones Endogámicos C57BL , Microglía/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Neuralgia/metabolismo , Neuralgia/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética

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OBJECTIVES: This work investigated the acute antinociceptive effect of a synthetic chalcone, 4-dimethylamino chalcone (DMAC), as well as its effects on vincristine-induced peripheral neuropathy (VIPN) in mice. METHODS: The inhibitory activity of myeloperoxidase was assessed by measuring HOCl formation. Formalin and hot plate tests were used to study the acute antinociceptive effect of DMAC. VIPN was induced through the administration of vincristine sulphate (0.1 mg/kg, i.p., 14 days). Then, DMSO, DMAC (10 or 30 mg/kg; i.p.), or pregabalin (10 mg/kg, i.p.) were administered for 14 consecutive days. Thermal hyperalgesia and mechanical allodynia were evaluated before and after VIPN induction and on days 1, 3, 7, and 14 of treatment. Neurodegeneration and neuroinflammation were assessed through immunohistochemistry for NF200, iNOS, and arginase-1 within the sciatic nerve. KEY FINDINGS: DMAC inhibited myeloperoxidase activity in vitro and presented an acute antinociceptive effect in both formalin and hot plate tests, with the involvement of muscarinic and opioid receptors. Treatment with 30 mg/kg of DMAC significantly attenuated thermal hyperalgesia and mechanical allodynia and prevented macrophage proinflammatory polarisation in VIPN mice. CONCLUSIONS: Our results show that DMAC, acting through different mechanisms, effectively attenuates VIPN.

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Analgésicos , Chalconas , Hiperalgesia , Neuralgia , Peroxidasa , Animales , Ratones , Masculino , Analgésicos/farmacología , Neuralgia/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Peroxidasa/metabolismo , Chalconas/farmacología , Vincristina/farmacología , Modelos Animales de Enfermedad , Dolor Agudo/tratamiento farmacológico , Nervio Ciático/efectos de los fármacos

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Protectin DX (PDX), a specialized pro-resolving lipid mediator, presents potential therapeutic applications across various medical conditions due to its anti-inflammatory and antioxidant properties. Since type-1 diabetes mellitus (T1DM) is a disease with an inflammatory and oxidative profile, exploring the use of PDX in addressing T1DM and its associated comorbidities, including diabetic neuropathic pain, depression, and anxiety becomes urgent. Thus, in the current study, after 2 weeks of T1DM induction with streptozotocin (60 mg/kg) in Wistar rats, PDX (1, 3, and 10 ng/animal; i.p. injection of 200 µl/animal) was administered specifically on days 14, 15, 18, 21, 24, and 27 after T1DM induction. We investigated the PDX's effectiveness in alleviating neuropathic pain (mechanical allodynia; experiment 1), anxiety-like and depressive-like behaviors (experiment 2). Also, we studied whether the PDX treatment would induce antioxidant effects in the blood plasma, hippocampus, and prefrontal cortex (experiment 3), brain areas involved in the modulation of emotions. For evaluating mechanical allodynia, animals were repeatedly submitted to the Von Frey test; while for studying anxiety-like responses, animals were submitted to the elevated plus maze (day 26) and open field (day 28) tests. To analyze depressive-like behaviors, the animals were tested in the modified forced swimming test (day 28) immediately after the open field test. Our data demonstrated that PDX consistently increased the mechanical threshold throughout the study at the two highest doses, indicative of antinociceptive effect. Concerning depressive-like and anxiety-like behavior, all PDX doses effectively prevented these behaviors when compared to vehicle-treated T1DM rats. The PDX treatment significantly protected against the increased oxidative stress parameters in blood plasma and in hippocampus and prefrontal cortex. Interestingly, treated animals presented improvement on diabetes-related parameters by promoting weight gain and reducing hyperglycemia in T1DM rats. These findings suggest that PDX improved diabetic neuropathic pain, and induced antidepressant-like and anxiolytic-like effects, in addition to improving parameters related to the diabetic condition. It is worth noting that PDX also presented a protective action demonstrated by its antioxidant effects. To conclude, our findings suggest PDX treatment may be a promising candidate for improving the diabetic condition per se along with highly disabling comorbidities such as diabetic neuropathic pain and emotional disturbances associated with T1DM.

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Ansiedad , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Ácidos Docosahexaenoicos , Ratas Wistar , Animales , Masculino , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/psicología , Ratas , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/psicología , Ácidos Docosahexaenoicos/farmacología , Ácidos Docosahexaenoicos/uso terapéutico , Ansiedad/tratamiento farmacológico , Ansiedad/etiología , Depresión/tratamiento farmacológico , Depresión/etiología , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Corteza Prefrontal/efectos de los fármacos , Neuropatías Diabéticas/tratamiento farmacológico

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Studies have suggested that endoplasmic reticulum stress (ERS) is involved in neurological dysfunction and that electroacupuncture (EA) attenuates neuropathic pain (NP) via undefined pathways. However, the role of ERS in the anterior cingulate cortex (ACC) in NP and the effect of EA on ERS in the ACC have not yet been investigated. In this study, an NP model was established by chronic constriction injury (CCI) of the left sciatic nerve in rats, and mechanical and cold tests were used to evaluate behavioral hyperalgesia. The protein expression and distribution were evaluated using western blotting and immunofluorescence. The results showed that glucose-regulated protein 78 (BIP) and inositol-requiring enzyme 1α (IRE-1α) were co-localized in neurons in the ACC. After CCI, BIP, IRE-1α, and phosphorylation of IRE-1α were upregulated in the ACC. Intra-ACC administration of 4-PBA and Kira-6 attenuated pain hypersensitivity and downregulated phosphorylation of IRE-1α, while intraperitoneal injection of 4-PBA attenuated hyperalgesia and inhibited the activation of P38 and JNK in ACC. In contrast, ERS activation by intraperitoneal injection of tunicamycin induced behavioral hyperalgesia in naive rats. Furthermore, EA attenuated pain hypersensitivity and inhibited the CCI-induced overexpression of BIP and pIRE-1α. Taken together, these results demonstrate that EA attenuates NP by suppressing BIP- and IRE-1α-mediated ERS in the ACC. Our study presents novel evidence that ERS in the ACC is implicated in the development of NP and provides insights into the molecular mechanisms involved in the analgesic effect of EA.

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Modelos Animales de Enfermedad , Electroacupuntura , Estrés del Retículo Endoplásmico , Giro del Cíngulo , Neuralgia , Ratas Sprague-Dawley , Animales , Electroacupuntura/métodos , Giro del Cíngulo/metabolismo , Neuralgia/terapia , Masculino , Estrés del Retículo Endoplásmico/fisiología , Ratas , Western Blotting , Proteínas de Choque Térmico/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Hiperalgesia/terapia , Chaperón BiP del Retículo Endoplásmico

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Neuropathic pain occurs in people experiencing lesion or disease affecting the somatosensorial system. It is present in 7 % of the general population and may not fully respond to first- and second-line treatments in up to 40 % of cases. Neuromodulation approaches are often proposed for those not tolerating or not responding to usual pharmacological management. These approaches can be delivered surgically (invasively) or non-invasively. Invasive neuromodulation techniques were the first to be employed in neuropathic pain. Among them is spinal cord stimulation (SCS), which consists of the implantation of epidural electrodes over the spinal cord. It is recommended in some guidelines for peripheral neuropathic pain. While recent studies have called into question its efficacy, others have provided promising data, driven by advances in techniques, battery capabilities, programming algorithms and software developments. Deep brain stimulation (DBS) is another well-stablished neuromodulation therapy routinely used for movement disorders; however, its role in pain management remains limited to specific research centers. This is not only due to variable results in the literature contesting its efficacy, but also because several different brain targets have been explored in small trials, compromising comparisons between these studies. Structures such as the periaqueductal grey, posterior thalamus, anterior cingulate cortex, ventral striatum/anterior limb of the internal capsule and the insula are the main targets described to date in literature. SCS and DBS present diverse rationales for use, mechanistic backgrounds, and varying levels of support from experimental studies. The present review aims to present their methodological details, main mechanisms of action for analgesia and their place in the current body of evidence in the management of patients with neuropathic pain, as well their particularities, effectiveness, safety and limitations.

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Estimulación Encefálica Profunda , Neuralgia , Estimulación de la Médula Espinal , Humanos , Neuralgia/terapia , Estimulación Encefálica Profunda/métodos , Estimulación de la Médula Espinal/métodos , Manejo del Dolor/métodos

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The purpose of this study was to investigate the mechanisms underlying sex differences in the role of spinal α6-subunit containing GABAA (α6GABAA) receptors in rats with neuropathic pain. Intrathecal 2,5-dihydro-7-methoxy-2-(4-methoxyphenyl)-3H-pyrazolo [4,3-c] quinoline-3-one (PZ-II-029, positive allosteric modulator of α6GABAA receptors) reduced tactile allodynia in female but not in male rats with neuropathic pain. PZ-II-029 was also more effective in females than males in inflammatory and nociplastic pain. Ovariectomy abated the antiallodynic effect of PZ-II-029 in neuropathic rats, whereas 17ß-estradiol or 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT), estradiol receptor-α agonist, restored the effect of PZ-II-029 in ovariectomized rats. Blockade of estradiol receptor-α, using MPP (1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride), prevented the effect of 17ß-estradiol on PZ-II-029-induced antiallodynia in ovariectomized neuropathic females. Nerve injury reduced α6GABAA receptor protein expression at the dorsal root ganglia (DRG) and spinal cord of intact and ovariectomized female rats. In this last group, reconstitution with 17ß-estradiol fully restored its expression in DRG and spinal cord. In male rats, nerve injury reduced α6GABAA receptor protein expression only at the spinal cord. Nerve injury enhanced estradiol receptor-α protein expression at the DRG in intact non-ovariectomized rats. However, ovariectomy decreased estradiol receptor-α protein expression at the DRG. In the spinal cord there were no changes in estradiol receptor-α protein expression. 17ß-estradiol restored estradiol receptor-α protein expression at the DRG and increased it at the spinal cord of neuropathic rats. These data suggest that 17ß-estradiol modulates the expression and function of the α6GABAA receptor through its interaction with estradiol receptor-α in female rats.

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Estradiol , Neuralgia , Receptores de GABA-A , Médula Espinal , Animales , Femenino , Estradiol/farmacología , Receptores de GABA-A/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Ratas , Masculino , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Ovariectomía , Ratas Sprague-Dawley , Caracteres Sexuales , Receptor alfa de Estrógeno/metabolismo , Pirazoles/farmacología

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Aim: This narrative review aimed at identifying the existing scientific literature investigating periodontitis and neuropathic diseases. Materials and Methods: A search of the literature published between 2000 and 2022 was carried out in the electronic databases of Scopus and PubMed. Studies in which the eligible articles were mainly published in English were included. Descriptive correlational studies, case-control studies, comparative studies, and cohort studies were also included. The following main keywords were used: "Neuropathic diseases," "Periodontitis," "Alzheimer's disease," and "Porphyromonas gingivalis." Results: This narrative review found that cognitively impaired persons with severe periodontitis had a higher prevalence and incidence of periodontal diseases than the rest of the population. A significant positive correlation of salivary interleukin (IL)-1beta and immediate recall scores involved in cognition was also evident. It indicates that the most investigated parameter was whether there is any common link between periodontal disease and neurodegeneration. No randomized controlled clinical studies were found in the current literature review. Conclusions: Based on the literature reviewed, there is currently no strong scientific evidence to support or discourage the cause-effect relationship of periodontal diseases and neurodegenerative diseases.

RESUMEN

Bestrophin-1, a calcium-activated chloride channel (CaCC), is involved in neuropathic pain; however, it is unclear whether it has a dimorphic role in female and male neuropathic rats. This study investigated if 17ß-estradiol and estrogen receptor alpha (ERα) activation regulate bestrophin-1 activity and expression in neuropathic rats. Neuropathic pain was induced by L5-spinal nerve transection (SNT). Intrathecal administration of CaCCinh-A01 (.1-1 µg), a CaCC blocker, reversed tactile allodynia induced by SNT in female but not male rats. In contrast, T16Ainh-A01, a selective anoctamin-1 blocker, had an equal antiallodynic effect in both sexes. SNT increased bestrophin-1 protein expression in injured L5 dorsal root ganglia (DRG) in female rats but decreased bestrophin-1 protein in L5 DRG in male rats. Ovariectomy prevented the antiallodynic effect of CaCCinh-A01, but 17ß-estradiol replacement restored it. The effect of CaCCinh-A01 was prevented by intrathecal administration of MPP, a selective ERα antagonist, in rats with and without prior hormonal manipulation. In female rats with neuropathy, ovariectomy prevented the increase in bestrophin-1 and ERα protein expression, while 17ß-estradiol replacement allowed for an increase in both proteins in L5 DRG. Furthermore, ERα antagonism (with MPP) prevented the increase in bestrophin-1 and ERα protein expression. Finally, ERα activation with PPT, an ERα selective activator, induced the antiallodynic effect of CaCCinh-A01 in neuropathic male rats and prevented the reduction in bestrophin-1 protein expression in L5 DRG. In summary, data suggest ERα activation is necessary for bestrophin-1's pronociceptive action to maintain neuropathic pain in female rats. PERSPECTIVE: The mechanisms involved in neuropathic pain differ between male and female animals. Our data suggest that ERα is necessary for expression and function of bestrophin-1 in neuropathic female but not male rats. Data support the idea that a therapeutic approach to relieving neuropathic pain must be based on patient's gender.

Asunto(s)

Bestrofinas , Estradiol , Receptor alfa de Estrógeno , Ganglios Espinales , Neuralgia , Caracteres Sexuales , Animales , Masculino , Femenino , Neuralgia/metabolismo , Neuralgia/tratamiento farmacológico , Ratas , Receptor alfa de Estrógeno/metabolismo , Estradiol/farmacología , Estradiol/administración & dosificación , Bestrofinas/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Ratas Sprague-Dawley , Hiperalgesia/metabolismo , Hiperalgesia/tratamiento farmacológico , Modelos Animales de Enfermedad , Ovariectomía

RESUMEN

BACKGROUND: Cannabidiol (CBD) is the second most abundant pharmacologically active component present in Cannabis sp. Unlike Δ-9-tetrahydrocannabinol (THC), it has no psychotomimetic effects and has recently received significant interest from the scientific community due to its potential to treat anxiety and epilepsy. CBD has excellent anti-inflammatory potential and can be used to treat some types of inflammatory and neuropathic pain. In this context, the present study aimed to evaluate the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain and determine the endogenous mechanisms involved with this analgesia. METHODS: Neuropathic pain was induced by sciatic nerve constriction surgery, and the nociceptive threshold was measured using the paw compression test in mice. RESULTS: CBD produced dose-dependent antinociception after intraperitoneal injection. Selective inhibition of PI3Kγ dose-dependently reversed CBD-induced antinociception. Selective inhibition of nNOS enzymes reversed the antinociception induced by CBD, while selective inhibition of iNOS and eNOS did not alter this antinociception. However, the inhibition of cGMP production by guanylyl cyclase did not alter CBD-mediated antinociception, but selective blockade of ATP-sensitive K+ channels dose-dependently reversed CBD-induced antinociception. Inhibition of S-nitrosylation dose-dependently and completely reversed CBD-mediated antinociception. CONCLUSION: Cannabidiol has an antinociceptive effect when administered systemically and this effect is mediated by the activation of PI3Kγ as well as by nitric oxide and subsequent direct S-nitrosylation of KATP channels on peripheral nociceptors.

Asunto(s)

Analgésicos , Cannabidiol , Fosfatidilinositol 3-Quinasa Clase Ib , Canales KATP , Neuralgia , Óxido Nítrico Sintasa de Tipo I , Óxido Nítrico , Transducción de Señal , Animales , Cannabidiol/farmacología , Canales KATP/metabolismo , Masculino , Transducción de Señal/efectos de los fármacos , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Ratones , Óxido Nítrico/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Analgésicos/farmacología , Analgesia

RESUMEN

Cisplatin is a platinum-based chemotherapy drug widely used to treat various solid tumours. Although it is effective in anti-cancer therapy, many patients develop peripheral neuropathy during and after cisplatin treatment. Peripheral neuropathy results from lesions or diseases in the peripheral somatosensory nervous system and is a significant cause of debilitation and suffering in patients. In recent years, preclinical studies have been conducted to elucidate the mechanisms involved in chemotherapy-induced peripheral neuropathic pain, as well as to promote new therapeutic targets since current treatments are ineffective and are associated with adverse effects. G-protein coupled receptors and ion channels play a significant role in pain processing and may represent promising targets for improving the management of cisplatin-induced neuropathic pain. This review describes the role of G protein-coupled receptors and ion channels in cisplatin-induced pain, analysing preclinical experimental studies that investigated the role of each receptor subtype in the modulation of cisplatin-induced pain.