RESUMO
Prolonged exposure of opioid receptors to agonists leads to their regulation by the classical process of clathrin-dependent internalization, followed by their intracellular degradation (down regulation). We have previously shown that the opioid agonist etorphine induced an additional process of down regulation of mu-opioid receptors (MOR) that occurred in intact MOR-transfected HEK-293 cells, as well as in isolated membranes. In the present study we show that etorphine similarly down regulated rat kappa-opioid receptors (KORs), which do not undergo the classical process of internalization and down regulation. This process was resistant to inhibitors of clathrin-coated pit formation (hypertonic sucrose, mono-dansyl-cadaverine) and was mainly mediated by membranous serine- and amino-peptidases. We further show that various opioid ligands, besides etorphine, induced down regulation of either KOR or MOR in isolated membranes. The ability of the various opioid ligands to induce membrane-delimited KOR or MOR down regulation did not correlate to their classical pharmacological profile, suggesting functional selectivity of the effect. Levorphanol, but not its stereoisomer dextrophan, induced membrane-delimited down regulation of both KOR and MOR, indicating that stereoselective binding to the receptor was necessary to initiate the process. Our findings that this proteolytic regulation of opioid receptors occurs not only in isolated membranes but also in intact cells and that it occurs even when the receptors are resistant to the conventional process of down regulation indicate its possible physiological role in the regulation of opioid activity.
Assuntos
Membrana Celular/enzimologia , Células Epiteliais/enzimologia , Peptídeo Hidrolases/fisiologia , Proteólise/efeitos dos fármacos , Receptores Opioides/metabolismo , Analgésicos Opioides/farmacologia , Animais , Ligação Competitiva/fisiologia , Membrana Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Etorfina/farmacologia , Células HEK293 , Humanos , Antagonistas de Entorpecentes , Ratos , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/metabolismo , Frações SubcelularesRESUMO
A partir de viñetas clínicas planteamos algunas reflexiones sobre el estatuto que la biografía del niño relatada por sus padres tiene en la mente del analista durante el trabajo analítico con su paciente; y su incidencia en la formulación de la interpretación en la sesión. Este trabajo transita entre dos posturas encontradas: aquella que plantea que la clínica de niños es imposible si no se atiende el discurso parental; aquella que plantea como posible el análisis de niños prescindiendo de la narrativa de los padres