RESUMO
This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.
Assuntos
Monoterpenos Acíclicos , Analgésicos , Capsaicina , Codeína , Dor Facial , Medição da Dor , Terpenos , Animais , Codeína/farmacologia , Dor Facial/induzido quimicamente , Dor Facial/tratamento farmacológico , Monoterpenos Acíclicos/farmacologia , Masculino , Medição da Dor/efeitos dos fármacos , Capsaicina/farmacologia , Terpenos/farmacologia , Analgésicos/farmacologia , Camundongos , Fatores de Tempo , Modelos Animais de Doenças , Reprodutibilidade dos Testes , Formaldeído , Ácido Glutâmico , Resultado do Tratamento , Nociceptividade/efeitos dos fármacos , Análise de Variância , Estatísticas não Paramétricas , Comportamento Animal/efeitos dos fármacosRESUMO
Burns are a global health problem and can be caused by several factors, including ultraviolet (UV) radiation. Exposure to UVB radiation can cause sunburn and a consequent inflammatory response characterised by pain, oedema, inflammatory cell infiltration, and erythema. Pharmacological treatments available to treat burns and the pain caused by them include nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antimicrobials and glucocorticoids, which are associated with adverse effects. Therefore, the search for new therapeutic alternatives is needed. Diosmetin, an aglycone of the flavonoid diosmin, has antinociceptive, antioxidant and anti-inflammatory properties. Thus, we evaluated the antinociceptive and anti-inflammatory effects of topical diosmetin (0.01, 0.1 and 1%) in a UVB radiation-induced sunburn model in mice. The right hind paw of the anaesthetised mice was exposed only once to UVB radiation (0.75 J/cm2) and immediately treated with diosmetin once a day for 5 days. The diosmetin antinociceptive effect was evaluated by mechanical allodynia and pain affective-motivational behaviour, while its anti-inflammatory activity was assessed by measuring paw oedema and polymorphonuclear cell infiltration. Mice exposed to UVB radiation presented mechanical allodynia, increased pain affective-motivational behaviour, paw oedema and polymorphonuclear cell infiltration into the paw tissue. Topical Pemulen® TR2 1% diosmetin reduced the mechanical allodynia, the pain affective-motivational behaviour, the paw oedema and the number of polymorphonuclear cells in the mice's paw tissue similar to that presented by Pemulen® TR2 0.1% dexamethasone. These findings indicate that diosmetin has therapeutic potential and may be a promising strategy for treating patients experiencing inflammatory pain, especially those associated with sunburn.
Assuntos
Anti-Inflamatórios , Modelos Animais de Doenças , Flavonoides , Inflamação , Nociceptividade , Queimadura Solar , Raios Ultravioleta , Animais , Queimadura Solar/tratamento farmacológico , Queimadura Solar/patologia , Camundongos , Raios Ultravioleta/efeitos adversos , Inflamação/tratamento farmacológico , Masculino , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Flavonoides/farmacologia , Flavonoides/administração & dosagem , Nociceptividade/efeitos dos fármacos , Administração Tópica , Analgésicos/farmacologia , Analgésicos/administração & dosagem , Edema/tratamento farmacológico , Hiperalgesia/tratamento farmacológicoRESUMO
Controlled ovarian hyperstimulation (COH) is a common step for treating infertile couples undergoing assisted reproductive technologies and in female fertility preservation cycles. In some cases, undergoing multiple COHs is required for couples to conceive. Behavioral changes such as anxiety and depression can be caused by ovulation-inducing drugs. Sex steroids play a role in locomotor activity, behavioral changes, and nociception, specifically during fluctuations and sudden drops in estrogen levels. This study evaluated the effect of repeated ovarian hyperstimulation (ROH) on weight, locomotor activity, anxiety-like and depression-like behavior, and nociception in female mice. The animals were divided into two groups: control (placebo; Control) and treated (ROH; Treatment). Ovulation was induced once weekly for 10 consecutive weeks. Locomotor activity (open field test), anxiety-like behavior (elevated plus maze, hole board, and marble burying tests), depression-like behavior (splash and forced swim tests), and nociception (hot plate and Von Frey tests) were evaluated before and after ROH. Statistical analysis was conducted using two-way analysis of variance to evaluate the effects of ROH, age of mice, and their interaction. The results suggested that ROH contributed to weight gain, increased locomotor activity, and induced depression-like behavior in female mice. Furthermore, the age of the mouse contributed to weight gain, increased locomotor activity, and induced anxiety-like and depression-like behavior in female mice. ROH could change the behavior of female mice, particularly inducing depression-like behavior. Further studies are required to evaluate various COH protocols, specifically with drugs that prevent fluctuations and drastic drops in estrogen levels, such as aromatase inhibitors.
Assuntos
Ansiedade , Depressão , Animais , Feminino , Camundongos , Comportamento Animal/fisiologia , Indução da Ovulação/métodos , Nociceptividade/fisiologia , Locomoção/fisiologia , Atividade Motora/fisiologia , Peso Corporal/fisiologiaRESUMO
Noradrenaline (NA) and serotonin (5-HT) induce nociception and antinociception. This antagonistic effect can be explained by the dose and type of activated receptors. We investigated the existence of synergism between the noradrenergic and serotonergic systems during peripheral antinociception. The paw pressure test was performed in mice that had increased sensitivity by intraplantar injection of prostaglandin E2 (PGE2). Noradrenaline (80 ng) administered intraplantarly induced an antinociceptive effect, that was reversed by the administration of selective antagonists of serotoninergic receptors 5-HT1B isamoltan, 5-HT1D BRL15572, 5-HT2A ketanserin, 5-HT3 ondansetron, but not by selective receptor antagonist 5-HT7 SB-269970. The administration of escitalopram, a serotonin reuptake inhibitor, potentiated the antinociceptive effect at a submaximal dose of NA. These results, indicate the existence of synergism between the noradrenergic and serotonergic systems in peripheral antinociception in mice.
Assuntos
Norepinefrina , Receptores de Serotonina , Antagonistas da Serotonina , Serotonina , Animais , Camundongos , Norepinefrina/metabolismo , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Masculino , Receptores de Serotonina/metabolismo , Dinoprostona/metabolismo , Citalopram/farmacologia , Nociceptividade/efeitos dos fármacos , Analgésicos/farmacologia , Ondansetron/farmacologia , Ketanserina/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
BACKGROUND: More than 80% of patients may experience acute pain after a surgical procedure, and this is often refractory to pharmacological intervention. The identification of new targets to treat postoperative pain is necessary. There is an association of polymorphisms in the Cav2.3 gene with postoperative pain and opioid consumption. Our study aimed to identify Cav2.3 as a potential target to treat postoperative pain and to reduce opioid-related side effects. EXPERIMENTAL APPROACH: A plantar incision model was established in adult male and female C57BL/6 mice. Cav2.3 expression was detected by qPCR and suppressed by siRNA treatment. The antinociceptive efficacy and safety of a Cav2.3 blocker-alone or together with morphine-was also assessed after surgery. KEY RESULTS: Paw incision in female and male mice caused acute nociception and increased Cav2.3 mRNA expression in the spinal cord but not in the incised tissue. Intrathecal treatment with siRNA against Cav2.3, but not with a scrambled siRNA, prevented the development of surgery-induced nociception in both male and female mice, with female mice experiencing long-lasting effects. High doses of i.t. SNX-482, a Cav2.3 channel blocker, or morphine injected alone, reversed postoperative nociception but also induced side effects. A combination of lower doses of morphine and SNX-482 mediated a long-lasting reversal of postsurgical pain in female and male mice. CONCLUSION: Our results demonstrate that Cav2.3 has a pronociceptive role in the induction of postoperative pain, indicating that it is a potential target for the development of therapeutic approaches for the treatment of postoperative pain.
Assuntos
Canais de Cálcio Tipo R , Dor Pós-Operatória , Medula Espinal , Animais , Feminino , Masculino , Camundongos , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/administração & dosagem , Canais de Cálcio Tipo R/metabolismo , Canais de Cálcio Tipo R/genética , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Morfina/administração & dosagem , Nociceptividade/efeitos dos fármacos , Dor Pós-Operatória/metabolismo , Dor Pós-Operatória/tratamento farmacológico , RNA Interferente Pequeno , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacosRESUMO
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.
Assuntos
Fibromialgia , Estimulação Transcraniana por Corrente Contínua , Humanos , Adulto , Ratos , Masculino , Animais , Estimulação Transcraniana por Corrente Contínua/métodos , Fibromialgia/tratamento farmacológico , Pregabalina/farmacologia , Fator Neurotrófico Derivado do Encéfalo , Ratos Wistar , Fator de Necrose Tumoral alfa , Nociceptividade/fisiologia , Reserpina , Dor , Ansiedade/tratamento farmacológico , BiomarcadoresRESUMO
Caffeine and anabolic-androgenic steroids (AAS) are commonly used to improve muscle mass and athletic performance. Nandrolone Decanoate (ND) is one of the most abused AAS worldwide, leading to behavioral changes in both humans and rodents. Caffeine, the most widely consumed psychostimulant globally, is present in various thermogenic and gym supplements. Low and moderate doses of caffeine antagonize adenosine receptors and have been linked to improved memory and pain relief. We have previously demonstrated that consuming caffeine prevents the risk-taking behavior triggered by nandrolone. In this study, we aimed to investigate the long-term effects of ND and caffeine, either alone or in combination, on passive avoidance memory and nociception. We used the step-down and hot-plate tasks in male and female Lister Hooded rats. Our results confirmed the antinociceptive effect of caffeine and indicated that chronic administration of the ND-caffeine association promotes the evocation of aversive memory in female rats.
Assuntos
Aprendizagem da Esquiva , Cafeína , Memória , Decanoato de Nandrolona , Nociceptividade , Animais , Cafeína/farmacologia , Feminino , Masculino , Ratos , Nociceptividade/efeitos dos fármacos , Decanoato de Nandrolona/farmacologia , Memória/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Nandrolona/farmacologia , Nandrolona/análogos & derivados , Estimulantes do Sistema Nervoso Central/farmacologia , Anabolizantes/farmacologiaRESUMO
OBJECTIVE: To evaluate the role of induced nitric oxide synthase (iNOS) in nociception/orofacial discomfort in rats submitted to tooth whitening with hydrogen peroxide (H2O2). DESIGN: Wistar rats were divided into three groups (n = 24/group): a sham group not submitted to whitening treatment, a saline group submitted to whitening treatment, and a test group submitted to whitening treatment and blockade of iNOS with aminoguanidine 50 mg/kg/day. After 24 and 48 h, and 7 days, the animals were euthanized to collect trigeminal ganglia and maxillae to histomorphometric analysis (size of neuronal bodies and percentage of pulp area filled by vessels) and behavior/nociception (Grimace scales, scratching and biting counting, weight loss and nociception assay). ANOVA-1- or - 2-way tests were used (p < 0.05, GraphPadPrism 5.0). RESULTS: The aminoguanidine-treated group showed a reduction in nociceptive threshold in the masseteric region (p < 0.001), Grimace scale scores (p < 0.001), number of scratching (p = 0.011) and body mass loss (p = 0.007). After 24 and 48 h of tooth bleaching, the saline group showed a significant increase in the mean area of the blood vessels (p = 0.020) and iNOS immunostaining in odontoblasts (p = 0.002) and non-odontoblasts cells (p = 0.025). Aminoguanidine reversed both increases. Tooth bleaching reduced the mean area of neuronal bodies, and aminoguanidine significantly reversed it (p = 0.019), but an increase in GFAP immunostaining in neuronal bodies did not reduce after seven-days or after aminoguanidine treatment (p = 0.003). CONCLUSION: iNOS blockage by aminoguanidine plays an important role in nociception and orofacial discomfort by control of inflammation in dental pulp after tooth bleaching with hydrogen peroxide (H2O2) 35%.
Assuntos
Guanidinas , Clareadores Dentários , Clareamento Dental , Ratos , Animais , Peróxido de Hidrogênio/farmacologia , Nociceptividade , Óxido Nítrico , Ratos Wistar , Óxido Nítrico SintaseRESUMO
Abnormal cognitive and sensorial properties have been reported in patients with psychiatric and neurodevelopmental conditions, such as attention deficit hyperactivity disorder (ADHD). ADHD patients exhibit impaired dopaminergic signaling and plasticity in brain areas related to cognitive and sensory processing. The spontaneous hypertensive rat (SHR), in comparison to the Wistar Kyoto rat (WKY), is the most used genetic animal model to study ADHD. Brain neurotrophic factor (BDNF), critical for midbrain and hippocampal dopaminergic neuron survival and differentiation, is reduced in both ADHD subjects and SHR. Physical exercise (e.g. swimming) promotes neuroplasticity and improves cognition by increasing BDNF and irisin. Here we investigate the effects of gestational swimming on sensorial and behavioral phenotypes, striatal dopaminergic parameters, and hippocampal FNDC5/irisin and BDNF levels observed in WKY and SHR. Gestational swimming improved nociception in SHR rats (p = 0.006) and increased hippocampal BDNF levels (p = 0.02) in a sex-dependent manner in adolescent offspring. Sex differences were observed in hippocampal FNDC5/irisin levels (p = 0.002), with females presenting lower levels than males. Our results contribute to the notion that swimming during pregnancy is a promising alternative to improve ADHD phenotypes in the offspring.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Humanos , Ratos , Feminino , Masculino , Animais , Adolescente , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fibronectinas , Nociceptividade , Encéfalo/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Modelos Animais de DoençasRESUMO
Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system (CNS) generating neuropathic pain and anxiety. Primary progressive MS (PPMS) is the most disabling clinical form, and the patients present an intense neurodegenerative process. In this context, the advanced oxidation protein products (AOPPs) are oxidized compounds and their accumulation in plasma has been related to clinical disability in MS patients. However, the involvement of AOPPs in neuropathic pain- and anxiety-like symptoms was not previously evaluated. To assess this, female mice C57BL/6J were used to induce progressive experimental autoimmune encephalomyelitis (PMS-EAE). Clinical score, weight, strength of plantar pressure, rotarod test, mechanical allodynia, and cold hypersensitivity were evaluated before induction (baseline) and on days 7th, 10th, and 14th post-immunization. We assessed nest building, open field, and elevated plus-maze tests 13 days post-immunization. Animals were killed at 14 days post-immunization; then, AOPPs levels, NADPH oxidase, and myeloperoxidase (MPO) activity were measured in the prefrontal cortex, hippocampus, and spinal cord samples. The clinical score increased 14th post-immunization without changes in weight and mobility. Reduced paw strength, mechanical allodynia, and cold allodynia increased in the PMS-EAE animals. PMS-EAE mice showed spontaneous nociception and anxiety-like behavior. AOPPs concentration, NADPH oxidase, and MPO activity increase in CNS structures. Multivariate analyses indicated that the rise of AOPPs levels, NADPH oxidase, and MPO activity influenced the clinical score and cold allodynia. Thus, we indicated the association between non-stimuli painful perception, anxiety-like, and CNS oxidative damage in the PMS-EAE model.