The role of SOCS3 in the hypothalamic paraventricular nucleus in rat model of inflammatory pain

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 ERK1/2 activation. These results suggest that morphine withdrawal increases noradrenaline turnover in the PVN, at least in part, via ERK1/2-dependent phosphorylation of TH at Ser31.

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Toll-Like Receptor 4 Promotes Autonomic Dysfunction, Inflammation and Microglia Activation in the Hypothalamic Paraventricular Nucleus: Role of Endoplasmic Reticulum Stress

PLoS ONE ◽

10.1371/journal.pone.0122850 ◽

2015 ◽

Vol 10 (3) ◽

pp. e0122850 ◽

Cited By ~ 28

Author(s):

Gustavo S. Masson ◽

Anand R. Nair ◽

Rahul B. Dange ◽

Pedro Paulo Silva-Soares ◽

Lisete C. Michelini ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Autonomic Dysfunction ◽

Paraventricular Nucleus ◽

Microglia Activation ◽

Hypothalamic Paraventricular Nucleus ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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Ascending Brainstem Pathways Are Not Involved in Lipopolysaccharide-Induced Suppression of Thyrotropin-Releasing Hormone Gene Expression in the Hypothalamic Paraventricular Nucleus

Endocrinology ◽

10.1210/en.2004-1429 ◽

2005 ◽

Vol 146 (3) ◽

pp. 1357-1363 ◽

Cited By ~ 14

Author(s):

Csaba Fekete ◽

Praful S. Singru ◽

Sumit Sarkar ◽

William M. Rand ◽

Ronald M. Lechan

Keyword(s):

Gene Expression ◽

Paraventricular Nucleus ◽

Hypothalamic Paraventricular Nucleus ◽

Nonthyroidal Illness ◽

Intact Side ◽

In Situ Hybridization Histochemistry ◽

Immunocytochemical Detection ◽

Lps Treatment

The nonthyroidal illness syndrome associated with fasting, infection, and chronic illness is characterized by low thyroid hormone levels and low or inappropriately normal TSH levels in circulating blood and reduced synthesis of TRH in hypophysiotropic neurons residing in the hypothalamic paraventricular nucleus (PVN). To test the hypothesis that ascending brainstem pathways are involved in mediation of bacterial lipopolysaccharide (LPS)-induced suppression of TRH mRNA in the PVN, we unilaterally transected brainstem pathways to the PVN and determined the effects of LPS on TRH gene expression and, as a control, on CRH gene expression in hypophysiotropic neurons using semiquantitative in situ hybridization histochemistry. The efficacy of the transection was determined by immunocytochemical detection of ascending adrenergic pathways in the PVN. In vehicle-treated animals, CRH mRNA in the PVN showed a significant reduction on the transected side compared with the intact side, whereas a significant increase in TRH mRNA was observed on the transected side compared with the intact side. After LPS administration (250 μg/100 g body weight), a dramatic increase in CRH mRNA was observed on the intact side, and a significantly lesser increase was found on the transected side. In contrast, LPS treatment resulted in reduction in TRH mRNA on the transected side compared with the intact side and a significant reduction in TRH mRNA on the transected side compared with vehicle-treated animals. These studies confirm an important role of ascending brainstem projections in LPS-induced activation of CRH gene expression, but indicate that they do not mediate the effect of LPS to inhibit hypophysiotropic TRH gene expression.

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