RESUMO
The pharmacotherapy for the treatment of pain is an active area of investigation. There are effective drugs to treat this problem, but there is also a need to find alternative treatments free of undesirable side effects. In the present work the capacity of a series of flavonoids to bind to the µ opioid receptor was evaluated. The most active compound, 3,3-dibromoflavanone (31), a synthetic flavonoid, presented a significant inhibition of the binding of the selective µ opioid ligand [(3)H]DAMGO, with a Ki of 0.846 ± 0.263 µM. Flavanone 31 was further synthesized using a simple and cheap procedure with good yield. Its in vivo effects in mice, after acute treatments, were studied using antinociceptive and behavioral assays. It showed no sedative, anxiolytic, motor incoordination effects or inhibition of the gastrointestinal transit in mice at the doses tested. It evidenced antinociceptive activity on the acetic acid-induced nociception, hot plate and formalin tests (at 10 mg/kg and 30 mg/kg). The results showed that the 5-HT2 receptor and the adrenoceptors seem unlikely to be involved in its antinociceptive effects. Naltrexone, a nonselective opioid receptors antagonist, totally blocked compound 31 antinociceptive effects on the hot plate test, but naltrindole (δ opioid antagonist) and nor-binaltorphimine (κ opioid antagonist) did not. These findings demonstrated that 3,3-dibromoflavanone (31), at doses that did not interfere with the motor performance, exerted clear dose dependent antinociception when assessed in the chemical and thermal models of nociception in mice and it seems that its action is related to the activation of the µ opioid receptor.
Assuntos
Analgésicos/uso terapêutico , Flavonoides/uso terapêutico , Receptores Opioides mu/metabolismo , Dor Visceral/metabolismo , Ácido Acético/farmacologia , Analgésicos/farmacologia , Analgésicos Opioides/farmacocinética , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Composição de Medicamentos , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacocinética , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Flavonoides/química , Flavonoides/farmacologia , Trânsito Gastrointestinal/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ligação Proteica/efeitos dos fármacos , Trítio/farmacocinética , Dor Visceral/diagnóstico , Dor Visceral/tratamento farmacológicoRESUMO
Behavioral sensitization to ethanol is characterized by an increased locomotor activity after repeated exposure. A great variability exists among species and strains in the development of sensitization. There is a growing amount of evidence to indicate that the opioid system is involved in alcoholism; it is possible, therefore, that this system also modulates the sensitization to ethanol. In this study we evaluated the role of the opioid system in determining the variability of the sensitized response to ethanol. Mice received repeated administrations of ethanol (2.2 g/kg) or saline every other day for 10 days. According to their locomotor response on the last day of treatment, ethanol-treated animals were classified into two groups: sensitized or non-sensitized mice. After the treatment, mice were submitted to four challenges 48 h apart. In experiments 1 and 2, mice were challenged, respectively, with i.p. administration of opioid antagonists (naloxone or naltrexone) or an opioid agonist (morphine), followed immediately by 2.2 g/kg ethanol. In experiment 3, animals received morphine by i.c.v., followed by 2.2 g/kg of ethanol (i.p.). Pretreatment with opioid antagonists (naloxone or naltrexone) did not block the expression of ethanol sensitization; however pretreatment with morphine attenuated the increased locomotor activity after ethanol administration in sensitized mice. In experiment 4, after the ethanol or saline treatment, mice brains were processed and brain mu opioid binding was assessed by autoradiography using [3H]D-Ala2,N-mePhe4, Gly-ol5-enkephalin ([3H]DAMGO). No differences were seen between any of the groups of mice, so the agonist effect is not likely to be mediated by differences in binding to mu opioid receptors.