RESUMEN
Chronic morphine treatment and naloxone precipitated morphine withdrawal activates stress-related brain circuit and results in significant changes in food intake, body weight gain and energy metabolism. The present study aimed to reveal hypothalamic mechanisms underlying these effects. Adult male rats were made dependent on morphine by subcutaneous implantation of constant release drug pellets. Pair feeding revealed significantly smaller weight loss of morphine treated rats compared to placebo implanted animals whose food consumption was limited to that eaten by morphine implanted pairs. These results suggest reduced energy expenditure of morphine-treated animals. Chronic morphine exposure or pair feeding did not significantly affect hypothalamic expression of selected stress- and metabolic related neuropeptides - corticotropin-releasing hormone (CRH), urocortin 2 (UCN2) and proopiomelanocortin (POMC) compared to placebo implanted and pair fed animals. Naloxone precipitated morphine withdrawal resulted in a dramatic weight loss starting as early as 15-30 min after naloxone injection and increased adrenocorticotrophic hormone, prolactin and corticosterone plasma levels in morphine dependent rats. Using real-time quantitative PCR to monitor the time course of relative expression of neuropeptide mRNAs in the hypothalamus we found elevated CRH and UCN2 mRNA and dramatically reduced POMC expression. Neuropeptide Y (NPY) and arginine vasopressin (AVP) mRNA levels were transiently increased during opiate withdrawal. These data highlight that morphine withdrawal differentially affects expression of stress- and metabolic-related neuropeptides in the rat hypothalamus, while relative mRNA levels of these neuropeptides remain unchanged either in rats chronically treated with morphine or in their pair-fed controls.
Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Dependencia de Morfina/genética , Morfina/farmacología , Neuropéptidos/metabolismo , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/genética , Hormona Adrenocorticotrópica/sangre , Animales , Arginina Vasopresina/genética , Arginina Vasopresina/metabolismo , Conducta Animal/efectos de los fármacos , Hormona Liberadora de Corticotropina/genética , Hormona Liberadora de Corticotropina/metabolismo , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Morfina/química , Dependencia de Morfina/metabolismo , Dependencia de Morfina/patología , Neuropéptidos/genética , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Ratas , Ratas Wistar , Urocortinas/genética , Urocortinas/metabolismoRESUMEN
To reveal neuroendocrine/neurochemical changes that are responsible for the robust metabolic alterations seen during chronic morphine treatment we followed hormonal-, transcriptional- and behavioral changes during chronic morphine administration in adult male Wistar rats. Animals were implanted with increasing amount of slow release morphine tablets for 8 days. Morphine treated animals gain significantly less weight than placebo implanted controls. This weight loss is due to the dramatic decrease in the food intake and caloric efficiency in the first days of drug administration and to the lasting disregulated feeding pattern. Changes in feeding behavior included increase of diurnal and decrease of nocturnal feeding frequency in morphine treated rats. Significantly less leptin and insulin plasma levels were detected in morphine implanted animals than in placebo implanted controls, while adiponectin and ACTH concentration remain unchanged. Morphine treated rats display an increase of FosB/Delta FosB immunoreactivity at brain sites that have been implicated regulation of food intake and energy expenditure, including hypothalamic arcuate, paraventricular and ventromedial nuclei and in the lateral hypothalamic area as well as in the caudal brainstem. However, morphine-induced long-term metabolic alterations were not accompanied with any significant changes in the expression of anorexigenic neuropeptides POMC and CART in the hypothalamus and in the brainstem. The disregulated feeding pattern was not reflected in changes of orexin transcription, however, a compensatory upregulation was revealed in hypothalamic NPY expression.