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Regulation of Serine (Ser)-31 and Ser40 Tyrosine Hydroxylase Phosphorylation during Morphine Withdrawal in the Hypothalamic Paraventricular Nucleus and Nucleus Tractus Solitarius-A₂ Cell Group: Role of ERK_1/2

Department of Pharmacology, University School of Medicine, 30100 Murcia, Spain

Address all correspondence and requests for reprints to: Professor M. Victoria Milanés, Department of Pharmacology, University School of Medicine, Campus de Espinardo, 30100 Murcia, Spain. E-mail: milanes{at}um.es.

Our previous studies have shown that naloxone-induced morphine withdrawal increases the hypothalamic-pituitary-adrenocortical (HPA) axis activity, which is dependent on a hyperactivity of noradrenergic pathways [nucleus tractus solitarius (NTS) A₂] innervating the hypothalamic paraventricular nucleus (PVN). Short-term regulation of catecholamine biosynthesis occurs through phosphorylation of tyrosine hydroxylase (TH), which enhances enzymatic activity. In the present study, the effect of morphine withdrawal on site-specific TH phosphorylation in the PVN and NTS-A₂ was determined by quantitative blot immunolabeling and immunohistochemistry using phosphorylation state-specific antibodies. We show that naloxone-induced morphine withdrawal phosphorylates TH at Serine (Ser)-31 but not Ser40 in PVN and NTS-A₂, which is associated with both an increase in total TH immunoreactivity in NTS-A₂ and an enhanced TH activity in the PVN. In addition, we demonstrated that TH neurons phosphorylated at Ser31 coexpress c-Fos in NTS-A₂. We then tested whether pharmacological inhibition of ERK activation by ERK kinase contributes to morphine withdrawal-induced phosphorylation of TH at Ser31. We show that the ability of morphine withdrawal to stimulate phosphorylation at this seryl residue is reduced by SL327, an inhibitor of ERK_1/2 activation. These results suggest that morphine withdrawal increases noradrenaline turnover in the PVN, at least in part, via ERK_1/2-dependent phosphorylation of TH at Ser31.

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