Involvement of Noradrenergic Transmission in the PVN on CREB Activation, TORC1 Levels, and Pituitary-Adrenal Axis Activity during Morphine Withdrawal

Experimental and clinical findings have shown that administration of adrenoceptor antagonists alleviated different aspects of drug withdrawal and dependence. The present study tested the hypothesis that changes in CREB activation and phosphorylated TORC1 levels in the hypothalamic paraventricular nucleus (PVN) after naloxone-precipitated morphine withdrawal as well as the HPA axis activity arises from α1- and/or β-adrenoceptor activation. The effects of morphine dependence and withdrawal on CREB phosphorylation (pCREB), phosphorylated TORC1 (pTORC1), and HPA axis response were measured by Western-blot, immunohistochemistry and radioimmunoassay in rats pretreated with prazosin (α1-adrenoceptor antagonist) or propranolol (β-adrenoceptor antagonist). In addition, the effects of morphine withdrawal on MHPG (the main NA metabolite at the central nervous system) and NA content and turnover were evaluated by HPLC. We found an increase in MHPG and NA turnover in morphine-withdrawn rats, which were accompanied by increased pCREB immunoreactivity and plasma corticosterone concentrations. Levels of the inactive form of TORC1 (pTORC1) were decreased during withdrawal. Prazosin but not propranolol blocked the rise in pCREB level and the decrease in pTORC1 immunoreactivity. In addition, the HPA axis response to morphine withdrawal was attenuated in prazosin-pretreated rats. Present results suggest that, during acute morphine withdrawal, NA may control the HPA axis activity through CREB activation at the PVN level. We concluded that the combined increase in CREB phosphorylation and decrease in pTORC1 levels might represent, in part, two of the mechanisms of CREB activation at the PVN during morphine withdrawal

Exposure to acute physical and psychological stress alters the response of rat macrophages to corticosterone, neuropeptide Y and beta-endorphin

The objective of the present study was to investigate the effect of acute exposure to electric tail shock stress (ES) and a stress witnessing procedure ( SW), as models for physical and psychological stress paradigms, respectively on adherence, phagocytosis and hydrogen peroxide (H2O2) release from rat peritoneal macrophages. In addition, we studied the in vitro effects of corticosterone (CORT), neuropeptide Y (NPY) and beta-endorphin (BE) on adherence, phagocytosis and H2O2 release from macrophages isolated from control rats and from rats that had been exposed to ES or SW procedures 24 h earlier. ES and SW comparably diminished phagocytosis and H2O2 release, but did not influence macrophage adherence. In vitro treatment with CORT and NPY notably suppressed phagocytosis and potentiated H2O2 release from macrophages. BE suppressed both phagocytosis and H2O2 release from macrophages. Previous exposure to ES and SW altered the responsiveness of the isolated macrophages to their in vitro treatment with mediators of stress, making the cells less sensitive to the influence of CORT and NPY and to a lesser extent to BE. It could be concluded that changes in the local macrophage milieu induced by ES and SW 24 h earlier modify macrophage responses to subsequent in vitro exposure to the stress mimics, CORT, NPY and BE