Abstract
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.
Highlights
Opiate addiction results in significant changes in mood and affective behaviour, while morphine withdrawal syndrome consists of severe somatic alterations [1], whose neurobiological background have not been fully resolved
This decrease of food intake was accompanied by a significant reduction in body weight gain (D bw24 h after placebo: +6.060.5 g, morphine: 27.362.5 g)
Subcutaneous implantation of slow release morphine pellets has been repeatedly shown to maintain constant level of morphine in rats to induce tolerance and physical dependence [8,13]. This paradigm is similar to the situations when patients are on chronic morphine therapy or when addicts are given long acting opioid methadone during detoxification [14]
Summary
Opiate addiction results in significant changes in mood and affective behaviour, while morphine withdrawal syndrome consists of severe somatic alterations [1], whose neurobiological background have not been fully resolved. Understanding activation of the stress-related brain circuit and changes in energy metabolism and feeding behaviour during drug withdrawal is important because these alterations have been reported to be among the most severe physical symptoms of morphine administration and withdrawal. An additional group of placebo implanted rats was pair fed to morphine implanted animals such that the amount of food provided to these animals was equal to that consumed by the morphine-treated group. This pair fed group permitted the investigation of the morphine’s effect on energy balance via mechanisms independent of food intake
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