Transcranial direct current stimulation is more effective than pregabalin in controlling nociceptive and anxiety-like behaviors in a rat fibromyalgia-like model.

OBJECTIVES: Despite the fact that fibromyalgia, a widespread disease of the musculoskeletal system, has no specific treatment, patients have shown improvement after pharmacological intervention. Pregabalin has demonstrated efficacy; however, its adverse effects may reduce treatment adherence. In this context, neuromodulatory techniques such as transcranial direct current stimulation (tDCS) may be employed as a complementary pain-relieving method. Consequently, the purpose of this study was to evaluate the effect of pregabalin and tDCS treatments on the behavioral and biomarker parameters of rats submitted to a fibromyalgia-like model. METHODS: Forty adult male Wistar rats were divided into two groups: control and reserpine. Five days after the end of the administration of reserpine (1 mg/kg/3 days) to induce a fibromyalgia-like model, rats were randomly assigned to receive either vehicle or pregabalin (30 mg/kg) along with sham or active- tDCS treatments. The evaluated behavioral parameters included mechanical allodynia by von Frey test and anxiety-like behaviors by elevated plus-maze test (time spent in opened and closed arms, number of entries in opened and closed arms, protected head-dipping, unprotected head-dipping [NPHD], grooming, rearing, fecal boluses). The biomarker analysis (brain-derived neurotrophic factor [BDNF] and tumor necrosis factor-α [TNF-α]) was performed in brainstem and cerebral cortex and in serum. RESULTS: tDCS reversed the reduction in the mechanical nociceptive threshold and the decrease in the serum BDNF levels induced by the model of fibromyalgia; however, there was no effect of pregabalin in the mechanical threshold. There were no effects of pregabalin or tDCS found in TNF-α levels. The pain model induced an increase in grooming time and a decrease in NPHD and rearing; while tDCS reversed the increase in grooming, pregabalin reversed the decrease in NPHD. CONCLUSIONS: tDCS was more effective than pregabalin in controlling nociception and anxiety-like behavior in a rat model-like fibromyalgia. Considering the translational aspect, our findings suggest that tDCS could be a potential non-pharmacological treatment for fibromyalgia.

Efeitos de um programa multiprofissional de tratamento da obesidade com treinamento aquático sobre parâmetros bioquímicos, composição corporal e aptidão física em adultos

Diante ao preocupante cenário mundial sobre a obesidade e a importância de intervenções multiprofissionais para mudança no estilo de vida da população com obesidade. O Objetivo foi analisar os efeitos de um programa multiprofissional para tratamento da obesidade com treinamento aquático, nos parâmetros bioquímicos, composição corporal e da aptidão física de adultos obesidade severa. O estudo foi conduzido por equipe multiprofissional com profissionais de Educação Física, Nutrição, Psicologia e Medicina, durante 24 semanas, com 16 indivíduos classificados com obesidade severa (IMC > 40 kg/m2). As Intervenções do programa proposto no estudo foram realizadas através treinamento aquático de exercícios aeróbicos associados com a orientação nutricional e psicológica. Foi analisada diminuição significativa no índice de Proteína C Reativa (mg/L) (p=0,0439); no percentual de gordura (%), ao final das 24 semanas do programa de tratamento (p=0,0136), também houve aumento significativo na força de pressão manual (kg) com 16 semanas (p=0,0006) e 24 semanas (p=0,0014). Este estudo apresentou resultados significativos na melhora dos parâmetros bioquímicos, composição corporal e da aptidão física em adultos com obesidade severa, justificando o quanto programas de tratamentos que visam a mudanças nos hábitos alimentares e estilo de vida são de grande importância para a saúde pública.

Ante el preocupante panorama mundial de la obesidad y la importancia de intervenciones multiprofesionales para el cambio en el estilo de vida de la población con obesidad, este estudio tiene como objetivo analizar los efectos de un programa multiprofesional para el tratamiento de la obesidad mediante entrenamiento acuático en parámetros bioquímicos, composición corporal y aptitud física en adultos con obesidad severa. El estudio fue llevado a cabo por un equipo multiprofesional compuesto por profesionales de Educación Física, Nutrición, Psicología y Medicina, durante un período de 24 semanas. Participaron 16 individuos clasificados con obesidad severa (IMC > 40 kg/m2). Las intervenciones del programa propuesto en el estudio incluyeron ejercicios aeróbicos acuáticos junto con orientación nutricional y psicológica. Se evidenció una disminución significativa en el índice de Proteína C Reactiva (mg/L) (p=0.0439); en el porcentaje de grasa (%), al final de las 24 semanas del programa de tratamiento (p=0,0136), también se evidencio un aumento estadísticamente significativo de la fuerza de presión manual (kg) con 16 semanas (p=0,0006) e 24 semanas (p=0,0014). Este estudio presentó resultados significativos en la mejora de los parámetros bioquímicos, composición corporal y aptitud física en adultos con obesidad severa, lo que justifica la importancia de los programas de tratamiento que se centran en los cambios en los hábitos alimentarios y el estilo de vida para la salud pública.

In the context of the concerning global prevalence of obesity and the critical need for multidisciplinary interventions to drive lifestyle changes among individuals with obesity, this study aims to investigate the effects of a comprehensive multidisciplinary program, including aquatic training, on biochemical parameters, body composition, and physical fitness in severely obese adults. Over a period of 24 weeks, a team of diverse professionals in Physical Education, Nutrition, Psychology, and Medicine collaborated on this research. The study enrolled sixteen participants with severe obesity (BMI > 40 kg/m2). The interventions encompassed aquatic aerobic exercises, accompanied by nutritional and psychological guidance. Significant improvements were observed in the C-Reactive Protein index (mg/L) (p=0.0439), with a notable reduction in body fat percentage (%) after the 24-week treatment program (p=0.0136). Additionally, manual pressure force (kg) displayed a statistically significant increase at 16 weeks (p=0.0006) and 24 weeks (p=0.0014). These compelling findings underscore the remarkable progress in biochemical parameters, body composition, and physical fitness among severely obese adults, underscoring the critical importance of treatment programs targeting dietary and lifestyle changes for public health improvement. By adopting a multidisciplinary approach, this study emphasizes the effectiveness of comprehensive interventions in addressing the complex challenges posed by severe obesity. In summary, this research reinforces the significance of implementing multidisciplinary programs to foster lifestyle modifications and provides valuable insights into tackling severe obesity in adult populations. By highlighting the pivotal role of holistic interventions, this study contributes to the ongoing global efforts to combat the escalating obesity epidemic.

Efetividade de um programa multiprofissional de tratamento da obesidade durante a pandemia de COVID-19: aplicação do monitoramento remoto da enfermagem / Efectividad de un programa multidisciplinario de tratamiento de la obesidad durante la pandemia de COVID-19: aplicación de monitoreo remoto de enfermería / Effectiveness of a multidisciplinary obesity treatment program during the COVID-19 pandemic: application of remote nursing monitoring

Objetivo: Verificar a efetividade do monitoramento remoto da enfermagem associada a um programa multi-profissional de tratamento de obesidade na melhora dos biomarcadores cardiometabólicos e indicadores da aptidão física relacionada à saúde de adultos com obesidade acompanhados durante a pandemia da COVID-19. Métodos: Estudo caracterizado como um Ensaio Clínico Pragmático, realizado em um município do Sul do Brasil, com 22 mulheres, com idade entre 18 e 50 anos, portadores de telefone celular com acesso ao aplicativo WhatsApp® durante 16 semanas. Foram realizadas avaliações pré e pós intervenção por meio de exames labo-ratoriais, capazes de determinar os biomarcadores cardiometabólicos: HDL, triglicerídeos, LDL, colesterol total, glicemia, hemoglobina glicada, insulina, Homa-IR, Homa-β, PCR-us; e de testes capazes de avaliar os níveis da aptidão física relacionada à saúde: composição corporal, aptidão cardiorrespiratória, força muscular e flexibili-dade. Os dados obtidos foram analisados através do teste t para amostras pareadas e correlacionados a partir do valor de delta absoluto de cada variável por meio da correlação de Pearson. Os resultados foram considerados significantes quando o valor de p foi < 0,05. Este estudo possui parecer favorável do Comitê Nacional de Ética em Pesquisas. Resultados: Foram observadas melhoras significativas nos níveis de glicemia, insulina, Homa-IR e HDL, bem como nos indicadores de aptidão cardiorrespiratória e força muscular. Conclusão: O monitoramento remoto da enfermagem associado a um programa multiprofissional de tratamento de obesidade é uma inter-venção efetiva na melhoria dos biomarcadores cardiometabólicos e dos indicadores da AFRS.

Objetivo: Evaluar la efectividad del monitoreo remoto de enfermería, en asociación con un programa multiprofesional de tratamiento de la obesidad, para mejorar los biomarcadores cardiometabólicos y los indicadores de aptitud física relacionados con la salud en adultos obesos durante la pandemia de COVID-19.Métodos: Se llevó a cabo un Ensayo Clínico Pragmático en un municipio del sur de Brasil, con la participación de 22 mujeres de edades comprendidas entre los 18 y 50 años, que contaban con teléfonos móviles con acceso a la aplicación WhatsApp® durante un período de 16 semanas. Se realizaron evaluaciones pre y postintervención mediante exámenes de laboratorio, que permitieron determinar los biomarcadores cardiometabólicos: HDL, triglicéridos, LDL, colesterol total, glucemia, hemoglobina glucosilada, insulinemia, Homa-IR, Homa-β, hs-CRP; y pruebas para evaluar los niveles de aptitud física relacionados con la salud: composición corporal, aptitud cardiorrespiratoria, fuerza muscular y flexibilidad. Los datos obtenidos se analizaron utilizando la prueba t para muestras pareadas y se correlacionaron mediante la correlación de Pearson, a partir del valor delta absoluto de cada variable. Se consideraron resultados significativos cuando el valor de p fue < 0,05. Este estudio recibió la aprobación del Comité Nacional de Ética en Investigación.Resultados: Se observaron mejoras significativas en los niveles de glucosa en sangre, insulina, Homa-IR y HDL, así como en los indicadores de aptitud cardiorrespiratoria y fuerza muscular.Conclusión: El monitoreo remoto de enfermería, en asociación con un programa multidisciplinario de tratamiento de la obesidad, resulta en una intervención eficaz para mejorar los biomarcadores cardiometabólicos y los indicadores de aptitud física relacionados con la salud.

Objective: To verify the effectiveness of remote nursing monitoring associated with a multi-professional obesity treatment program to improve cardiometabolic biomarkers and health-related physical fitness indicators in obese adults followed during the COVID-19 pandemic. Methods: The study was characterized as a Pragmatic Clinical Trial, carried out in a municipality in the south of Brazil. It involved 22 women aged between 18 and 50 years, who had cell phones with access to the WhatsApp® application for 16 weeks. Pre- and post-intervention evaluations were carried out through laboratory tests capable of determining cardiometabolic biomarkers: HDL, triglycerides, LDL, total cholesterol, glycemia, glycated hemoglobin, insulinemia, Homa-IR, Homa-β, hs-CRP. As well as tests capable of assessing the levels of physical fitness related to health: body composition, cardiorespiratory fitness, muscle strength and flexibility. The data obtained were analyzed using the t-test for paired samples and correlated from the absolute delta value of each variable using Pearson's correlation. Results were considered significant when the p value was <0.05. This study received a favorable opinion from the National Research Ethics Committee. Results: The study observed significant improvements in blood glucose, insulin, Homa-IR and HDL levels, as well as in indicators of cardiorespiratory fitness and muscle strength. Conclusion: Remote nursing monitoring associated with a multidisciplinary obesity treatment program is an effective intervention for improving cardiometabolic biomarkers and AFRS indicators.

Preemptive transcranial direct current stimulation induces analgesia, prevents chronic inflammation and fibrosis, and promotes tissue repair in a rat model of postoperative pain.

This study evaluated the effects of previous exposure to Transcranial Direct Current Stimulation (tDCS) on nociceptive, neuroinflammatory, and neurochemical parameters, in rats subjected to an incisional pain model. Forty adult male Wistar rats (60 days old; weighing âˆ¼ 250 g) were divided into five groups: 1. control (C); 2. drugs (D); 3. surgery (S); 4. surgery + sham-tDCS (SsT) and 5. surgery + tDCS (ST). Bimodal tDCS (0.5 mA) was applied for 20 min/day/8 days before the incisional model. Mechanical allodynia (von Frey) was evaluated at different time points after surgery. Cytokines and BDNF levels were evaluated in the cerebral cortex, hippocampus, brainstem, and spinal cord. Histology and activity of myeloperoxidase (MPO) and N-acetyl-ß-D-glucosaminidase (NAGase) were evaluated in the surgical lesion sites in the right hind paw. The results demonstrate that the surgery procedure increased BDNF and IL-6 levels in the spinal cord levels in the hippocampus, and decreased IL-1ß and IL-6 levels in the cerebral cortex, IL-6 levels in the hippocampus, and IL-10 levels in the brainstem and hippocampus. In addition, preemptive tDCS was effective in controlling postoperative pain, increasing BDNF, IL-6, and IL-10 levels in the spinal cord and brainstem, increasing IL-1ß in the spinal cord, and decreasing IL-6 levels in the cerebral cortex and hippocampus, IL-1ß and IL-10 levels in the hippocampus. Preemptive tDCS also contributes to tissue repair, preventing chronic inflammation, and consequent fibrosis. Thus, these findings imply that preemptive methods for postoperative pain management should be considered an interesting pain management strategy, and may contribute to the development of clinical applications for tDCS in surgical situations.

Involvement of GABAergic, glutamatergic, opioidergic, and brain-derived neurotrophic factor systems in the trigeminal neuropathic pain process.

Trigeminal neuropathic pain (TNP) is an intense pain condition characterized by hyperalgesia and allodynia; however, its neural mechanisms are not completely understood. Its management is complex, and studies that investigate its biochemical mechanisms are important for improving clinical approaches. This study aimed to evaluate the involvement of GABAergic, glutamatergic, and opioidergic systems and brain-derived neurotrophic factor (BDNF) levels in the TNP process in rats. TNP is induced by chronic constriction injury of the infraorbital nerve (CCI-ION). Nociceptive responses were evaluated using the facial von Frey test before and after the administration of GABAergic and opioidergic agonists and glutamatergic antagonists. The rats were divided into vehicle-treated control (C), sham-surgery (SS), and CCI-ION groups, and then subdivided into the vehicle (V)-treated SS-V and CCI-ION-V groups, SS-MK801 and CCI-ION-MK801, treated with the N-methyl-d-aspartate receptor selective antagonist MK801; SS-PB and CCI-ION-PB, treated with phenobarbital; SS-BZD and CCI-ION-BZD, treated with diazepam; SS-MOR and CCI-ION-MOR, treated with morphine. BDNF levels were evaluated in the cerebral cortex, brainstem, trigeminal ganglion, infraorbital branch of the trigeminal nerve, and serum. CCI-ION induced facial mechanical hyperalgesia. Phenobarbital and morphine reversed the hyperalgesia induced by CCI-ION, and the CCI-BZD group had an increased nociceptive threshold until 60 min. CCI-ION-GLU increased the nociceptive threshold at 60 min. Cerebral cortex and brainstem BDNF levels increased in the CCI-ION and SS groups. Only the CCI group presented high levels of BDNF in the trigeminal ganglion. Our data suggest the involvement of GABAergic, glutamatergic, and opioidergic systems and peripheral BDNF in the TNP process.

Short-term effectiveness of transcranial direct current stimulation in the nociceptive behavior of neuropathic pain rats in development.

Neuropathic pain (NP) is caused by a lesion that triggers pain chronification and central sensitization and it can develop in a different manner, dependent of age. Recent studies have demonstrated the efficacy of transcranial direct current stimulation (tDCS) for treating NP. Then, we aimed to investigate the effects of tDCS and BDNF levels in neuropathic pain rats in development, with 30 days old in the beginning of experiments. Eight-five male Wistar rats were subjected to chronic constriction injury. After establishment of NP, bimodal tDCS was applied to the rats for eight consecutive days, for 20 minutes each session. Subsequently, nociceptive behavior was assessed at baseline, 14 days after surgery, 1 day and 7 days after the end of tDCS. The rats were sacrificed 8 days after the last session of tDCS. An increase in the nociceptive threshold was observed in rats in development 1 day after the end of tDCS (short-term effect), but this effect was not maintained 7 days after the end of tDCS (long-term effect). Furthermore, brain derived neurotrophic factor (BDNF) levels were analyzed in the frontal cortex, spinal cord and serum using ELISA assays. The neuropathic pain model showed an effect of BDNF in the spinal cord of rats in development. There were no effects of BNDF levels of pain or tDCS in the frontal cortex or serum. In conclusion, tDCS is an effective technique to relieve nociceptive behavior at a short-term effect in neuropathic pain rats in development, and BDNF levels were not altered at long-term effect.

Cancer symptoms: do patients, family caregivers and professionals agree?

OBJECTIVES: To assess the level of agreement among patients, their family caregivers and health professionals regarding the symptoms presented by patients with cancer. METHODS: This is a cross-sectional study carried out in patients with cancer admitted to a hospital in Brazil from December 2019 to July 2020. One family caregiver for each patient was included in the study. In addition, nurses and physicians involved in patient care were included. Patients, family caregivers and health professionals responded to the Palliative Outcome Scale (POS). RESULTS: Sixty-one patients with their family caregivers, 18 nurses and 8 physicians were included. Physicians reported a lower mean POS score than patients (p=0.008). In general, physicians and nurses underestimated the anxiety of the patient and the anxiety of the family caregivers and how much the patient feels that his or her life is worthwhile. Intraclass correlation coefficient showed moderate and good levels of agreement between patients' and family caregivers' responses (0.61). Agreement between patient and nurse (0.02) and physician (0.21) responses was poor. CONCLUSIONS: The level of agreement between patients and healthcare professionals was very poor regarding patients' symptoms. However, the caregiver's perception of the patient's symptoms can be a reliable source of information.

Measuring emotional preoperative stress by an app approach and its applicability to predict postoperative pain.

BACKGROUND: The Brief Measure of Emotional Preoperative Stress (B-MEPS) was developed to evaluate the preoperative individual vulnerability to emotional stress. To obtain a refined version of B-MEPS suitable for an app approach, this study aimed: (i) to identify items with more discriminant properties; (ii) to classify the level of preoperative emotional stress based on cut-off points; (iii) to assess concurrent validity through correlation with the Central Sensitization Inventory (CSI) score; (iv) to confirm whether the refined version of B-MEPS is an adequate predictive measure for identification of patients prone to intense postoperative pain. METHODS: We include 1016 patients who had undergone surgical procedures in a teaching hospital. The generalized partial credit model of item response theory and latent class model were employed, respectively, to reduce the number of items and to create cut-off points. We applied the CSI and assessed pain by Visual Analog Scale (0-10) and by the amount of postoperative morphine consumption. RESULTS: The refined B-MEPS shows satisfactory reliability (Cronbach's alpha 0.79). Preoperative emotional stress, according to the cut-off points, is classified into categories: low, intermediate or high stress. The refined B-MEPS exhibited a linear association with the CSI scores (r2 = 0.53, p < 0.01). Patients with higher levels of emotional stress displayed a positive association with moderate to severe pain and greater morphine consumption. CONCLUSION: The refined version of B-MEPS, along with an interface of easy applicability, assess emotional vulnerability at the bedside before surgery. This app may support studies focused on intervening with perioperative stress levels.

Dysfunctional eating behavior in fibromyalgia and its association with serum biomarkers of brain plasticity (BDNF and S100B): an exploratory study

ABSTRACT Objectives: To assess disordered eating, hunger and satiety perceptions in women with fibromyalgia (FM) compared to healthy controls (HC) and their association with biomarkers of brain plasticity (brain-derived neurotrophic factor (BDNF) and S100 calcium-binding protein B (S100B)). Subjects and methods: Cross-sectional exploratory study. The sample included FM (n = 20) and HC (n = 19), matched to age and waist perimeter. Dysfunctional eating was assessed through the Three Factor Eating Questionnaire and Eating Disorders Examination with a questionnaire. Hunger and satiety levels were rated by a Numerical Scale. Serum leptin, S100B and BDNF were analyzed. Results: The MANCOVA analysis showed that the mean of Emotional Eating rates was 30.65% higher in FM compared to HC ( p = 0.015). Eating, shape and weight concerns were 77.77%, 57.14% and 52.22% higher in FM ( p = <0.001) compared to HC, respectively. Moreover, the FM group reported higher scores for feeling of hunger "[5.2 (±2.9) vs. 4.8 (±2.0); p = 0.042] and lower scores for satiety [7.0 (±1.7) vs . 8.3 (±1.0); p = 0.038]. In the FM group, serum BDNF was negatively associated with hunger (r = - 0.52; p = 0.02), while S100B was positively associated with hunger scores (r = 0.463; p = 0.004). Conclusion: The present findings support the hypothesis that the association between FM and obesity can be mediated by a hedonistic pathway. Further research is needed.

Dysfunctional eating behavior in fibromyalgia and its association with serum biomarkers of brain plasticity (BDNF and S100B): an exploratory study.

OBJECTIVE: To assess disordered eating, hunger and satiety perceptions in women with fibromyalgia (FM) compared to healthy controls (HC) and their association with biomarkers of brain plasticity (brain-derived neurotrophic factor (BDNF) and S100 calcium-binding protein B (S100B)). METHODS: Cross-sectional exploratory study. The sample included FM (n = 20) and HC (n = 19), matched to age and waist perimeter. Dysfunctional eating was assessed through the Three Factor Eating Questionnaire and Eating Disorders Examination with a questionnaire. Hunger and satiety levels were rated by a Numerical Scale. Serum leptin, S100B and BDNF were analyzed. RESULTS: The MANCOVA analysis showed that the mean of Emotional Eating rates was 30.65% higher in FM compared to HC (p = 0.015). Eating, shape and weight concerns were 77.77%, 57.14% and 52.22% higher in FM (p = <0.001) compared to HC, respectively. Moreover, the FM group reported higher scores for feeling of hunger "[5.2 (±2.9) vs. 4.8 (±2.0); p = 0.042] and lower scores for satiety [7.0 (±1.7) vs. 8.3 (±1.0); p = 0.038]. In the FM group, serum BDNF was negatively associated with hunger (r = - 0.52; p = 0.02), while S100B was positively associated with hunger scores (r = 0.463; p = 0.004). CONCLUSION: The present findings support the hypothesis that the association between FM and obesity can be mediated by a hedonistic pathway. Further research is needed.

Repetitive Transcranial Magnetic Stimulation (rTMS) Reverses the Long-term Memory Impairment and the Decrease of Hippocampal Interleukin-10 Levels, both Induced by Neuropathic Pain in Rats.

Neuropathic pain (NP) is characterized by the presence of spontaneous pain, allodynia and hyperalgesia. Repetitive transcranial magnetic stimulation (rTMS) is one of neuromodulatory techniques that induces satisfactory NP relief, including that from refractory pain patients. The objective of this study was to evaluate rTMS treatment over long term memory (LTM) and hippocampal BDNF and IL-10 levels in rats submitted to a NP model. A total of 81 adult (60-days old) male Wistar rats were randomly allocated to one of the following 9 experimental groups: control, control + sham rTMS, control + rTMS, sham neuropathic pain, sham neuropathic pain + sham rTMS, sham neuropathic pain + rTMS, neuropathic pain (NP), neuropathic pain + sham rTMS and neuropathic pain + rTMS. Fourteen days after the surgery for chronic constriction injury (CCI) of the sciatic nerve, NP establishment was accomplished. Then, rats were treated with daily 5-minute sessions of rTMS for eight consecutive days. LTM was assessed by the object recognition test (ORT) twenty-four hours after the end of rTMS treatment. Biochemical assays (BDNF and IL-10 levels) were performed in hippocampus tissue homogenates. rTMS treatment reversed the reduction of the discrimination index in the ORT and the hippocampal IL-10 levels in NP rats. This result shows that rTMS reverses the impairment LTM and the increase in the hippocampal IL-10 levels, both induced by NP. Moreover, it appears to be a safe non-pharmacological therapeutic tool since it did not alter LTM and neurochemical parameters in naive animals.

Antinociceptive and neurochemical effects of a single dose of IB-MECA in chronic pain rat models.

This study aimed to evaluate the effect of a single administration of IB-MECA, an A3 adenosine receptor agonist, upon the nociceptive response and central biomarkers of rats submitted to chronic pain models. A total of 136 adult male Wistar rats were divided into two protocols: (1) chronic inflammatory pain (CIP) using complete Freund's adjuvant and (2) neuropathic pain (NP) by chronic constriction injury of the sciatic nerve. Thermal and mechanical hyperalgesia was measured using von Frey (VF), Randal-Selitto (RS), and hot plate (HP) tests. Rats were treated with a single dose of IB-MECA (0.5 µmol/kg i.p.), a vehicle (dimethyl sulfoxide-DMSO), or positive control (morphine, 5 mg/kg i.p.). Interleukin 1ß (IL-1ß), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) levels were measured in the brainstem and spinal cord using enzyme-linked immunosorbent assay (ELISA). The establishment of the chronic pain (CIP or NP) model was observed 14 days after induction by a decreased nociceptive threshold in all three tests (GEE, P < 0.05). The antinociceptive effect of a single dose of IB-MECA was observed in both chronic pain models, but this was more effective in NP model. There was an increase in IL-1ß levels promoted by CIP. NP model promoted increase in the brainstem BDNF levels, which was reversed by IB-MECA.

Effects of gestational and breastfeeding caffeine exposure in adenosine A1 agonist-induced antinociception of infant rats.

OBJECTIVES: Caffeine is extensively consumed as a psychostimulant drug, acting on A1 and A2A adenosine receptors blockade. Chronic exposure to caffeine during gestation and breast-feeding may be involved in infant rat's behavioral and biochemical alterations. Our goal was to evaluate the effect of chronic caffeine exposure during gestation and breast-feeding in the functionality of adenosine A1 receptors in infant rats at P14. NTPDase and 5'-nucleotidase activities were also evaluated. METHODS: Mating of adult female Wistar rats was confirmed by presence of sperm in vaginal smears. Rats were divided into three groups on the first day of pregnancy: (1) control: tap water, (2) caffeine: 0.3 g/L until P14, and (3) washout caffeine: caffeine was changed to tap water at P7. Evaluation of nociceptive response was performed at P14 using hot plate (HP) and tail-flick latency (TFL) tests. A1 receptor involvement was assessed using caffeine agonist (CPA) and antagonist (DPCPX). Enzymatic activities assays were conducted in the spinal cord. RESULTS: Gestational and breastfeeding exposure to caffeine (caffeine and washout groups) did not induce significant alterations in thermal nociceptive thresholds (HP and TF tests). Both caffeine groups did not show analgesic response induced by CPA when compared to the control group at P14, indicating chronic exposure to caffeine in the aforementioned periods inhibits the antinociceptive effects of the systemic A1 receptor agonist administration. No effect was observed upon ectonucleotidase activities. CONCLUSIONS: Our results demonstrate that chronic caffeine exposure in gestational and breastfeeding alters A1-mediated analgesic response in rats.

Transcranial Direct Current Stimulation (tDCS) Induces Analgesia in Rats with Neuropathic Pain and Alcohol Abstinence.

Neuromodulatory techniques have been studied to treat drug addiction or compulsive eating as well as different chronic pain conditions, such as neuropathic and inflammatory pain in the clinical and preclinical settings. In this study, we aimed to investigate the effect of transcranial direct current stimulation (tDCS) on the association of alcohol withdrawal with neuropathic pain based on nociceptive and neurochemical parameters in rats. Thirty-six adult male Wistar rats were randomized into five groups: control, neuropathic pain, neuropathic pain + tDCS, neuropathic pain + alcohol, and neuropathic pain + alcohol + tDCS. The neuropathic pain model was induced by chronic constriction injury (CCI) to the sciatic nerve. Rats were then exposed to alcohol (20%) by oral gavage administration for 15 days (beginning 24 h after CCI). tDCS was started on the 17th day after surgery and lasted for 8 consecutive days. The nociceptive test (hot plate) was performed at baseline, 16 days after CCI, and immediately and 24 h after the last session of tDCS. Rats were killed by decapitation, and structures were removed and frozen for biochemical analysis (nerve growth factor and interleukin (IL-1α, IL-1ß, and IL-10 measurements). Neuropathy-induced thermal hyperalgesia was reversed by tDCS, an effect that was delayed by alcohol abstinence. In addition, tDCS treatment induced modulation of central levels of IL-1α, IL-1ß, and IL-10 and neurotrophic growth factor. We cannot rule out that the antinociceptive effect of tDCS could be related to increased central levels of IL-1α and IL-10. Therefore, tDCS may be a promising non-pharmacological therapeutic approach for chronic pain treatment.

Single exercise stress reduces central neurotrophins levels and adenosine A1 and A2 receptors expression, but does not revert opioid-induced hyperalgesia in rats.

BACKGROUND: This study assessed the effects of an acute stress model upon the long-term hyperalgesia induced by repeated morphine administration in neonatal rats. We also evaluated neurotrophins and cytokines levels; expressions of adenosine and acetylcholine receptors, and acetylcholinesterase enzyme at the spinal cord. MATERIAL AND METHODS: Male Wistar rats were subjected to morphine or saline administration from P8 to P14. Thermal hyperalgesia and mechanical hyperesthesia were assessed using the hot plate (HP) and von Frey (vF) tests, respectively, at postnatal day P30 and P60. After baseline measurements, rats were subjected to a single exercise session, as an acute stress model, at P30 or P60. We measured the levels of BDNF and NGF, interleukin-6, and IL-10 in the cerebral cortex and the brainstem; and the expression levels of adenosine and muscarinic receptors, as well as acetylcholinesterase (AChE) enzyme at the spinal cord. RESULTS: A stress exercise session was not able to revert the morphine-induced hyperalgesia. The morphine and exercise association in rats induced a decrease in the neurotrophins brainstem levels, and A1 , A2A , A2B receptors expression in the spinal cord, and an increase in the IL-6 cortical levels. The exercise reduced M2 receptors expression in the spinal cord of naive rats, while morphine prevented this effect. CONCLUSIONS: Single session of exercise does not revert hyperalgesia induced by morphine in rats; however, morphine plus exercise modulate neurotrophins, IL-6 central levels, and expression of adenosine receptors.

LOW-DOSE NALTREXONE REVERSES FACIAL MECHANICAL ALLODYNIA IN A RAT MODEL OF TRIGEMINAL NEURALGIA.

Trigeminal neuralgia (TN) is a type of neuropathic pain characterized by intense pain; although anticonvulsants are used as an option to relieve pain, adverse side effects can decrease patient adherence. In this context, a low dose of naltrexone is effective in relieving pain in other pain conditions. Thus, the objective of the present study was to evaluate the analgesic effect of low-dose naltrexone on facial mechanical allodynia in a rat model of TN, as well as its effect(s) on biomarkers in the central nervous system (tumor necrosis factor-alpha, brain-derived neurotrophic factor [BDNF], interleukin [IL]-10, and toll-like receptor-4). Fifty-nine adult male Wistar rats (CEUA-HCPA#2017-0575) were allocated to following groups: control; sham-pain + vehicle; sham-pain + carbamazepine (100 mg/kg); sham-pain + naltrexone (0.5 mg/kg); pain + vehicle; pain + carbamazepine; and pain + naltrexone. TN was induced using chronic constriction of the infraorbital nerve. Facial allodynia was assessed using von Frey test. Drugs were administered by gavage 14 days after surgery for 10 days. At baseline, the mechanical threshold was similar between groups (P > 0.05; generalized estimating equation). Seven days after surgery, facial allodynia was observed in sham-TN and pain-TN groups (P < 0.05). Fourteen days after surgery, only pain-TN groups exhibited facial allodynia. The first dose of low-dose naltrexone or carbamazepine partially reversed facial allodynia. After 10 days of treatment, both drugs completely reversed it. Spinal cord levels of BDNF and IL-10 were modulated by low-dose naltrexone. Thus, low-dose naltrexone may be suitable to relieve TN; however, the exact mechanisms need to be clarified.

The Brief Measure of Emotional Preoperative Stress (B-MEPS) as a new predictive tool for postoperative pain: A prospective observational cohort study.

BACKGROUND: Preoperative patients' vulnerabilities such as physical, social, and psychological are implicated in postoperative pain variability. Nevertheless, it is a challenge to analyze a patient's psychological profile in the preoperative period in a practical and consistent way. Thus, we sought to identify if high preoperative emotional stress, evaluated by the Brief Measure of Emotional Preoperative Stress (B-MEPS) scale is associated with higher postoperative pain levels and poor rehabilitation in patients submitted to intermediate or major surgery. Moreover, the possible neurobiological or neurophysiological mechanisms implicated in high preoperative emotional stress, evaluated through preoperative quantitative sensory pain tests and serum biomarkers BDNF and S100B were investigated. METHODS: We conducted a prospective, observational, cohort study of ASA 2 and 3 adult patients undergoing major urologic, gynecologic, proctologic and orthopedic surgeries from March 2017 to March 2018. B-MEPS and Central Sensitivity Inventory were evaluated preoperatively, followed by a sequence of experimental pain tests and serum biomarkers collection. Postoperative evaluation carried out within the first 48 hours after surgery comprehended pain at rest and movement-evoked pain, and the consumption of morphine. Quality-of-Recovery was also evaluated in the 3rd postoperative day. RESULTS: 23 (15%) out of 150 patients included in the study presented high emotional preoperative stress. Variables significantly related to preoperative stress were: previous psychiatric diagnosis and Central Sensitization Inventory result. Mean movement-evoked pain in the first 12 to 48 hours was 95-105% higher than pain at rest. A mixed model for repeated measures showed a sustainable effect of B-MEPS as a movement-evoked pain predictor. Previous pain, cancer surgery, and preoperative pressure pain tolerance were also independent predictors of postoperative pain. Moderate to severe postoperative movement-evoked pain was predictive of poor rehabilitation in 48 hours after surgery. CONCLUSION: We confirmed that a brief screening method of preoperative emotional states could detect individuals prone to experience severe postoperative pain. Specific interventions considering the stress level may be planned in the future to improve perioperative outcomes.

Differential Neuroplastic Changes in Fibromyalgia and Depression Indexed by Up-Regulation of Motor Cortex Inhibition and Disinhibition of the Descending Pain System: An Exploratory Study.

Background: Major depressive disorder (MDD) and fibromyalgia (FM) present overlapped symptoms. Although the connection between these two disorders has not been elucidated yet, the disruption of neuroplastic processes that mediate the equilibrium in the inhibitory systems stands out as a possible mechanism. Thus, the purpose of this cross-sectional exploratory study was: (i) to compare the motor cortex inhibition indexed by transcranial magnetic stimulation (TMS) measures [short intracortical inhibition (SICI) and intracortical facilitation (ICF)], as well as the function of descending pain modulatory systems (DPMS) among FM, MDD, and healthy subjects (HS); (ii) to compare SICI, ICF, and the role of DPMS evaluated by the change on Numerical Pain Scale (NPS) during the conditioned pain modulation test (CPM-test) between FM and MDD considering the BDNF-adjusted index; (iii) to assess the relationship between the role of DPMS and the BDNF-adjusted index, despite clinical diagnosis. Patients and Methods: A cohort of 63 women, aged 18 to 75 years [FM (n = 18), MDD (n = 19), and HC (n = 29)]. Results: The MANCOVA analysis revealed that the mean of SICI was 53.40% larger in FM compared to MDD [1.03 (0.50) vs. 0.55 (0.43)] and 66.99% larger compared to HC [1.03 (0.50) vs. 0.34 (0.19)], respectively. The inhibitory potency of the DPMS assessed by the change on the NPS during CPM-test was 112.29 % lower in the FM compared to MDD [0.22 (1.37) vs. -0.87 (1.49)]. The mean of BDNF from FM compared to MDD was 35.70% higher [49.82 (16.31) vs. 14.12 (8.86)]. In FM, the Spearman's coefficient between the change in the NPS during CPM-test with the SICI was Rho = -0.49, [confidence interval (CI) 95%; -0.78 to -0.03]. The BDNF-adjusted index was positively correlated with the disinhibition of the DPMS. Conclusion: These findings support the hypothesis that in FM a deteriorated function of cortical inhibition, indexed by a higher SICI parameter, a lower function of the DPMS, together with a higher level of BDNF indicate that FM has different pathological substrates from depression. They suggest that an up-regulation phenomenon of intracortical inhibitory networks associated with a disruption of the DPMS function occurs in FM.

BDNF and serum S100B levels according the spectrum of structural pathology in chronic pain patients.

Central sensitivity syndrome (CSS) consists of adaptive pathophysiological changes associated with neuroplasticity in some chronic pain disorders. It could be grouped in two main conceptual conditions: one includes those chronic pain patients without overt structural pathology such as fibromyalgia, and the other subgroup includes conditions with recognizable structural abnormalities, both somatic (osteoarthritis) and visceral (endometriosis). In order to understand the role of neuromodulators in CCS we aim to determine whether brain-derived neurotrophic factor (BDNF) and S100B are associated to specific chronic pain disorders. Serum BDNF and S100B were measured in chronic pain women with different diagnosis: 88 with osteoarthritis, 36 with endometriosis, 117 with fibromyalgia, 33 with chronic tension type headache and in 41 healthy controls. ANCOVA analysis followed by heteroscedasticity-consistent covariance matrix was performed to evaluate BDNF and S100B levels, adjusted for depression severity, pain levels and use of analgesics according different pathologies. Serum BDNF concentrations were higher and not different in patients with fibromyalgia and headache, the CSS group without structural pathology. In contrast, the concentrations of S100B were higher in patients with osteoarthritis and endometriosis, in comparison to controls, fibromyalgia and tensional headache patients. This study supports the hypothesis that BDNF and S100B neuromodulators present different serum levels according to the background disease associated to the chronic pain. These have the potential to be studied as markers of active disease or treatment evolution.

Transcranial direct current stimulation (tDCS) and trigeminal pain: A preclinical study.

OBJECTIVE: Our objective was to evaluate the Transcranial direct current stimulation (tDCS) effect on facial allodynia induced by chronic constriction of the infraorbital nerve (CCI-ION) and on the brainstem levels of TNF-α, NGF, IL-10, and serum LDH in rats. METHODS: Rats were exposed to the CCI-ION model. Facial allodynia was assessed by von Frey filaments test at baseline, 3, 7, 10, and 14 days postsurgery and 24 hr and 7 days after the bimodal tDCS sessions for 20 min/day/8 days. RESULTS: Chronic constriction of the infraorbital nerve induced a significant decrease in the mechanical threshold 14 days after surgery. This effect was reversed by tDCS treatment, with the mechanical threshold returning to basal levels at 24 hr after the end of the treatment and it persisted for 7 days after the end of the treatment. tDCS also decreased LDH serum levels compared to those in the control group. There was an interaction between pain and treatment with respect to brainstem levels of NGF, TNF-α, and IL-10. CONCLUSION: Chronic constriction of the infraorbital nerve model was effective in establishing trigeminal neuropathic pain on 14 days after surgery, and tDCS reduced allodynia and LDH serum levels and promoted alterations in NGF, TNF-α, and IL-10 brainstem levels. Thus, we suggest that tDCS may be a potential therapy in the trigeminal pain treatment.