| Title | Crosstalk between PKA and MAP kinases signalling in the adaptive changes observed during morphine withdrawal in the heart. | | Author(s) | Almela P, Atucha NM, Milanes MV, Laorden ML | | Institution | University of Murcia. | | Source | J Pharmacol Exp Ther 2009 Jun 30. | | Abstract | Our previous studies have shown that morphine withdrawal induced an increase in the expression of protein kinase (PK) A and mitogen-activated extracellular kinase (MAPK) pathways in the heart during morphine withdrawal. The purpose of the present study was to evaluate the interaction between PKA and extracellular signal-regulated kinase (ERK) signalling pathways mediating the cardiac adaptive changes observed after naloxone administration to morphine-dependent rats. Dependence on morphine was induced by a 7-day s.c. implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (2 mg/kg). ERK1/2 and tyrosine hydroxylase (TH) phosphorylation were determined by quantitative blot immunolabelling using phosphorylation state-specific antibodies. Naloxone-induced morphine withdrawal activates ERK1/2 and phosphorylates TH at Ser31 in the right and left ventricle with an increase in the mean arterial blood pressure (MAP) and heart rate (HR). When HA-1004 (PKA inhibitor) was infused, concomitantly with morphine, it diminished the expression of ERK1/2. In contrast, the infusion of Calphostin C (PKC inhibitor) did not modify the morphine withdrawal-induced activation of ERK1/2. The ability of morphine withdrawal to activate ERK that phosphorylates TH at Ser 31 was reduced by HA-1004. The present findings demonstrate that the enhancement of ERK1/2 expression and the phosphorylation state of TH at Ser 31 during morphine withdrawal are dependent on PKA and suggest crosstalk between PKA and ERK1/2 transduction pathway mediating morphine withdrawal-induced activation (phosphorylation) of TH. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19567779 |
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