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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.

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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.

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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.

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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.

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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.

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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.

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