RESUMO

Fibromyalgia is a complex pain syndrome without a precise etiology. Reduced monoamines levels in serum and cerebrospinal fluid in fibromyalgia patients has been reported and could lead to a dysfunction of descending pain modulatory system producing the painful syndrome. This study evaluated the role of D1-like dopamine receptors in the reserpine-induced fibromyalgia-like pain model in female Wistar rats. Reserpine-treated animals were intrathecally injected with different dopamine receptors agonists and antagonists, and small interfering RNAs (siRNAs) against D1 and D5 receptor subtypes. Withdrawal and muscle pressure thresholds were assessed with von Frey filaments and the Randall-Selitto test, respectively. Expression of D1-like receptors in lumbar spinal cord and dorsal root ganglion was determined using real time polymerase chain reaction (qPCR). Reserpine induced tactile allodynia and muscle hyperalgesia. Intrathecal dopamine and D1-like receptor agonist SKF-38393 induced nociceptive hypersensitivity in naïve rats, whilst this effect was prevented by the D1-like receptor antagonist SCH-23390. Moreover, SCH-23390 induced a sex-dependent antiallodynic effect in reserpine-treated rats. Furthermore, transient silencing of D1 and D5 receptors significantly reduced reserpine-induced hypersensitivity in female rats. Reserpine slightly increased mRNA D5 receptor expression in dorsal spinal cord, but not in DRG. This work provides new insights about the involvement of the spinal dopaminergic D1/D5 receptors in reserpine-induced hypersensitivity in rats.

Assuntos

Fibromialgia , Ratos , Feminino , Animais , Fibromialgia/induzido quimicamente , Dopamina/fisiologia , Reserpina/efeitos adversos , Ratos Wistar , Dor/induzido quimicamente , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Receptores Dopaminérgicos , Receptores de Dopamina D1/agonistas

RESUMO

The use of alternative medicine to treat pain has been increased, and the combination of several medicinal plants for its relief is a common practice in traditional medicine. The present study is aimed at determining whether a combination of Syzygium aromaticum (S. aromaticum) and Rosmarinus officinalis L. (R. officinalis) potentiates their antinociceptive and anti-inflammatory effects. These effects were explored using the formalin and carrageenan assays in rats, respectively. Animals received local pretreatment with S. aromaticum oil or R. officinalis ethanolic extract (0.1-100 µg/paw) alone or combined in a 1 : 1 rate. Concentration-response curves were built to compare pharmacological responses after an individual administration of S. aromaticum, R. officinalis, or their combination. The pharmacological interaction was investigated by an isobolographic study using the EC50 of each component in a fixed 1 : 1 ratio. S. aromaticum and R. officinalis administered alone showed significant and concentration-dependent antinociceptive and anti-inflammatory effects, but R. officinalis was more potent than S. aromaticum in both the antinociceptive and anti-inflammatory effects (EC50 = 7.96 ± 0.6 µg/paw vs. EC50 = 41.6 ± 1.7 µg/paw; EC50 = 1.97 ± 0.3 µg/paw vs. EC50 = 26.9 ± 2.5 µg/paw, respectively). The isobolographic analysis of the combination of these species in a 1 : 1 ratio showed a synergistic interaction between S. aromaticum and R. officinalis since Z mix (experimental value) was lower than Z add (theoretical value) for both the antinociceptive effect (Z mix = 0.45 ± 0.1 < Z add = 24.8 ± 1.3) and the anti-inflammatory effect (Z mix = 5.2 ± 0.6 < Z add = 14.4 ± 2.2), suggesting a potentiation for both pharmacological effects. These results prove evidence of the efficacy of mixture herb-herb used in folk medicine for pain therapy. It also emphasizes the requirement of pharmacological studies to explore the efficacy and safety of herb interactions.

RESUMO

Zinagrandinolide E (1, ZGE) is an elemanolide with antinociceptive action isolated from Zinnia grandiflora (Asteraceae), valued in North México and southwestern United States for pain relief. Herein, we report the anti-inflammatory and antiallodynic action of ZGE (1) in carrageenan-induced inflammation and tactile allodynia in mice and in a neuropathic pain model in hyperglycemic mice. Local peripheral administration of ZGE (1-30 µg/paw) induced dose-dependent acute anti-inflammatory and antiallodynic effects. The anti-inflammatory effect was comparable to diclofenac (30 µg/paw). Intrathecal (i.t.) administration of ZGE (30 µg) in acute experiments did not affect carrageenan-induced inflammation but significantly reduced tactile allodynia in a dose-dependent fashion. In long-term experiments (15 or 6 days), using two different scheme treatments (pretreatment or post-treatment), ZGE (3-30 µg/paw) showed antiallodynic but not anti-inflammatory action. Local peripheral (3-30 µg/paw) or intrathecal (3-30 µg) administration of ZGE partially reversed tactile allodynia in hyperglycemic mice, better or comparable, respectively, with those of pregabalin (30 µg/paw or 30 µg i.t.). The effects were dose-dependent. According to the pharmacological tools employed, the anti-inflammatory and antiallodynic activities of ZGE are multitarget; these involve the opioidergic, serotoninergic, and GABAergic systems, as well as the NO-cGMP-ATP-sensitive K+ channel signaling pathway.

Assuntos

Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Asteraceae/química , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Modelos Animais de Doenças , Feminino , México , Camundongos

RESUMO

Neuropathic pain is characterized by the presence of hyperalgesia and allodynia. Pharmacological treatments include the use of antiepileptics such as pregabalin or gabapentin, as well as antidepressants; however, given the role of the sigma-1 receptor in the generation and maintenance of pain, it has been suggested that sigma-1 receptor antagonists may be effective. There are also other alternatives that have been explored, such as the use of flavonoids such as quercetin. Due to the relevance of drug combinations in therapeutics, the objective of this work was to evaluate the effect of the combination of BD-1063 with quercetin in a chronic sciatic nerve constriction model using the "Surface of Synergistic Interaction" analysis method. The combination had preferable additive or synergistic effects, with BD-1063 (17.8 mg/kg) + QUER (5.6 mg/kg) showing the best antinociceptive effects. The required doses were also lower than those used individually to obtain the same level of effect. Our results provide the first evidence that the combination of a sigma-1 receptor antagonist and the flavonoid quercetin may be useful in the treatment of nociceptive behaviors associated with neuropathic pain, suggesting a new therapeutic alternative for this type of pain.

Assuntos

Analgésicos/administração & dosagem , Antioxidantes/administração & dosagem , Neuralgia/tratamento farmacológico , Piperazinas/administração & dosagem , Quercetina/administração & dosagem , Receptores sigma/antagonistas & inibidores , Animais , Constrição , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Masculino , Neuralgia/metabolismo , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Wistar , Receptores sigma/metabolismo , Receptor Sigma-1

RESUMO

Tagetes lucida has been used in traditional medicine as a remedy to alleviate several gastrointestinal disorders that provoke stomachaches, abdominal cramps, and diarrhea. However, there is not enough scientific evidence that supports these effects. Therefore, the purpose of this study was to evaluate antispasmodic and antidiarrheal activities of aqueous extract of T. lucida (AqExt-TL) as well as its mechanism of action in experimental models. Antispasmodic activity and the mechanism of action of AqExt-TL were assessed on segments of the guinea pig ileum precontracted with KCl, acetylcholine (ACh), or electrical field stimulation (EFS). Furthermore, the antispasmodic effect of two coumarins (umbelliferone and herniarin) previously identified in this species was evaluated. Antidiarrheal activity of AqExt-TL was determined using the charcoal meal test in mice. AqExt-TL showed antispasmodic activity in segments of the guinea pig ileum precontracted with KCl (83.7 ± 1.9%) and ACh (77.2 ± 5.3%) at the maximal concentration; however, practically, it did not alter the contractions induced by EFS (10.1 ± 2.2%). Antispasmodic activity of AqExt-TL was not significantly altered by hexamethonium (a ganglionic blocker) or L-NAME (an inhibitor of nitric oxide synthase). However, this extract decreased the maximal contractile response to calcium (82.7 ± 8.5%), serotonin (68.1 ± 8.5%), and histamine (63.9 ± 5.9%) in their concentration-response curves. Umbelliferone and herniarin also induced an antispasmodic effect on tissues precontracted with KCl. In addition, low doses of AqExt-TL reduced to 50% the distance traveled by charcoal meal in the gastrointestinal transit model in mice as loperamide, an antidiarrheal agent, did. These results provided evidence of the antispasmodic and antidiarrheal activity of T. lucida, which supports its use in the folk medicine in relieving symptoms in some gastrointestinal disorders. In the antispasmodic effect, the blockade of histaminergic and serotoninergic pathway as well as the calcium channels seems to be involved. Finally, umbelliferone and herniarin could be partially responsible for the antispasmodic activity induced by T. lucida.

RESUMO

The present work aimed to determine the safety parameters of two new alkamides, affinin and hexahydroaffinin, with antinociceptive activity. To predict the preliminary acute toxicity, we used the acute and subchronic toxicity (50 mg/kg, orally [po]) in Swiss Webster mice. Genotoxicity assayed via analysis of cell micronuclei of the femoral bone marrow in mice; at the same time, metabolic parameters determined from peripheral blood samples. Furthermore, to discard the neuropharmacological effects, we assessed the ambulatory activity in mice to determine the possible effects in the central nervous system. Finally, we used capsaicin as a positive control of alkamides. According to our results, hexahydroaffinin (LD50 ≥ 5,000 mg/kg, po) is significantly less noxious than affinin (LD50 = 1,442.2 mg/kg, po) or capsaicin (LD50 = 489.9 mg/kg, po). In subchronic administration, we did not observe any changes in hematological or biochemical parameters in any compound analyzed from peripheral blood samples. Finally, the data from the genotoxicity assay showed micronuclei formation in 28%, 5%, and 3% of mice in the capsaicin, affinin, and hexahydroaffinin groups, respectively. With the results obtained in the present investigation, we suggest that affinin and hexahydroaffinin are not only useful candidates for possible new drugs but also safe compounds.

RESUMO

An aqueous extract prepared from the aerial parts of Zinnia grandiflora was found not to induce acute toxicity (LD50> 5g/kg, p.o.) in mice when tested by the Lorke method. This extract showed notable antinociceptive and anti-inflammatory actions when evaluated by the formalin- (ED50 = 224.62 ± 38.17 mg/kg, p.o.) and the carrageenan-induced paw edema models in mice, respectively. The organic-soluble fractions obtained by partitioning the infusion with CH2Cl2 and EtOAc were also active in the formalin test. The most important antinociceptive effect was observed with the CH2Cl2 fraction; extensive fractionation of the latter yielded three new elemanolides, namely, zinagranolides D-F (1-3), which were characterized structurally by spectroscopic means. The structure of compound 2 was established unequivocally by an X-ray crystallographic analysis. This compound exerted a significant antinociceptive effect in the formalin assay, better than that of diclofenac used as a positive control.

Assuntos

Analgésicos/farmacologia , Asteraceae/química , Extratos Vegetais/farmacologia , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Relação Dose-Resposta a Droga , Dose Letal Mediana , Camundongos , Estrutura Molecular , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Espectroscopia de Prótons por Ressonância Magnética

RESUMO

The aim of this work was to design, synthesize and characterize the potential anti-nociceptive and anti-inflammatory activities of a new series of bioisosteres and hybrids from known non-steroidal anti-inflammatory drugs (NSAIDs). The compounds 4-(acetylamino)phenyl (2S)-2-(6-methoxy-2-naphthyl)propanoate (GUF-1) and 4-(acetylamino)phenyl 2-(R,S)-(4-isobutylphenyl)propanoate (GUF-2) were synthesized as hybrids (also known as heterodimers); whereas those named 2-(R,S)-(4-isobutylphenyl)-N-1H-tetrazol-5-ylpropanamide (GUF-3), (2S)-2-(6-methoxy-2-naphthyl)-N-1H-tetrazol-5-ylpropanamide (GUF-4), [2-(R,S)-N-hydroxy-2-[4-(2-methylpropyl)phenyl]propanamide] (GUF-5), and (2S)-N-hydroxy-2-(6-methoxy-2-naphthyl)propanamide (GUF-6) were synthesized as bioisosteres of the NSAIDs paracetamol, ibuprofen, and naproxen, respectively. All these compounds were characterized by spectroscopic and spectrometric analysis. Antinociceptive activity of GUF-1 to GUF-6 was evaluated using the formalin test in rats. Pharmacological responses of GUF-1, GUF-2 (hybrids), and GUF-5 (bioisostere) demonstrated significant antinociceptive effects; thus these compounds were assayed in an inflammation test like carrageenan-induced paw oedema in rats. Complete molecular docking of cyclooxygenase and the GUF-1 and GUF-2 hybrids showed high docking scores, compared to the reference drugs. Our data demonstrate that compounds GUF-1, GUF-2, and GUF-5 possesses antinociceptive and antiinflammatory activities resembling and improving those known for the traditional NSAIDs, paracetamol, naproxen and ibuprofen.

Assuntos

Acetaminofen/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Ibuprofeno/síntese química , Simulação de Acoplamento Molecular/métodos , Naproxeno/síntese química , Medição da Dor/efeitos dos fármacos , Acetaminofen/metabolismo , Acetaminofen/farmacologia , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Sítios de Ligação/fisiologia , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Ibuprofeno/metabolismo , Ibuprofeno/farmacologia , Imageamento Tridimensional/métodos , Naproxeno/metabolismo , Naproxeno/farmacologia , Medição da Dor/métodos , Ratos , Ratos Wistar

RESUMO

OBJECTIVE: To analyse the most frequent self-reported adverse reactions (ARs), the durability and the causes of antiretrovirals (ARVs) regimens change, concomitant treatments and drug interactions related to the use of ARVs in a group of people living with HIV in Cuernavaca, Morelos, Mexico. MATERIALS AND METHODS: Cross-sectional study conducted in a clinic specialising in HIV 'CAPASITS-Cuernavaca' in Mexico from February to June 2015. People who wanted to participate were given a questionnaire on demographic characteristics, adherence, concomitant treatments and ARs. To understand the clinical variables, the clinical records were reviewed. Quantitative variables were compared using Student's t-test for normal data and the Mann-Whitney U test for non-normal data. For comparisons between categorical variables, the χ2 test was used. All tests used a significance level of 0.05. RESULTS: A total of 96 people participated, and 218 ARs (mean= 2.3±1.9) were found. The most frequently encountered ARs were dizziness (53.1%), insomnia (21.9%) and lucid dreams (17.7%). Twenty-three people (24%) were polymedicated, and 18 potential interactions were detected in 12 people. CONCLUSIONS: The results suggest that a thorough analysis of the possible drug interactions should be performed for polymedicated people on ARV treatment and that a protocol should be designed for the monitoring and management of AR to ensure a good adherence to ARV treatment.