Hormone replacement therapy did not alleviate temporomandibular joint inflammatory pain in ovariectomized rats.

This study had the aim of examining the relationships between variations in estrogen levels resulting from ovariectomy, and estrogen hormone replacement therapy (HRT) in rats subjected to an orofacial inflammatory pain model. Eighty adult female Wistar rats were initially divided into 2 groups: Sham or ovariectomy (OVX-D1). Seven days later (D7), the rats were subjected to an unilateral infiltration of Freund's Complete Adjuvant (CFA) or saline solution into the right temporomandibular joint (TMJ). Then, rats received 17ß-estradiol (28 µg/kg/day) or placebo for 21 days (D10-D31). Nociception was evaluated by the von Frey (VF) and the Hot Plate (HP) tests, and depressive-like behavior by the Forced Swimming (FS) test. On D32 all rats were euthanized and serum, hippocampus and brainstem were collected. The CFA groups presented a mechanical hyperalgesia until day 21 (p ≤ 0.05). No differences were observed among groups in the HP (p = 0.735), and in the immobility and swimming time of the FS (p = 0.800; p = 0.998, respectively). In the brainstem, there was a significant difference in the TNF-ɑ levels (p = 0.043), and a marginal significant difference in BDNF levels (p = 0.054), without differences among groups in the hippocampal BDNF and TNF-ɑ levels (p = 0.232; p = 0.081, respectively). In conclusion, the hormone replacement therapy did not alleviate orofacial pain in ovariectomized rats. However, there is a decrease in brainstem TNF-ɑ levels in the animals submitted to both models, which was partially reverted by HRT.

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.

Efficacy of Home-Based Transcranial Direct Current Stimulation Over the Primary Motor Cortex and Dorsolateral Prefrontal Cortex in the Disability Due to Pain in Fibromyalgia: A Factorial Sham-Randomized Clinical Study.

This randomized, double-blind, controlled clinical trial compared the effectiveness of home-based-(HB) active transcranial direct current stimulation (a-tDCS) over the left dorsolateral prefrontal cortex (l-DLPFC) or primary motor cortex (M1) with their respective sham-(s)-tDCS to determine whether a-tDCS would be more effective than s-tDCS in reducing pain and improving disability due to pain. The study included 102 patients with fibromyalgia aged 30 to 65 years old randomly assigned to 1 of 4 tDCS groups using a ratio of 2:1:2:1. The groups included l-DLPFC (a-tDCS, n = 34) and (s-tDCS, n = 17), or tDCS on the M1 (a-tDCS, n = 34) or (s-tDCS, n = 17). Patients self-administered 20 sessions of tDCS, with 2 mA for 20 minutes each day under remote supervision after in-person training. The Mixed Model for Repeated Measurements revealed that a-tDCS on DLPFC significantly reduced pain scores by 36.53% compared to 25.79% in s-tDCS. From baseline to the fourth week of treatment, a-tDCS on M1 reduced pain scores by 45.89% compared to 22.92% over s-tDCS. A generalized linear model showed a significant improvement in the disability scale in the groups that received a-tDCS compared to s-tDCS over M1 20.54% versus 2.49% (χ2 = 11.06, df = 1, P < .001]), while on DLPFC the improvement was 14.29% and 5.77%, with a borderline significance (χ2 = 3.19, df = 1, P = .06]), respectively. A higher reduction in serum brain-derived neurotrophic factor from baseline to treatment end was positively correlated with decreased pain scores regardless of the treatment group. The application of a-tDCS over M1 increased the heat pain threshold and the function of the descending pain inhibitory system. PERSPECTIVE: These findings provide important insights: (1) HB-tDCS has effectively reduced pain scores and improved disability due to fibromyalgia. (2) The study provides evidence that HB-a-tDCS is a viable and effective therapeutic approach. (3) HB-a-tDCS over M1 improved the function of the descending pain inhibitory system and increased the heat pain threshold. Finally, our findings also emphasize that brain-derived neurotrophic factor, as an index of neuroplasticity, may serve as a valuable marker associated with changes in clinical pain measures. TRIAL REGISTRATION: Number NCT03843203.

Multidisciplinary treatment program for improvement in pain and disability associated with nonspecific chronic low back pain / Programa de tratamento multidisciplinar para melhora da dor e incapacidade associada a dor crônica lombar inespecífica

ABSTRACT BACKGROUND AND OBJECTIVES: Lumbar disorders, which contribute to significant workplace absenteeism and chronic disability, are associated with a considerable financial and social burden. Although a conservative approach provides satisfactory pain relief, biomechanical improvement and is associated with a low risk of adverse effects, there is lack of consensus in the literature regarding the best therapeutic strategy in such cases. METHODS: This retrospective longitudinal study used secondary data from the institutional medical records of patients who completed a multidisciplinary program for the treatment of low back pain between 2019 and 2021. Data regarding pain levels and motor skills were obtained from patients who completed the care program at a private hospital in Bento Gonçalves, RS. The following step-wise treatment algorithm was used: evaluation by a specialist physician for the etiological diagnosis of pain, pharmacological management and dry needling, followed by standard rehabilitation intervention performed by the physiotherapy team and exercises by the physical education team. The visual analogue scale (VAS) was used to measure pain at the start and at the completion of the intervention, and the Oswestry Disability Index (ODI) was used to measure motor skills at the start and at 6 and 12 months following the multiprofessional intervention for rehabilitation. RESULTS: A reduction in pain and motor disability in patients who completed all stages of the treatment program was observed. Pain by the VAS presented the following scores: baseline 7 [5-8] and after treatment 2 [0-4]; and the scores of the ODI were: at baseline 0.34 [0.26 - 0.40], at 6 months 0.16 [0.08 - 0.26] and after treatment 0.12 [0.04 - 0.21]. CONCLUSION: The treatment program reduced the pain and disability associated with low back pain and can serve as the basis for further studies carried out to confirm the effectiveness of this intervention.

RESUMO JUSTIFICATIVA E OBJETIVOS: As doenças lombares, que contribuem para um absenteísmo significativo no local de trabalho e para a incapacidade crônica, estão associadas a um encargo financeiro e social considerável. Embora a abordagem conservadora proporcione alívio satisfatório da dor, melhore a biomecânica e esteja associada a baixo risco de efeitos adversos, não há consenso na literatura sobre a melhor estratégia terapêutica nesses casos. MÉTODOS: Neste estudo longitudinal retrospectivo, foram utilizados dados secundários dos prontuários médicos institucionais de pacientes que completaram um programa multidisciplinar para tratamento de dor lombar entre 2019 e 2021. Dados sobre níveis de dor e habilidades motoras foram obtidos de pacientes que completaram o programa assistencial de um hospital privado de Bento Gonçalves, RS. Foi utilizado o seguinte tratamento passo a passo: avaliação por médico especialista para diagnóstico etiológico da dor, manejo farmacológico e agulhamento a seco, seguido de intervenção de reabilitação padrão realizada pela equipe de fisioterapia e exercícios pela equipe de educação física. A escala analógica visual (EAV) foi utilizada para medir a dor no início e após a conclusão da intervenção, e o Índice de Incapacidade de Oswestry (ODI) foi usado para medir as habilidades motoras no início e aos 6 e 12 meses após a intervenção multiprofissional para reabilitação. RESULTADOS: Observou-se redução na dor e na incapacidade motora em pacientes que completaram todas as etapas do programa de tratamento. A intensidade da dor medida pela EAV apresentou as seguintes pontuações: basal 7 [5-8] e após tratamento 2 [0-4]; enquanto o ODI apresentou as pontuações: basal 0,34 [0,26 - 0,40], até 6 meses 0,16 [0,08 - 0,26] e após o tratamento 0,12 [0,04 - 0,21]. CONCLUSÃO: O programa de tratamento reduziu a dor e a incapacidade associadas à dor lombar e pode servir de base para novos estudos realizados para confirmar a eficácia desta intervenção.

Transcranial direct current stimulation effects in the pain threshold and in oxidative stress parameters of neuropathic pain rats.

Transcranial direct current stimulation (tDCS) can modulate cortical excitability and relieve neuropathic pain (NP), but the role of several biomarkers in this process is not well understood. This study aimed to analyze the effects of tDCS on biochemical parameters in rats with neuropathic pain (NP) induced by chronic constriction injury (CCI) of the right sciatic nerve. Eighty-eight male 60-day-old Wistar rats were divided into nine groups: control (C), control-electrode off (CEoff), control-tDCS (C-tDCS), sham-lesion (SL), sham-lesion electrode off (SLEoff), sham-lesion (SL-tDCS), lesion (L), lesion electrode off (LEoff), and lesion-tDCS (L-tDCS). After NP establishment, 20-minute bimodal tDCS for 8 consecutive days was applied to the rats. Fourteen days after the induction of NP, rats developed mechanical hyperalgesia with a decreased threshold, and at the end of treatment, an increase in the pain threshold was observed in NP rats. In addition, NP rats had increased levels of reactive species (RS) in the prefrontal cortex, while superoxide dismutase (SOD) activity was decreased in NP rats. In the spinal cord, nitrite levels and glutathione-S-transferase (GST) activity decreased in the L-tDCS group, and it was observed that increased levels in total sulfhydryl content for neuropathic pain rats were reversed by tDCS. In serum analyses, the neuropathic pain model increased the levels of RS and thiobarbituric acid-reactive substances (TBARS) and decreased the activity of butyrylcholinesterase (BuChE). In conclusion, bimodal tDCS increased total sulfhydryl content in the spinal cord of rats with neuropathic pain, positively modulating this parameter.

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.

Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial.

INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA). The following categories were assessed: sociodemographic, Visual Analog Pain Scale (VAS), Pain Catastrophizing Scale (PCS), State-Trait Anxiety Inventory (STAI), Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Inventory (BDI-II), Profile of Chronic Pain Scale (PCP:S), Pain Pressure Threshold (PPT), and Conditioned Pain Modulation (CPM). Blood samples were collected to analyze BDNF serum levels. RESULTS: At baseline, no significant difference was found regarding all measurements. VAS pain was significantly reduced in the LDN + tDCS (p = 0.010), LDN + tDCS Sham (p = 0.001), and placebo+tDCS Sham (p = 0.009) groups. In the PCP:S, the LDN+tDCS group showed reduced pain frequency and intensity (p = 0.001), effect of pain on activities (p = 0.014) and emotions (p = 0.008). Depressive symptoms reduced after all active interventions (p > 0.001). CONCLUSION: Combined LDN+tDCS has possible benefits in reducing pain frequency and intensity; however, a placebo effect was observed in pain using VAS, and further studies should be performed to analyze the possible association.

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.

Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial

Abstract Introduction Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. Objective The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. Methods This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA). The following categories were assessed: sociodemographic, Visual Analog Pain Scale (VAS), Pain Catastrophizing Scale (PCS), State-Trait Anxiety Inventory (STAI), Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Inventory (BDI-II), Profile of Chronic Pain Scale (PCP:S), Pain Pressure Threshold (PPT), and Conditioned Pain Modulation (CPM). Blood samples were collected to analyze BDNF serum levels. Results At baseline, no significant difference was found regarding all measurements. VAS pain was significantly reduced in the LDN + tDCS (p = 0.010), LDN + tDCS Sham (p= 0.001), and placebo+tDCS Sham (p= 0.009) groups. In the PCP:S, the LDN+tDCS group showed reduced pain frequency and intensity (p= 0.001), effect of pain on activities (p= 0.014) and emotions (p= 0.008). Depressive symptoms reduced after all active interventions (p > 0.001). Conclusion Combined LDN+tDCS has possible benefits in reducing pain frequency and intensity; however, a placebo effect was observed in pain using VAS, and further studies should be performed to analyze the possible association.

The effect of home-based transcranial direct current stimulation in cognitive performance in fibromyalgia: A randomized, double-blind sham-controlled trial.

Background: Transcranial Direct Current Stimulation (tDCS) is a promising approach to improving fibromyalgia (FM) symptoms, including cognitive impairment. So, we evaluated the efficacy and safety of home-based tDCS in treating cognitive impairment. Besides, we explored if the severity of dysfunction of the Descendant Pain Modulation System (DPMS) predicts the tDCS effect and if its effect is linked to changes in neuroplasticity as measured by the brain-derived neurotrophic factor (BDNF). Methods: This randomized, double-blind, parallel, sham-controlled clinical trial, single-center, included 36 women with FM, aged from 30 to 65 years old, assigned 2:1 to receive a-tDCS (n = 24) and s-tDCS (n = 12). The primary outcome was the Trail Making Test's assessment of executive attention, divided attention, working memory (WM), and cognitive flexibility (TMT-B-A). The secondary outcomes were the Controlled Oral Word Association Test (COWAT), the WM by Digits subtest from the Wechsler Adult Intelligence Scale (WAIS-III), and quality of life. Twenty-minute daily sessions of home-based tDCS for 4 weeks (total of 20 sessions), 2 mA anodal-left (F3) and cathodal-right (F4) prefrontal stimulation with 35 cm2 carbon electrodes. Results: GLM showed a main effect for treatment in the TMT-B-A [Wald χ2 = 6.176; Df = 1; P = 0.03]. The a-tDCS improved cognitive performance. The effect size estimated by Cohen's d at treatment end in the TMT-B-A scores was large [-1.48, confidence interval (CI) 95% = -2.07 to-0.90]. Likewise, the a-tDCS effects compared to s-tDCS improved performance in the WM, verbal and phonemic fluency, and quality-of-life scale. The impact of a-tDCS on the cognitive tests was positively correlated with the reduction in serum BDNF from baseline to treatment end. Besides, the decrease in the serum BDNF was positively associated with improving the quality of life due to FM symptoms. Conclusion: These findings revealed that daily treatment with a home-based tDCS device over l-DLPFC compared to sham stimulation over 4 weeks improved the cognitive impairment in FM. The a-tDCS at home was well-tolerated, underlining its potential as an alternative treatment for cognitive dysfunction. Besides, the a-tDCS effect is related to the severity of DPMS dysfunction and changes in neuroplasticity state. Clinical trial registration: [www.ClinicalTrials.gov], identifier [NCT03843203].

Nociceptive Profile and Analgesic use of Patients Submitted to Rotator Cuff Repair Surgery: A Prospective Cohort.

Objective This study aimed to evaluate the nociceptive profile and the intake of analgesic drugs of patients submitted to rotator cuff repair surgery. Also, to evaluate the nociceptive thresholds and the integrity of the descending inhibitory system, pain catastrophism and prevalence of nociceptive or neuropathic pain. Methods Approved by the Ethics Committee of La Salle University (1.325.433/2015). 40 patients (>18 years old) who underwent rotator cuff repair surgery (divided in small and large injuries) were recruited. The used instruments were: Sociodemographic Questionnaire, Functional Pain Scale, Visual Analogue Scale (VAS), Quantitative Sensory Test (QST) and Conditioned Pain Modulation Task (CPM). Results Patients had a significant difference in pain thresholds QST heat (independent samples t test) and quality of sleep, mood and anxiety (paired t test) in groups preoperative. There was a significant correlation between preoperative CPM and postoperative VAS (Pearson Correlation). It was observed that, in preoperative, 38 patients used analgesics continuously. Besides that, in postoperative, use of opioid drugs was higher in patients with small injury (13 patients) than in those with large injury (9 patients). Conclusion Therefore, patients with rotator cuff injuries did not present alterations in the descending inhibitory system, but showed alterations in pain thresholds, which may interfere in the postoperative period and still be related to the consumption of analgesics.

Nociceptive Profile and Analgesic use of Patients Submitted to Rotator Cuff Repair Surgery: A Prospective Cohort / Perfil nociceptivo e uso de analgésicos em pacientes submetidos à cirurgia de reparo do manguito rotador: Coorte prospectiva

Abstract Objective This study aimed to evaluate the nociceptive profile and the intake of analgesic drugs of patients submitted to rotator cuff repair surgery. Also, to evaluate the nociceptive thresholds and the integrity of the descending inhibitory system, pain catastrophism and prevalence of nociceptive or neuropathic pain. Methods Approved by the Ethics Committee of La Salle University (1.325.433/2015). 40 patients (>18 years old) who underwent rotator cuff repair surgery (divided in small and large injuries) were recruited. The used instruments were: Sociodemographic Questionnaire, Functional Pain Scale, Visual Analogue Scale (VAS), Quantitative Sensory Test (QST) and Conditioned Pain Modulation Task (CPM). Results Patients had a significant difference in pain thresholds QST heat (independent samples t test) and quality of sleep, mood and anxiety (paired t test) in groups preoperative. There was a significant correlation between preoperative CPM and postoperative VAS (Pearson Correlation). It was observed that, in preoperative, 38 patients used analgesics continuously. Besides that, in postoperative, use of opioid drugs was higher in patients with small injury (13 patients) than in those with large injury (9 patients). Conclusion Therefore, patients with rotator cuff injuries did not present alterations in the descending inhibitory system, but showed alterations in pain thresholds, which may interfere in the postoperative period and still be related to the consumption of analgesics.

Resumo Objetivo O objetivo deste estudo foi avaliar o perfil nociceptivo e o uso de analgésicos em pacientes submetidos à cirurgia de reparo do manguito rotador. Além disso, os limiares nociceptivos e a integridade do sistema inibidor descendente, o catastrofismo da dor e a prevalência de dor nociceptiva ou neuropática também foram analisados. Métodos Este estudo foi aprovado pelo Comitê de Ética da Universidade La Salle (1.325.433/2015). Quarenta pacientes (maiores de 18 anos) submetidos à cirurgia de reparo do manguito rotador (divididos entre aqueles com lesões pequenas e grandes) participaram do estudo. Os instrumentos utilizados foram o Questionário Sociodemográfico, a Escala Funcional de Dor, a Escala Visual Análoga (EVA), o Teste Sensorial Quantitativo (QST) e a Tarefa de Modulação Condicionada da Dor (CPM). Resultados Os pacientes apresentaram diferenças significativas nos limiares de dor e QST de calor (teste t de amostras independentes) e qualidade do sono, humor e ansiedade (teste t pareado) nos grupos pré-operatórios. Houve uma correlação significativa entre CPM pré-operatória e EVA pós-operatória (correlação de Pearson). Observou-se que, no período pré-operatório, 38 pacientes utilizavam analgésico de forma contínua. Além disso, no período pós-operatório, o uso de opioides foi maior nos pacientes com lesões pequenas (13 pacientes) em comparação àqueles com lesões grandes (nove pacientes). Conclusão Os pacientes com lesão do manguito rotador não apresentaram alterações no sistema inibidor descendente, mas sim alterações nos limiares de dor, o que pode interferir no período pós-operatório e estar relacionado ao consumo de analgésicos.

Evidence of Anti-Inflammatory Effect of Transcranial Direct Current Stimulation in a CFA-Induced Chronic Inflammatory Pain Model in Wistar Rats.

INTRODUCTION: Given that chronic inflammatory pain is highly prevalent worldwide, it is important to study new techniques to treat or relieve this type of pain. The present study evaluated the effect of transcranial direct current stimulation (tDCS) in rats submitted to a chronic inflammatory model by nociceptive response, biomarker levels (brain-derived neurotrophic factor [BDNF] and interleukin [IL]-6 and IL-10), and by histological parameters. METHODS: Sixty-day-old male Wistar rats were used in this study and randomized by weight into 6 major groups: total control, control + sham-tDCS, control + active tDCS, total CFA, CFA + sham-tDCS, and CFA + active tDCS. After inflammatory pain was established, the animals were submitted to the treatment protocol for 8 consecutive days, according to the experimental group. The nociceptive tests (von Frey and hot plate) were assessed, and euthanasia by decapitation occurred at day 8 after the end of tDCS treatment, and the blood serum and central nervous structures were collected for BDNF and IL measurements. All experiments and procedures were approved by the Institutional Committee for Animal Care and Use (UFPel #4538). RESULTS: The tDCS treatment showed a complete reversal of the mechanical allodynia induced by the pain model 24 h and 8 days after the last tDCS session, and there was partial reversal of the thermal hyperalgesia at all time points. Serum BDNF levels were decreased in CFA + sham-tDCS and CFA + tDCS groups compared to the control + tDCS group. The control group submitted to tDCS exhibited an increase in serum IL-6 levels in relation to the other groups. In addition, there was a significant decrease in IL-10 striatum levels in control + tDCS, CFA, and CFA + sham-tDCS groups in relation to the control group, with a partial tDCS effect on the CFA pain model. Local histology demonstrated tDCS effects in decreasing lymphocytic infiltration and neovascularization and tissue regeneration in animals exposed to CFA. CONCLUSION: tDCS was able to reverse the mechanical allodynia and decrease thermal hyperalgesia and local inflammation in a chronic inflammatory pain model, with a modest effect on striatum IL-10 levels. As such, we suggest that analgesic tDCS mechanisms may be related to tissue repair by modulating the local inflammatory process.

A3 receptor agonist modulates IL-1ß hippocampus levels in a rat model of neuropathic pain

Introduction: Considering the lack of specific treatments for neuropathic pain, this study aimed to evaluate the effect of a single dose of adenosine A3 receptor IB-MECA on inflammatory and neurotrophic parameters in rats subjected to a neuropathic pain model. Methods: 64 adult male Wistar rats were used. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve and the treatment consisted of a 0.5 µmol/kg dose of IB-MECA, a selective A3 adenosine receptor agonist, dissolved in 3% DMSO; vehicle groups received DMSO 3% in saline solution, and morphine groups received 5 mg/kg. Cerebral cortex and hippocampus IL-1ß, BDNF, and NGF levels were determined by Enzyme-Linked Immunosorbent assay. Results: The main outcome was that a single dose of IB-MECA was able to modulate the IL-1ß hippocampal levels in neuropathic pain induced by CCI and the DMSO increased IL-1ß and NGF hippocampal levels in sham-operated rats. However, we did not observe this effect when the DMSO was used as vehicle for IB-MECA, indicating that IB-MECA was able to prevent the effect of DMSO. Conclusions: Considering that the IL-1ß role in neuropathic pain and the contributions of the hippocampus are well explored, our result corroborates the relationship between the A3 receptor and the process of chronic pain maintenance.

Fibromyalgia: A Review of Related Polymorphisms and Clinical Relevance.

Fibromyalgia (FM) is a chronic pain syndrome that affects the central nervous system and generates disability, which is characterized by generalized pain, fatigue, and functional decline. In this review, we aimed to identify the polymorphisms related to the pathophysiology of FM and the clinical characteristics generated by genetic influence. Only original studies with genes related to FM were considered, totaling 27 articles. The genes found were: MTHFR, RGS4, MYT1L, TACR1, SCN9A, DRD3, ADRB2, IL-4, HLA-DRB1, EDN1, CNR1, TAAR1, OPRM1, ADRA1A, ADRB3, BDNF, GRIA4, HTR3A, HTR3B, HTR2A, SERPINA 1 or A1AT, NRXN3, GCH1, MEFV, TRPV3, SLC6A4, ACE I/D, TSPO, COMT, and MAOA. Several genes related to different pain syndromes and altered pain thresholds have been identified and some polymorphisms were related to susceptibility to FM. It was observed that 73.33% of the genes related to FM were also associated with some psychological disorders, such as anxiety, depression, schizophrenia, and obsessive and compulsive disorder, and 40.00% with pain sensitivity and/or migraine, besides other disorders associated (drug addiction, autoimmune disorders, circulatory problems, and metabolic alterations). This review demonstrated an association of FM and genetic polymorphisms that can expand our knowledge about the pathophysiology of this disease.

Bimodal transcranial direct current stimulation reduces alcohol consumption and induces long-term neurochemical changes in rats with neuropathic pain.

This study aimed to evaluate the effects of repeated bimodal transcranial direct current stimulation (tDCS) on alcohol consumption and immunohistological and neurochemical parameters in nerve-injured rats. Forty-eight adult male Wistar rats were distributed into six groups: control, neuropathic pain (NP) + sham-tDCS, NP + alcohol + sham-tDCS, alcohol + sham-tDCS, alcohol + tDCS, and NP + alcohol + tDCS. NP is induced by chronic sciatic nerve constriction (CCI). The rats were exposed to a 10% alcohol solution by voluntary consumption for 14 days. From the 16th day after surgery, bimodal tDCS was applied for 20 min/day for 8 days. Brain structures were collected to evaluate the number of neuropeptide Y (NPY)-positive neurons, neurites, and argyrophilic grains by immunohistochemistry, and brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), interleukin (IL)-6, and IL-10 by ELISA. Nerve-injured rats showed a progressive increase in alcohol consumption compared to the non-injured rats. In addition, there was a reduction in voluntary alcohol consumption over time induced by tDCS. Alcohol exposure, chronic pain, and tDCS treatment modulated the central NPY immunoreactivity. tDCS increased the cerebellar levels of IL-6 and IL-10, and CCI and/or tDCS reduced striatal BDNF levels. The current data suggest that tDCS could be a promising non-pharmacological adjuvant to treat patients with chronic pain who use alcohol to relieve their symptoms.

Transcranial direct current stimulation did not revert the increased central and peripheral NGF levels induced by neuropathic pain in rats / Tratamento com estimulação transcraniana por corrente contínua não reverteu o aumento de NGF induzido por modelo de dor neuropática em ratos

ABSTRACT BACKGROUND AND OBJECTIVES: The expression of nerve growth factor (NGF) in the large-size neurons may represent a key role in the neuronal synaptic plasticity and re-organization of neuronal function after a nerve injury. Transcranial direct current stimulation (tDCS) is a non-invasive method of cerebral stimulation and represents a promising tool to pain management since it promotes neuroplasticity in the central system, and it can be combined with other interventions. The aim was to investigate the effects of tDCS in the NGF levels in central and peripheral nervous system structures of rats submitted to a neuropathic pain (NP) model. METHODS: The chronic constriction injury (CCI) of sciatic nerve was used for the induction of NP. For sham surgery, the sciatic nerve was exposed, but without any ligation. The control group did not undergo surgical procedure. After the establishment of NP, treated groups were subjected to tDCS treatment 0.5 mA/20min/day/8 days. NGF levels in cerebral cortex, spinal cord and sciatic nerve were determined by sandwich-ELISA at 48 hours and 7 days after the end of treatment. RESULTS: The CCI model increased NGF levels in all three structures analyzed at long-lasting time, evidencing the importance of this neurotrophin in neuropathic pain condition. On the other hand, there was no tDCS effect in the central and peripheral NGF levels discarding the participation of this neurotrophin in the analgesic tDCS effect. CONCLUSION: tDCS modulation effects of nociceptive pathways seem not to be linked to the NGF signaling in this chronic pain model.

RESUMO JUSTIFICATIVA E OBJETIVOS: A expressão do fator de crescimento neural (NGF) em neurônios de diâmetro largo pode representar um papel importante na plasticidade sináptica neuronal e na reorganização da função neuronal após lesão neural. A estimulação transcraniana por corrente contínua (ETCC) é um método não invasivo de estimulação cerebral e representa uma ferramenta promissora para o manejo da dor, pois promove neuroplasticidade no sistema central, podendo ser combinada com outras intervenções. O objetivo foi investigar os efeitos da ETCC nos níveis de NGF em estruturas do sistema nervoso central e periférico de ratos submetidos a um modelo de dor neuropática (DN). MÉTODOS: A constrição crônica (CCI) do nervo isquiático foi utilizada para indução do modelo de DN. Na cirurgia sham, o nervo foi exposto, no entanto não houve constrição do nervo. O grupo controle não foi submetido ao procedimento cirúrgico. Após estabelecimento da DN, os grupos tratados foram submetidos a ETCC 0,5 mA/20min/dia/8 dias. Os níveis de NGF no córtex cerebral, medula espinal e nervo isquiático foram mensurados pela técnica de ELISA 48 horas e 7 dias após o final do tratamento. RESULTADOS: O modelo de dor CCI aumentou os níveis de NGF nas três estruturas analisadas, evidenciando a importância desta neurotrofina na dor neuropática. Por outro lado, não houve efeito da ETCC nos níveis de NGF central e periférico, descartando o papel desta neurotrofina no efeito analgésico da ETCC. CONCLUSÃO: Efeitos da ETCC sobre vias nociceptivas não estão diretamente relacionados com a sinalização do NGF neste modelo de dor crônica.

tDCS and exercise improve anxiety-like behavior and locomotion in chronic pain rats via modulation of neurotrophins and inflammatory mediators.

Anxiety disorders cause distress and are commonly found to be comorbid with chronic pain. Both are difficult-to-treat conditions for which alternative treatment options are being pursued. This study aimed to evaluate the effects of transcranial direct current stimulation (tDCS), treadmill exercise, or both, on anxiety-like behavior and associated growth factors and inflammatory markers in the hippocampus and sciatic nerve of rats with neuropathic pain. Male Wistar rats (n = 216) were subjected to sham-surgery or sciatic nerve constriction for pain induction. Fourteen days following neuropathic pain establishment, either bimodal tDCS, treadmill exercise, or a combination of both was used for 20 min a day for 8 consecutive days. The elevated plus-maze test was used to assess anxiety-like behavior and locomotor activity during the early (24 h) or late (7 days) phase after the end of treatment. BDNF, TNF-ɑ, and IL-10 levels in the hippocampus, and BDNF, NGF, and IL-10 levels in the sciatic nerve were assessed 48 h or 7 days after the end of treatment. Rats from the pain groups developed an anxiety-like state. Both tDCS and treadmill exercise provided ethological and neurochemical alterations induced by pain in the early and/or late phase, and a modest synergic effect between tDCS and exercise was observed. These results indicate that non-invasive neuromodulatory approaches can attenuate both anxiety-like status and locomotor activity and alter the biochemical profile in the hippocampus and sciatic nerve of rats with neuropathic pain and that combined interventions may be considered as a treatment option.

The profile of dexamethasone combined with transcranial direct current stimulation in rats submitted to an arthritis model / O perfil da dexametasona combinada com estimulação transcraniana por corrente contínua em ratos submetidos a um modelo de artrite

ABSTRACT BACKGROUND AND OBJECTIVES: To pursue safer and more effective treatments for rheumatoid arthritis, the effect of dexamethasone treatment (DEX, 0.25mg/kg) combined with transcranial direct current stimulation (tDCS) in the behavior and neurochemical parameters of arthritic rats was evaluated. METHODS: Thirty-six Wistar rats were divided into four groups: control+DEX (CTRL+DEX), arthritis+DEX (RA+DEX), arthritis+DEX+sham-tDCS (RA+DEX+sham-tDCS) and arthritis+DEX+tDCS (RA+DEX+tDCS). The arthritic model (RA) was induced by complete Freund's adjuvant (CFA) paw administration. Paw edema and mechanical allodynia were assessed by plethysmometer and von Frey apparatus, respectively. Fourteen days after the CFA injection, rats received the treatment for eight days (DEX and/or tDCS). Behavioral parameters were measured with the Open-Field test. ELISA was used to evaluate hippocampal and spinal cord tumor necrosis factor (TNF-α) levels, cerebral cortex and brainstem BDNF levels. RESULTS: In pre-treatment measurements, arthritic rats presented an increase in joint swelling and mechanical allodynia when compared to the control group, confirming chronic pain establishment. A slight antinociceptive effect of dexamethasone combined with tDCS in the pain model was observed. The pain model significantly induced an increase in the grooming behavior and a reduction in the spinal cord and hippocampal TNF-α levels; these effects were reverted in the sham- and active-tDCS-treated rats. However, no effects of DEX or tDCS were observed in the BDNF levels in the cerebral cortex and brainstem. CONCLUSION: Despite the small effect observed, tDCS treatment cannot be discarded as a non-pharmacological adjuvant technique for inflammatory chronic pain treatment.

RESUMO JUSTIFICATIVA E OBJETIVOS: Para investigar métodos mais seguros e eficazes para o manejo da artrite reumatoide, avaliou-se o efeito do tratamento com dexametasona (DEX, 0,25mg/kg) combinado com estimulação transcraniana por corrente contínua (ETCC) sobre parâmetros comportamentais e bioquímicos de ratos submetidos a um modelo de artrite reumatoide. MÉTODOS: Trinta e seis ratos Wistar foram alocados em 4 grupos: controle+DEX (CTRL+DEX), artrite+DEX (AR+DEX), artrite+DEX+sham-ETCC (AR+DEX+sham-ETCC) e artrite+DEX+ETCC (AR+DEX+ETCC). O modelo de artrite foi induzido pela administração de complete Freund's adjuvant (CFA) na pata. Edema na pata e a alodínia mecânica foram avaliadas por pletismômetro e teste de von Frey, respectivamente. 14 dias após injeção de CFA, ratos foram tratados por 8 dias (DEX e/ou ETCC). Atividade locomotora foi avaliada pelo teste do campo aberto. TNF-alfa (hipocampo e medula espinal) e BDNF (córtex e tronco) foram mensurados por ELISA. RESULTADOS: Nas medições pré-tratamento, ratos com artrite exibiram aumento de o inchaço articular e alodínia mecânica comparados ao grupo controle, confirmando o estabelecimento de modelo de dor crônica. Também se observou discreto efeito antinociceptivo da dexametasona combinada com ETCC no modelo de artrite. O modelo de dor induziu um aumento no comportamento de grooming e reduziu os níveis de TNF-alfa no hipocampo; estes efeitos foram revertidos nos grupos sham- e ETCC ativo. Entretanto, não foram observados efeitos da DEX ou ETCC nos níveis de BDNF no córtex cerebral ou no tronco encefálico. CONCLUSÃO: Apesar dos discretos efeitos observados, não se pode descartar a ETCC como uma abordagem terapêutica não farmacológica para o manejo da dor crônica inflamatória na artrite reumatoide.

Neuroinflammatory effects of tDCS in ovariectomized rats with chronic inflammation

Introduction: Postmenopausal women are more susceptible to chronic conditions, such as osteoporosis, arthritis, and other inflammatory diseases. We investigated the effects of transcranial direct current stimulation (tDCS) on biomarker levels in ovariectomized rats subjected to an inflammatory model. Methods: Twenty adult female Wistar rats underwent ovariectomy and complete Freund's adjuvant (CFA)-induced inflammation. We divided them into 2 groups: OAS (sham tDCS) and OAT (active tDCS). Fifteen days later, the rats underwent bimodal tDCS treatment (20 min, 0.5 mA, 8 days). After 24 h of the last tDCS session, we killed the rats and collected tissue samples (hypothalamus, cerebral cortex, and brainstem) for biomarker analysis by ELISA. We removed the paws for histological analysis. Results: Active tDCS increased hypothalamic and cortical TNF-α and NGF levels, hypothalamic and brainstem IL-1ß levels, and hypothalamic IL-10 levels. Histology of paws showed an inflammatory profile. We observed a small tDCS effect, not statistically significant. Discussion: Bimodal tDCS had an effect on the central inflammatory axis, with a small effect on the peripheral site as evaluated by histology in the current study. (AU)