RESUMEN
The delta opioid system is involved in the behavioral effects of various drugs of abuse. However, only a few studies have focused on the possible interactions between the opioid system and the effects of 3,4-methylenedioxymethamphetamine (MDMA). In order to examine the possible role of the delta opioid system in MDMA-induced behaviors in mice, locomotor activity and conditioned place preference (CPP) were investigated in the presence of naltrindole (NTI), a selective delta opioid antagonist. Moreover, the consequences of acute and chronic MDMA administration on pro-enkephalin (Penk) and pro-opiomelanocortin (Pomc) gene expression were assessed by real-time quantitative polymerase chain reaction (QPCR). The results showed that, after acute MDMA administration (9 mg/kg; i.p.), NTI (5 mg/kg, s.c.) was able to totally block MDMA-induced hyperlocomotion. Penk gene expression was not modulated by acute MDMA, but a decrease of Pomc gene expression was observed, which was not antagonized by NTI. Administration of the antagonist prevented the acquisition of MDMA-induced CPP, suggesting an implication of the delta opioid receptors in this behavior. Following chronic MDMA treatment, only the level of Pomc was modulated. The observed increase was totally blocked by NTI pre-treatment. All these results confirm the interactions between the delta opioid system (receptors and peptides) and the effects of MDMA.
Asunto(s)
Trastornos Relacionados con Anfetaminas/genética , Conducta Animal/efectos de los fármacos , Encefalinas/genética , Alucinógenos/toxicidad , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Naltrexona/análogos & derivados , Antagonistas de Narcóticos/farmacología , Proopiomelanocortina/genética , Precursores de Proteínas/genética , Receptores Opioides delta/antagonistas & inhibidores , Transcripción Genética/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Conducta de Elección/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Ratones , Actividad Motora/efectos de los fármacos , Naltrexona/farmacología , ARN Mensajero/genética , Medio SocialRESUMEN
Chronic morphine treatment alters gene expression in brain structures. There are increasing evidences showing a correlation, in gene expression modulation, between blood cells and brain in psychological troubles. To test whether gene expression regulation in blood cells could be found in drug addiction, we investigated gene expression profiles in peripheral blood mononuclear (PBMC) cells of saline and morphine-treated rats. In rats chronically treated with morphine, the behavioral signs of spontaneous withdrawal were observed and a withdrawal score was determined. This score enabled to select the time points at which the animals displayed the mildest and strongest withdrawal signs (12 h and 36 h after the last injection). Oligonucleotide arrays were used to assess differential gene expression in the PBMCs and quantitative real-time RT-PCR to validate the modulation of several candidate genes 12 h and 36 h after the last injection. Among the 812 differentially expressed candidates, several genes (Adcy5, Htr2a) and pathways (Map kinases, G-proteins, integrins) have already been described as modulated in the brain of morphine-treated rats. Sixteen out of the twenty-four tested candidates were validated at 12 h, some of them showed a sustained modulation at 36 h while for most of them the modulation evolved as the withdrawal score increased. This study suggests similarities between the gene expression profile in PBMCs and brain of morphine-treated rats. Thus, the searching of correlations between the severity of the withdrawal and the PBMCs gene expression pattern by transcriptional analysis of blood cells could be promising for the study of the mechanisms of addiction.
Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Leucocitos Mononucleares/efectos de los fármacos , Morfina/administración & dosificación , Narcóticos/administración & dosificación , Síndrome de Abstinencia a Sustancias/metabolismo , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Perfilación de la Expresión Génica , Leucocitos Mononucleares/metabolismo , Masculino , Morfina/farmacología , Narcóticos/farmacología , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias/genética , Factores de TiempoRESUMEN
Despite their widespread use in opioid maintenance treatment and pain management, little is known about the intracellular effectors of methadone and buprenorphine and the transcriptional responses they induce. We therefore studied the acute effects of these two opioids in rats, comparing our observations with those for the reference molecule, morphine. We determined the analgesic ED50 of the three molecules in the tail flick test, to ensure that transcriptional effects were compared between doses of equivalent analgesic effect. We analysed changes in gene expression over time in three cerebral structures involved in several opioid behaviours-the dorsal striatum, thalamus and nucleus accumbens-by real-time quantitative PCR. We analysed the expression of genes encoding proteins of the endogenous opioid system in parallel with that of Fos, a marker of neuronal activation. The acute transcriptional effects of methadone resembled those of morphine more closely than did those of buprenorphine, in terms of kinetics and intensities. Our results provide the first evidence that these two drugs widely used in pain management and opioid maintenance treatment can disturb the regulation of endogenous opioid system genes and induce molecular outcomes different from those observed with morphine.