RESUMO
BACKGROUND: Pannexin1 (Panx1) is a membrane channel expressed in different cells of the nervous system and is involved in several pathological conditions, including pain and inflammation. At the central nervous system, the role of Panx1 is already well-established. However, in the periphery, there is a lack of information regarding the participation of Panx1 in neuronal sensitization. The dorsal root ganglion (DRG) is a critical structure for pain processing and modulation. For this reason, understanding the molecular mechanism in the DRG associated with neuronal hypersensitivity has become highly relevant to discovering new possibilities for pain treatment. Here, we aimed to investigate the role of Panx1 in acute nociception and peripheral inflammatory and neuropathic pain by using two different approaches. METHODS: Rats were treated with a selective Panx1 blocker peptide (10Panx) into L5-DRG, followed by ipsilateral intraplantar injection of carrageenan, formalin, or capsaicin. DRG neuronal cells were pre-treated with 10Panx and stimulated by capsaicin to evaluate calcium influx. Panx1 knockout mice (Panx1-KO) received carrageenan or capsaicin into the paw and paclitaxel intraperitoneally. The von Frey test was performed to measure the mechanical threshold of rats' and mice's paws before and after each treatment. RESULTS: Pharmacological blockade of Panx1 in the DRG of rats resulted in a dose-dependent decrease of mechanical allodynia triggered by carrageenan, and nociception decreased in the second phase of formalin. Nociceptive behavior response induced by capsaicin was significantly lower in rats treated with Panx1 blockade into DRG. Neuronal cells with Panx1 blockage showed lower intracellular calcium response than untreated cells after capsaicin administration. Accordingly, Panx1-KO mice showed a robust reduction in mechanical allodynia after carrageenan and a lower nociceptive response to capsaicin. A single dose of paclitaxel promoted acute mechanical pain in wildtype (WT) but not in Panx1-KO mice. Four doses of chemotherapy promoted chronic mechanical allodynia in both genotypes, although Panx1-KO mice had significant ablation in the first eight days. CONCLUSION: Our findings suggest that Panx1 is critical for developing peripheral inflammatory pain and acute nociception involving transient receptor potential vanilloid subtype 1 (TRPV1) but is not essential for neuropathic pain chronicity.
Assuntos
Hiperalgesia , Neuralgia , Ratos , Camundongos , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Capsaicina/farmacologia , Capsaicina/uso terapêutico , Paclitaxel/efeitos adversos , Carragenina/efeitos adversos , Cálcio , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Formaldeído/efeitos adversos , Gânglios Espinais , Proteínas do Tecido Nervoso , Conexinas/genética , Conexinas/uso terapêuticoRESUMO
Descending control of nociception (DCN), a measure of efficiency of descending pain inhibition, can be assessed in animals by the combined application of test and conditioning noxious stimuli. Evidence from pre-clinical and clinical studies indicates that this mechanism of pain control may differ between sexes and might be impaired in many chronic pain states. However, little is known about sex differences in DCN efficiency in models of acute and chronic orofacial pain. Herein, we first evaluated DCN responses in male and female rats by the applying formalin into the upper lip or capsaicin into the forepaw as the conditioning stimulus, followed by mechanical stimulation (Randall-Selitto) of the hind paw as the test stimulus. The same protocol (i.e., capsaicin in the forepaw followed by mechanical stimulation of the hind paw) was evaluated in male and female rats on day 3 after intraoral incision and on day 15 and 30 after chronic constriction injury of the infraorbital nerve (CCI-ION). Additionally, we assessed the effect of the kappa opioid receptor (KOR) antagonist Norbinaltorphimine (nor-BNI) on DCN responses of female nerve-injured rats. This study shows that naïve female rats exhibit less efficient DCN compared to males. Postoperative pain did not alter DCN responses in female and male rats, but CCI-ION induced loss of DCN responses in females but not in males. Systemic pretreatment with nor-BNI prevented the loss of DCN induced by CCI-ION in female rats. The results reveal sex differences in DCN responses and female-specific impairment of DCN following chronic orofacial pain. Moreover, the findings suggest that, at least for females, blocking KOR could be a promising therapeutic approach to prevent maladaptive changes in chronic orofacial pain.
Assuntos
Dor Crônica , Neuralgia , Feminino , Ratos , Masculino , Animais , Dor Crônica/tratamento farmacológico , Receptores Opioides kappa , Neuralgia/tratamento farmacológico , Capsaicina/farmacologia , Capsaicina/uso terapêutico , Hiperalgesia/tratamento farmacológico , Caracteres Sexuais , Nociceptividade , Ratos Sprague-Dawley , Dor Facial/tratamento farmacológico , Antagonistas de Entorpecentes/farmacologia , Antagonistas de Entorpecentes/uso terapêuticoRESUMO
Capsaicin, a lipophilic, volatile compound, is responsible for the pungent properties of chili peppers. In recent years, a significant increase in investigations into its properties has allowed the production of new formulations and the development of tools with biotechnological, diagnostic, and potential therapeutic applications. Most of these studies show beneficial effects, improving antioxidant and anti-inflammatory status, inducing thermogenesis, and reducing white adipose tissue. Other mechanisms, including reducing food intake and improving intestinal dysbiosis, are also described. In this way, the possible clinical application of such compound is expanding every year. This opinion article aims to provide a synthesis of recent findings regarding the mechanisms by which capsaicin participates in the control of non-communicable diseases such as obesity, diabetes, and dyslipidemia.
Assuntos
Capsicum , Neuralgia , Capsaicina/uso terapêutico , Capsaicina/farmacologia , Neuralgia/tratamento farmacológico , Obesidade/tratamento farmacológicoRESUMO
The aim of this study is to report the results obtained with a protocol of topical application of capsaicin gel 0.025 % in the management of burning mouth syndrome (BMS) to evaluate the influence of the disease and treatment on their quality of life (QOL) using the OHIP-14 questionnaire (Oral Health Impact Profile). After clinical examination and diagnosis of BMS, 10 patients reported the intensity of the burning by means of a subjective score ranging from 0 to 10 and also answered the OHIP-14. Then, a topical application protocol of capsaicin gel 0.025 % was initiated, with weaning from medication and complete withdrawal within 180 days. At each reassessment consultation (30, 60, 90 and 180 days), the patients answered the OHIP-14 and subjective burning scores were collected again. Overall, the capsaicin gel showed gradual reduction or elimination of symptoms of BMS, as well as an improvement in the QOL of patients throughout treatment. At 180 days, after medication withdrawal, 6 patients (60 %) reported total absence of burning and in four patients (40 %) the score remained or decreased. In one patient (10 %) the score increased, although it remained below the initial score. The results showed an improvement in the QOL of all patients who completed the protocol and the impact of BMS on the QOL decreased in relation to the initial score in all patients. The topical use of 0.025 % capsaicin gel was effective in reducing or remitting symptoms of BMS. The OHIP-14 questionnaire showed the negative impact of BMS on patients' QOL and the role of treatment in its improvement.
El objetivo de este estudio fue reportar los resultados obtenidos con un protocolo de aplicación tópica de gel de capsaicina al 0,025 % en el manejo del síndrome de boca ardiente (SBA), para evaluar la influencia de la enfermedad y el tratamiento en su calidad de vida (CV) mediante el cuestionario OHIP-14. Tras el examen clínico y diagnóstico de SBA, 10 pacientes refirieron la intensidad del ardor mediante una puntuación subjetiva de 0 a 10 y también respondieron la OHIP-14. Luego, se inició un protocolo de aplicación tópica de gel de capsaicina al 0,025%, con destete de la medicación y retiro completo en 180 días. En cada consulta de reevaluación (30, 60, 90 y 180 días), los pacientes respondieron el OHIP-14 y se recogieron nuevamente las puntuaciones subjetivas de quemado. En general, el gel de capsaicina mostró una reducción o eliminación gradual de los síntomas del SBA, así como una mejora en la calidad de vida de los pacientes durante todo el tratamiento. A los 180 días, después de la retirada de la medicación, 6 pacientes (60 %) informaron ausencia total de ardor y en cuatro pacientes (40%) la puntuación se mantuvo o disminuyó. En un paciente (10 %) la puntuación aumentó, aunque se mantuvo por debajo de la puntuación inicial. Los resultados mostraron una mejora en la CV de todos los pacientes que completaron el protocolo y el impacto de SBA en la CV disminuyó en relación con la puntuación inicial en todos los pacientes. El uso tópico de gel de capsaicina al 0,025 % fue efectivo para reducir o remitir los síntomas del SBA. El cuestionario OHIP-14 mostró el impacto negativo de SBA en la CV de los pacientes y el papel del tratamiento en su mejora.
Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Síndrome da Ardência Bucal/diagnóstico , Síndrome da Ardência Bucal/terapia , Qualidade de Vida , Síndrome da Ardência Bucal/classificação , Síndrome da Ardência Bucal/etiologia , Capsaicina/uso terapêutico , Inquéritos e QuestionáriosRESUMO
Acidic environments, such as in inflamed tissues, favor the charged form of local anesthetics (LA). Hence, these drugs show less cell permeation and diminished potency. Since the analgesic capsaicin (CAP) triggers opening of the TRPV1 receptor pore, its combination with LAs could result in better uptake and improved anesthesia. We tested the above hypothesis and report here for the first time the analgesia effect of a two-drug combination (LA and CAP) on an inflamed tissue. First, CAP solubility increased up to 20 times with hydroxypropyl-beta-cyclodextrin (HP-ß-CD), as shown by the phase solubility study. The resulting complex (HP-ß-CD-CAP) showed 1:1 stoichiometry and high association constant, according to phase-solubility diagrams and isothermal titration calorimetry data. The inclusion complex formation was also confirmed and characterized by differential scanning calorimetry (DSC), X-ray diffraction, and 1H-NMR. The freeze-dried complex showed physicochemical stability for at least 12 months. To test in vivo performance, we used a pain model based on mouse paw edema. Results showed that 2% mepivacaine injection failed to anesthetize mice inflamed paw, but its combination with complexed CAP resulted in pain control up to 45 min. These promising results encourages deeper research of CAP as an adjuvant for anesthesia in inflamed tissues and cyclodextrin as a solubilizing agent for targeting molecules in drug delivery.
Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Anestesia Local/métodos , Anestésicos Locais/uso terapêutico , Capsaicina/uso terapêutico , Composição de Medicamentos/métodos , Excipientes/química , Hiperalgesia/tratamento farmacológico , Mepivacaína/uso terapêutico , Dor/tratamento farmacológico , Animais , Varredura Diferencial de Calorimetria , Capsaicina/química , Carragenina/efeitos adversos , Modelos Animais de Doenças , Estabilidade de Medicamentos , Quimioterapia Combinada , Hiperalgesia/induzido quimicamente , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Microscopia Eletrônica de Varredura , Manejo da Dor/métodos , Solubilidade , Difração de Raios XRESUMO
The purpose of the present study was to analyze the actions of transient receptor potential vanilloid type 1 (TRPV1) agonist capsaicin (CS) and of its antagonist capsazepine (CZ), on cardiac function as well as endothelial biomarkers and some parameters related with nitric oxide (NO) release in L-NG-nitroarginine methyl ester (L-NAME)-induced hypertensive rats. NO has been implicated in the pathophysiology of systemic arterial hypertension (SAHT). We analyzed the levels of nitric oxide (NO), tetrahydrobiopterin (BH4), malondialdehyde (MDA), total antioxidant capacity (TAC), cyclic guanosin monophosphate (cGMP), phosphodiesterase-3 (PDE-3), and the expression of endothelial nitric oxide synthase (eNOS), guanosine triphosphate cyclohydrolase 1 (GTPCH-1), protein kinase B (AKT), and TRPV1 in serum and cardiac tissue of normotensive (118±3 mmHg) and hypertensive (H) rats (165 ± 4 mmHg). Cardiac mechanical performance (CMP) was calculated and NO was quantified in the coronary effluent in the Langendorff isolated heart model. In hypertensive rats capsaicin increased the levels of NO, BH4, cGMP, and TAC, and reduced PDE-3 and MDA. Expressions of eNOS, GTPCH-1, and TRPV1 were increased, while AKT was decreased. Capsazepine diminished these effects. In the hypertensive heart, CMP improved with the CS treatment. In conclusion, the activation of TRPV1 in H rats may be an alternative mechanism for the improvement of cardiac function and systemic levels of biomarkers related to the bioavailability of NO.
Assuntos
Coração/efeitos dos fármacos , Hipertensão/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Biomarcadores/sangue , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Pressão Sanguínea , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Capsaicina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Hipertensão/tratamento farmacológico , Masculino , NG-Nitroarginina Metil Éster , Óxido Nítrico Sintase Tipo III , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Wistar , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Resistência VascularRESUMO
Capsaicin (trans-8-methyl-n-vanillyl-6-nonenamide) is the main pungent component found in hot peppers. AIM: In this study, we investigated the effect of capsaicin treatment on tumor growth and the metabolic indicators of cachexia in Walker 256 tumor-bearing rats. METHODS: Male Wistar rats were inoculated subcutaneously in the right flank with 1 ml of a sterile suspension of 3 × 107 Walker tumor cells. The treated groups received capsaicin intraperitoneal 5 mg/kg body weight for 13 days. RESULTS: The tumor weight on Day 14 in the non-treated group was 18 g. The rats also had a body weight loss, hypoglycemia, hyperlactacidemia, hypertriacylglycerolemia, and a depletion in glycogen storage. Treatment with capsaicin decreased tumor growth by 49% and a reversal of triacylglycerol serum. We also found a 32% reduction in tumor cell proliferation ex vivo. Lactate serum concentrations and body weight were lower but did not reach control levels. CONCLUSION: The treatment with capsaicin reduces tumor growth and cellular proliferation along with increased apoptosis and partial cachexia reversal.
Assuntos
Caquexia/tratamento farmacológico , Capsaicina/uso terapêutico , Carcinoma 256 de Walker/tratamento farmacológico , Animais , Carcinoma 256 de Walker/patologia , Proliferação de Células/efeitos dos fármacos , Ácido Láctico/sangue , Masculino , Ratos , Ratos Wistar , Canais de Cátion TRPV/fisiologia , Triglicerídeos/sangueRESUMO
The transient receptor potential vanilloid 1 (TRPV1) can modulate stress-related behaviours, thus representing an interesting target for new antidepressant drugs. TRPV1 can trigger glutamate release and nitric oxide synthesis in the brain, mechanisms also involved in the neurobiology of depression. However, it is not known if these mechanisms are involved in TRPV1-induced behavioural effects. Therefore, the aim of this study was to verify if the antidepressant-like effect induced by a TRPV1 antagonist in mice submitted to the forced swimming test (FST) would be facilitated by combined treatment with neuronal nitric oxide synthase (nNOS) inhibition and N-methyl-D-aspartate (NMDA) blockade. Male Swiss mice were given (intracerebroventricular) injections of capsazepine (CPZ) (TRPV1 antagonist - 0.05/0.1/0.3/0.6 nmol/µl), and AP7 (NMDA antagonist - 1/3/10 nmol/µl) or N-propyl-L-arginine (NPA, nNOS inhibitor - 0.001/0.01/0.1 nmol/µl), and 10 min later, submitted to an open field test, and immediately afterwards, to the FST. An additional group received coadministration of CPZ and AP7 or CPZ and NPA, in subeffective doses. The results demonstrated that CPZ (0.1 nmol/µl), AP7 (3 nmol/µl) and NPA (0.01/0.1 nmol/µl) induced antidepressant-like effects. Moreover, coadministration of subeffective doses of CPZ and AP7 or CPZ and NPA induced significant antidepressant-like effects. Altogether, the data indicate that blockade of TRPV1 receptors by CPZ induces antidepressant-like effects and that both nNOS inhibition and NMDA blockade facilitate CPZ effects in the FST.
Assuntos
Antidepressivos/uso terapêutico , Capsaicina/análogos & derivados , Depressão/tratamento farmacológico , Ácido Glutâmico/metabolismo , Óxido Nítrico/metabolismo , Natação/psicologia , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Apomorfina/análogos & derivados , Apomorfina/farmacologia , Arginina/farmacologia , Capsaicina/uso terapêutico , GMP Cíclico/metabolismo , Depressão/metabolismo , Depressão/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Inibidores Enzimáticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Masculino , Microinjeções , Nitroprussiato/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Estatísticas não ParamétricasRESUMO
OBJECTIVE: Sepsis, a serious and life threatening complication arising from infection caused by lipopolysaccharide, is a complex inflammatory syndrome, and one of the main causes of death in intensive care units (ICU). It is characterized as an over-response of pro-coagulant agents promotes coagulopathy and thrombus formation, resulting in disseminated intravascular coagulation (DIC). Furthermore, it can cause multiple organ dysfunction and hypotension (septic shock) resulting in death. Thrombocytopenia, which is a hallmark of sepsis, is strongly correlated as a negative marker of the infection. Additionally, platelets contribute with the oxidative stress in septic patients in order to exterminate the microbial pathogen. This review summarises the important role of platelets in the pathology of sepsis, and highlights potential treatment targets to improve the outcome of sceptic patients. METHODS: The search was performed in PubMed, books and retrieved journal articles for a period of three months. The figures were developed through Servier Medical Arts software. CONCLUSION: The exact treatment of sepsis is still the subject of considerable debate. Although here we presented several therapies that have shown promise for improving the outcome of patients, researching platelet function in sepsis has provided us targets to develop new medical approaches focusing specially on thrombocytopenia and DIC.