Glioblastoma: a comprehensive approach combining bibliometric analysis, Latent Dirichlet Allocation, and HJ-Biplot : Glioblastoma insights and trends: a 49-year bibliometric analysis.

Glioblastoma is a common and aggressive malignant central nervous system tumor in adults. This study aims to evaluate and analyze the scientific results, collaboration countries, main research topics, and topics over time reported about glioblastoma. A bibliometric analysis of glioblastoma publications was performed mainly using R and Multbiplot software for author, journal, and resume. Associated statistic methods Latent Dirichlet Allocation (LDA) and HJ-Biplot. Inclusion criteria were research articles from the PubMed database published in English between 1973 and December 2022. A total of 64,823 documents with an annual growth rate of 8.27% indicates a consistent increase in research output over time. The results for the number of citations and significant publications showed Cancer Res, J Neuro-Oncol, and Neuro-Oncology are the most influential journals in the field of glioblastoma. The countries that concentrated research were the tumor United States, China, Germany, and Italy. Finally, there has been a marked growth in studies on prognosis and patient survival, therapies, and treatments for glioblastoma. These findings reinforce the need for increased global resources to address glioblastoma, particularly in underdeveloped countries. Glioblastoma research's exponential growth reflects sustained interest in early diagnosis and patient survival.

Neurological manifestations associated with SARS-CoV-2 infection: an updated review / Manifestaciones neurológicas asociadas con la infección por SARS-CoV-2: una revisión actualizada

Abstract SARS-CoV-2 is a single-stranded RNA virus that belongs to the group of seven coronaviruses that affect humans, and its infection causes the COVID-19 disease. The association between the COVID-19 condition and risk factors of neurological manifestations is unclear to date. This review aims to update the main neurological manifestations associated with SARS-CoV-2 disease. First, we present the hypothesis of the neuroinvasion mechanisms of SARS-CoV-2. Then, we discuss the possible symptoms related to patients with COVID-19 infection in the central and peripheral nervous systems, followed by the perspectives of diagnosis and treatment of possible neurological manifestations. The hypothesis of the neuroinvasion mechanism includes direct routes, as the virus crosses the blood-brain barrier or the ACE2 receptor pathway role, and indirect pathways, such as malfunctions of the immune system and vascular system dysregulation. Various studies report COVID-19 consequences, such as neuroanatomic alterations and cognitive impairment, besides peripheral conditions, such as anosmia, ageusia, and Guillain Barré Syndrome. However, the heterogeneity of the studies about neurologic damage in patients after COVID-19 infection precludes any generalization of current findings. Finally, new studies are necessary to understand the adequate diagnosis, therapeutic method of early treatment, and risk group of patients for neurological manifestations of COVID-19 post-infection.

Resumen El SARS-CoV-2 es un virus de ARN monocatenario que pertenece al grupo de los siete coronavirus que afectan a los humanos y cuya infección causa la enfermedad COVID-19. La asociación entre la infección por COVID-19 y factores de riesgo de manifestaciones neurológicas aún no está clara. Esta revisión tiene como objetivo actualizar la descripción de las principales manifestaciones neurológicas asociadas a la infección por SARS-CoV-2. Presentamos la hipótesis de los mecanismos de neuroinvasión del SARS-CoV-2. Luego discutimos los posibles síntomas asociados a los pacientes con infección por COVID-19 en el sistema nervioso central y periférico y, posteriormente, las perspectivas de diagnóstico y tratamiento de las posibles manifestaciones neurológicas. La hipótesis del mecanismo de neuroinvasión incluye rutas directas cuando el virus cruza la barrera hematoencefálica o tiene acción vía del receptor ACE2 y vías indirectas tales como el mal funcionamiento del sistema inmunitario y la desregulación del sistema vascular. Diversos estudios reportan consecuencias del COVID-19, como la presencia de alteraciones neuroanatómicas y deterioro cognitivo, además de condiciones periféricas como anosmia, ageusia y Síndrome de Guillain Barré. La heterogeneidad de los estudios sobre el daño neurológico en pacientes después de la infección por COVID-19 impide cualquier generalización de los hallazgos actuales. Finalmente, son necesarios nuevos estudios enfocándose en comprender el diagnóstico adecuado, el método terapéutico de tratamiento temprano y el grupo de riesgo para las manifestaciones neurológicas de la pos infección por COVID-19.

Analysis of Socio-demographic, Economic and Individual Reasons for COVID-19 Vaccination Hesitancy in Ecuador: A Nationwide Longitudinal Study.

The current outbreak of SARS-Cov-2, a virus responsible for COVID-19, has infected millions and caused a soaring death toll worldwide. Vaccination represents a powerful tool in our fight against the transmission of SARS-CoV-2. Ecuador is one of the Latin American countries most impacted by COVID-19. Despite free COVID-19 vaccines, Ecuadorians still hesitate to get vaccinated. A multivariate binary logistic regression was used to analyze data from the Ecuadorian National Institute of Statistics and Censuses. This study investigated socio-demographics, economic, and individual reasons associated with a person having "no intention" to receive COVID-19 vaccine across the study period of October 2021 to March 2022. The survey revealed an increase of unvaccinated people having no intention of COVID-19 vaccination from 57.4% (October-December 2021) to 72.9% (January-March 2022). COVID-19 vaccine hesitancy was dependent on factors like sex, age and ethnicity. Socio-economic characteristics and education level were not found to be statistically significant in lack of vaccine intention, but most vaccination hesitancy was due to distrust in the COVID-19 vaccine. People who believed that the vaccine could be unsafe because of possible side effects represented half of the surveyed participants, a proportion that barely diminished during the progress of the vaccination campaign across October-December 2021 (57.04%) and January-March 2022 (49.59%) periods. People who did not believe that the vaccine was effective enough increased from 11.47 to 18.46%. Misbeliefs about effectiveness and safety of vaccines should be considered in the implementation of public health initiatives of communication, education and intervention to improve vaccination campaigns.

Suicide rates in Ecuador: A nationwide study from 2011 until 2020.

Suicide, suicide ideations, and psychiatric disorder rates tend to increase after natural disasters such as earthquake. In 2016 Ecuador experienced a 7.8Mw earthquake and, more recently, the Covid-19 confinement. Both events may have negatively affected the mental health of the Ecuadorian population. Therefore, the present study aimed to evaluate the suicide rates and choice of suicide method in the Ecuadorian population between January 2011 and December 2020. The dataset used is publicly available on the Ecuadorian National Institute of Statistics and Censuses. Multivariate logistic regression models were used to calculate adjusted odds ratios (OR) for potential sociodemographic factors associated with each suicide method compared to other reported suicide methods. There were 10,380 registered cases of suicide in Ecuador between 2011 and 2020. Significant suicide rates per provinces were seen in Napo with 12.63 and Azuay with 12.52, followed by Bolívar with 12.30, and Orellana with 11.36 suicides/100,000 habitants. Hanging accounted for 7082 cases (68.2 %). The mestizos (82 %) were the most prevalent ethnicity of all suicide cases. School-age children with 6-12 years (OR 8.83, 95 % CI 5.34-14.59) and adolescents with 13-19 years (OR 1.46, 95 % CI 1.29-1.66) were more likely to use hanging as method of suicide. In conclusion, we observed an increase of suicide rates from 8.15 per 100,000 in 2011 to 8.81 in 2020. The confinement of COVID-19 pandemic in the period evaluated did not significantly affect the suicide rates. An increased suicide rate was observed in the province hardest hit by the 2016 earthquake.

Neuroendocrine Tumors: An Analysis of Prevalence, Incidence, and Survival in a Hospital-Based Study in Ecuador.

Neuroendocrine tumors (NETs) represent a heterogeneous malignancy group of neoplasms, with a limited amount of data from Latin America. Thus, this observational study aimed to provide data about the prevalence, incidence, and survival rates for NET in Ecuadorian hospitals. The study was conducted using data from the Society for the Fight Against Cancer (SOLCA). We evaluated patients with NETs (2000−2020) using the HJ-Biplot method and Cox proportional hazards. Annual age-adjusted incidence and limited-duration prevalence in multivariable analyses as well as hazard ratios (HRs) for mortality and survival were obtained. In the years 2000−2020, the age-adjusted incidence rate increased by 9-fold in the stomach and by 7-fold in the breast. The incidence rates were 1.38 per 100,000 persons in the lung and at 1.79 per 100,000 persons in gastroenteropancreatic sites (rectum, stomach, and pancreas). The prevalence increased from 0.0027% in 2000 to 0.0736% in 2019 and 0.0245% in 2020. Overall survival was worse for metastatic NETs (HR, 4.061; 95% CI, 1.932−8.540; p < 0.001) and advanced local NETs (HR, 2.348; 95% CI, 1.007−5.475 p < 0.048) than for localized NETs. In conclusion, the NET incidence increased in the last 20 years and survival decreased over time, especially for metastatic tumors in the pancreas and the nostril.

Clinical related factors to neuroendocrine tumors in Ecuadorian patients: a logistic biplot approach / Factores clínicos asociados a tumores neuroendocrinos en pacientes ecuatorianos: un análisis biplot logístico

Abstract Neuroendocrine tumors (NETs) are relative rare, affecting neuroendocrine cells throughout the body. Most tumors are diagnosed at advanced stages. NETs prevalence has increased in the last years but there is little data available in developing countries. The aim of this study was to describe symptoms associated with NETs in patients of the Society for the Fight Against Cancer (SOLCA) in Ecuador from 2005 to 2020; using logistic biplots, in a hospital database, generating binary responses (presence/absence) relevant to this study. The results showed that the mean age was 59 and the study showed no difference in prevalence between genders. NETs were mainly found in lungs (19%), followed by stomach (18%) and skin (9%). Most patients had pathological diagnosis G2 and G3 (30% and 70%, respectively). Symptoms as cough, dyspnea, weight loss, diarrhea, constipation, abdominal pain, dyspepsia, hypertensive crisis, distended abdomen and intestinal obstruction had p values <0.05. Additionally, the statistical analysis showed that cough and intestinal obstruction were also common, bearing in mind that patients had most frequent NETs in the lungs and skin. In summary, our results indicate that symptoms of NETs patients were positively associated with lung and skin. Further investigation is needed focusing on the type of NETs and their symptoms in order to establish an early marker for diagnosis.

Resumen Los tumores neuroendocrinos (TNE) son relativamente raros y afectan a las células neuroendocrinas de todo el cuerpo. La mayoría de los tumores se diagnostican en etapas avanzadas. La prevalencia de los TNE ha aumentado en los últimos años, pero hay pocos datos en los países en desarrollo. El objetivo de este estudio fue determinar los síntomas asociados a los TNE en pacientes de la Sociedad de Lucha contra el Cáncer (SOLCA) en Ecuador entre 2005 y 2020, utilizando biplots logísticos en una base de datos hospitalaria, generando respuestas binarias (presencia / ausencia) relevantes para este estudio. Los resultados mostraron que la edad promedio era de 59 años y el estudio no encontró diferencias en la prevalencia entre géneros. Los TNE se encontraron con mayor frecuencia en los pulmones (19%), seguidos del estómago (18%) y piel (9%). La mayoría de los pacientes tenían diagnóstico patológico G2 y G3 (30% y 70% respectivamente). Los síntomas como tos, disnea, pérdida de peso, diarrea, estreñimiento, dolor abdominal, dispepsia, crisis hipertensiva, abdomen distendido y obstrucción intestinal tuvieron valores de p <0,05. Además, el análisis estadístico mostró que la tos y la obstrucción intestinal también eran comunes, teniendo en cuenta que los pacientes tenían TNE más frecuentes en los pulmones y la piel. En resumen, nuestros resultados indican que los síntomas de los pacientes con TNE se asociaron positivamente con los pulmones y la piel. Se necesitan más investigaciones que se centren en el tipo de TNE y sus síntomas a fin de establecer un marcador más temprano para el diagnóstico.

A low-dose combination of ketamine and guanosine counteracts corticosterone-induced depressive-like behavior and hippocampal synaptic impairments via mTORC1 signaling.

Ketamine exhibits rapid and sustained antidepressant responses, but its repeated use may cause adverse effects. Augmentation strategies have been postulated to be useful for the management/reduction of ketamine's dose and its adverse effects. Based on the studies that have suggested that ketamine and guanosine may share overlapping mechanisms of action, the present study investigated the antidepressant-like effect of subthreshold doses of ketamine and guanosine in mice subjected to repeated administration of corticosterone (CORT) and the role of mTORC1 signaling for this effect. The ability of the treatment with ketamine (0.1 mg/kg, i.p.) plus guanosine (0.01 mg/kg, p.o.) to counteract the depressive-like behavior induced by CORT (20 mg/kg, p.o., for 21 days) in mice, was paralleled with the prevention of the CORT-induced reduction on BDNF levels, Akt (Ser473) and GSK-3ß (Ser9) phosphorylation, and PSD-95, GluA1, and synapsin immunocontent in the hippocampus. No changes on mTORC1 and p70S6K immunocontent were found in the hippocampus and prefrontal cortex of any experimental group. No alterations on BDNF, Akt/GSK-3ß, mTORC1/p70S6K, and synaptic proteins were observed in the prefrontal cortex of mice. The antidepressant-like and pro-synaptogenic effects elicited by ketamine plus guanosine were abolished by the pretreatment with rapamycin (0.2 nmol/site, i.c.v., a selective mTORC1 inhibitor). Our results showed that the combined administration of ketamine and guanosine at low doses counteracted CORT-induced depressive-like behavior and synaptogenic disturbances by activating mTORC1 signaling. This study supports the notion that the combined administration of guanosine and ketamine may be a useful therapeutic strategy for the management of MDD.

Physical exercise stimulates hippocampal mTORC1 and FNDC5/irisin signaling pathway in mice: Possible implication for its antidepressant effect.

Several lines of evidence have consistently indicated that physical exercise has antidepressant effects by improving hippocampal function, although the signaling pathways underpinning these responses are not well established. Therefore, this study investigated the role of mechanistic target of rapamycin complex 1 (mTORC1) and fibronectin type III domain-containing protein 5 (FNDC5)/irisin signaling in the antidepressant-like effect of physical exercise. We showed that physical exercise (treadmill running - 45 min/day/5 days/week for 4 weeks) produced an antidepressant-like effect as indicated by a reduction on the immobility time in mice subjected to the forced swimming test (FST) without altering locomotor activity in the open field test (OFT). Rapamycin (a selective mTORC1 inhibitor, 0.2 nmol/site, i.c.v.) administration completely abolished the antidepressant-like effect of physical exercise in the FST, suggesting that mTORC1 activation plays a role for its behavioral effect. Accordingly, physical exercise increased the number of phosphorylated mTORC1 (Ser2448)-positive cells in the entire and ventral subgranular zone of the hippocampal dentate gyrus. Physical exercise was also effective in augmenting the hippocampal FNDC5/irisin immunocontent, but rapamycin administration did not alter this effect. Our results reinforce the notion that physical exercise exerts an antidepressant-like effect and identifies the mTORC1-mediated signaling pathway as a target for its behavioral effects. This study provides additional evidence that physical exercise increases hippocampal FNDC5/irisin immunocontent, but this effect seems to be independent on hippocampal mTORC1 activation. Altogether the results contribute to elucidate possible molecular targets implicated in the antidepressant effects of physical exercise and highlight the role of mTORC1 signaling for its behavioral response.

mTORC1-dependent signaling pathway underlies the rapid effect of creatine and ketamine in the novelty-suppressed feeding test.

The development of fast-acting antidepressants is crucial considering that conventional antidepressants require a long period to elicit therapeutic effects. Creatine, an ergogenic guanidine-like compound, stands out as a candidate to exert fast antidepressant-like responses. The present study investigated whether a single dose of creatine elicits a fast response in mice submitted to the novelty-suppressed feeding (NSF) test, a paradigm that may assess depression-like and anxiety-like behaviors. Ketamine, an NMDA receptor antagonist that has rapid antidepressant effects, and conventional antidepressants were also tested. The involvement of the mTORC1 signaling pathway in the behavioral responses was also investigated. Biochemical analyses included hippocampal BDNF level (ELISA) and total and phospho-mTORC1 (Ser2448), PSD95 and synapsin immunocontent (Western Blotting). Creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.) reduced the latency to feed in the NSF test. Conversely, fluoxetine (10 mg/kg, p.o.), imipramine (1 mg/kg, p.o.) or bupropion (10 mg/kg, p.o.) did not alter this parameter. The administration of rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the effects of creatine or ketamine in the NSF test. Creatine or ketamine-treated mice presented increased hippocampal BDNF level, an effect abolished by rapamycin. The hippocampal phospho-mTORC1 (Ser2448) immunocontent was increased by creatine, but not by ketamine. However, ketamine, but not creatine, increased PSD95 and synapsin immunocontent. Creatine and ketamine elicit a rapid response in the NSF test by a mechanism dependent on the mTORC1 signaling pathway.

High-intensity swimming exercise reduces inflammatory pain in mice by activation of the endocannabinoid system.

As exercise intervention solely for pain reduction is relatively new, the available research still leaves an incomplete picture of responsible mechanisms and pathways. Nonetheless, evidence indicates that exercise-induced analgesia involves activation of the endocannabinoid (eCB) system. The present study investigated the role of the eCB system on the antihyperalgesic effect of high-intensity swimming exercise (HISE) in an animal model of peripheral persistent inflammation. Male Swiss mice were allocated to non-exercised and exercised groups and subjected to subcutaneous intraplantar injection (i.pl.) of a single dose of complete Freund's adjuvant (CFA) to induce inflammatory pain. Cumulative HISE was performed once a day, and mechanical hyperalgesia and edema were evaluated 0.5 hour after HISE for seven consecutive days. To investigate the role of the eCB system on the antihyperalgesic effect of HISE, non-exercised and exercised mice received intraperitoneal (ip), intrathecal (i.t.) or i.pl. injections of vehicle, AM281 (a CB1 cannabinoid receptor antagonist) or AM630 (a CB2 cannabinoid receptor antagonist) from the 3rd to 5th day after CFA injection. Mechanical hyperalgesia was evaluated 0.5 hour after HISE. In addition, the effect of the fatty acid amide hydrolase [FAAH] inhibitor or monoacylglycerol lipase [MAGL] inhibitor on the antihyperalgesic action of HISE was investigated. HISE reduced mechanical hyperalgesia with effects prevented by AM281 or AM630 pretreatment in all delivery routes tested. The inhibition of FAAH and MAGL prolonged the antihyperalgesic effect of HISE. These data demonstrate evidence for the role of the eCB system upon exercise-induced analgesia in a murine model of inflammatory pain.

Antidepressant-like and pro-neurogenic effects of physical exercise: the putative role of FNDC5/irisin pathway.

Physical exercise has been shown to exert antidepressant effects, but the mechanisms underlying this effect are not completely elucidated. Therefore, we aimed at investigating the antidepressant, pro-neurogenic, and neuroprotective effects of physical exercise and the possible role of FNDC5/irisin for this effect. Treadmill running was used as a protocol of physical exercise (45 min/day/5 days/week for 4 weeks) in female Swiss mice. Immobility time was registered in the tail suspension test (TST) and forced swim test (FST). Immunohistochemical analyses to evaluate hippocampal cell proliferation, neuronal survival, and neuronal commitment and maturation, as well as expression of FNDC5 C-terminal fragment were performed in the entire, dorsal, and ventral dentate gyrus (DG) of the hippocampus. Fluoro-Jade B staining was performed to evaluate degenerating neurons in DG. FNDC5 C-terminal and FNDC5/irisin immunocontents were analyzed by western blot. Exposure to physical exercise reduced the immobility time both in the TST and the FST. This antidepressant-like effect was accompanied by an increase in hippocampal cell proliferation, hippocampal neuronal differentiation, and neuronal survival in the dorsal and ventral DG. Fluoro-Jade B staining was reduced in entire and dorsal DG in exercised mice. Finally, physical exercise also resulted in increased number of FNDC5-positive cells in the hippocampal DG as well as elevated FNDC5 C-terminal and FNDC5/irisin immunocontent in the entire hippocampus. The results suggest that the FNDC5 C-terminal fragment/irisin pathway may be implicated in the antidepressant-like, pro-neurogenic, and neuroprotective effects of treadmill running.

Central irisin administration affords antidepressant-like effect and modulates neuroplasticity-related genes in the hippocampus and prefrontal cortex of mice.

Evidence has indicated that the practice of physical exercise has antidepressant effects that might be associated with irisin release and BDNF signaling. In this study we investigated the effects of the central administration of irisin or BDNF in predictive tests of antidepressant properties paralleled with the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex of mice. Irisin (0.5-1 ng/mouse, i.c.v.) reduced the immobility time in the tail suspension test (TST) and forced swim test (FST), without altering locomotion in the open field test (OFT). Irisin reduced the immobility time in the TST up to 6 h after its administration. Irisin administration (6 h) increased PGC-1α mRNA in the hippocampus and prefrontal cortex and reduced (1 h) PGC-1α mRNA in the prefrontal cortex. FNDC5 and BDNF mRNA expression was decreased (1 h) in both structures and remained reduced up to 6 h in the prefrontal cortex. Moreover, BDNF administered at 0.25 µg/mouse, i.c.v. (1 and 6 h before the test) reduced the immobility time in the TST. BDNF administration reduced PGC-1α mRNA in the hippocampus (6 h) and prefrontal cortex (1 and 6 h). It also increased FNDC5 mRNA expression in the hippocampus (1 and 6 h), but reduced the expression of this gene and also BDNF mRNA in the prefrontal cortex (1 and 6 h). None of the treatments altered BDNF protein levels in both structures. In conclusion, irisin presents a behavioral antidepressant profile similar to BDNF, an effect associated with the modulation of gene expression of PGC-1α, FNDC5 and BDNF, reinforcing the pivotal role of these genes in mood regulation.

Anxiolytic effects of ascorbic acid and ketamine in mice.

Some studies have demonstrated that ascorbic acid, similarly to ketamine, exhibits antidepressant-like effects mediated, at least in part, by modulation of the glutamatergic system. Despite the involvement of glutamatergic system in the pathophysiology of anxiety disorders, the ability of ascorbic acid and ketamine to elicit anxiolytic effects in animal models remains to be established. Therefore, this study investigated the effects of a single administration of ascorbic acid, ketamine or diazepam (positive control) in different animal models of anxiety. Mice were treated with ascorbic acid (1, 3 and 10 mg∕kg, p.o.), ketamine (1 and 10 mg∕kg, i.p.) or diazepam (2 mg∕kg, p.o) and their behavioral responses were assessed in the elevated plus maze, open field test (OFT), ligh∕dark preference test and marble burying test. Ascorbic acid increased total time spent in the open arms of elevated plus maze, increased total time in the center of the OFT, decreased rearing responses, increased the latency to grooming, decreased the rostral grooming, but did not affect body grooming. Furthermore, ascorbic acid increased the latency time and total time in light area in the ligh∕dark preference test, but did not affect the performance of mice in the marble burying test. Ketamine demonstrated an anxiolytic-like effect in elevated plus maze, OFT, and ligh∕dark preference test. Diazepam exhibited an anxiolytic-like effect in all the behavioral tests. Altogether, the results indicate the potential anxiolytic effect of ascorbic acid and ketamine, providing a possible new avenue for the management of anxiety-related disorders.

Neurobiological mechanisms of antiallodynic effect of transcranial direct current stimulation (tDCS) in a mice model of neuropathic pain.

BACKGROUND: Neuropathic pain is relatively common and occurs in approximately 6-8% of the population. It is associated with allodynia and hyperalgesia. Thus, non-pharmacological treatments, such as transcranial direct current stimulation (tDCS) may be useful for relieving pain. OBJECTIVES: This study aimed to investigate the antiallodynic effect of tDCS in a mice model of neuropathic pain, and the underlying neurotransmission systems that could drive these effects. METHODS: Male, Swiss mice, weighing 25-35 g, were subjected to partial sciatic nerve ligation (PSNL). Allodynia was assessed using a Von Frey filament (0.6 g). First, the behavioral time-course of these mice was assessed after 5, 10, 15 and 20 min of tDCS (0.5 mA). Second, the mice that underwent PSNL were assigned to either the tDCS (0.5 mA, 15 min) or tDCS sham group, and further assigned to receive either saline or a drug (i.e., naloxone, yohimbine, a-methyl-p-tyrosine, q-chlorophenylalanine methyl ester, caffeine, 1,3-dipropyl-8-cyclopentylxanthine, AM281, AM630, flumazenil, MK-801, or lidocaine). RESULTS: The antiallodynic effect of tDCS lasted 2 h and 4 h, after 10 min and 15 or 20 min of treatment, respectively (P < .001, P < .01, and P < .05, respectively). The antiallodynic effect of tDCS was associated with all the systems that were analyzed, i.e., the opioidergic (P < .01), adenosinergic (P < .001), serotonergic (P < .01), noradrenergic (P < .001), cannabinoid (P < .001), GABAergic, and glutamatergic (P < .001) systems. Lidocaine did not reverse the antiallodynic effect of tDCS (P > .05). CONCLUSION: The antiallodynic effect of tDCS was associated with different neurotransmitters systems; the duration of these after-effects depended on the time exposure to tDCS.

High-Intensity Swimming Exercise Decreases Glutamate-Induced Nociception by Activation of G-Protein-Coupled Receptors Inhibiting Phosphorylated Protein Kinase A.

Several studies in humans have reported that improved pain control is associated with exercise in a variety of painful conditions, including osteoarthritis, fibromyalgia, and neuropathic pain. Despite the growing amount of experimental data on physical exercise and nociception, the precise mechanisms through which high-intensity exercise reduces pain remain elusive. Since the glutamatergic system plays a major role in pain transmission, we firstly analyzed if physical exercise could be able to decrease glutamate-induced nociception through G-protein-coupled receptor (G-PCR) activation. The second purpose of this study was to examine the effect of exercising upon phosphorylation of protein kinase A (PKA) isoforms induced by intraplantar (i.pl.) glutamate injection in mice. Our results demonstrate that high-intensity swimming exercise decreases nociception induced by glutamate and that i.pl. or intrathecal injections of cannabinoid, opioid, and adenosine receptor antagonists, AM281, naloxone, and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), respectively, prevent this effect. Furthermore, the peripheral A1 and opioid receptors, but not CB1, are also involved in exercise's effect. We also verified that glutamate injection increases levels of phosphorylated PKA (p-PKA). High-intensity swimming exercise significantly prevented p-PKA increase. The current data show the direct involvement of the glutamatergic system on the hyponociceptive effect of high-intensity swimming exercise as well as demonstrate that physical exercise can activate multiple intracellular pathways through G-PCR activation, which share the same endogenous mechanism, i.e., inhibition of p-PKA.