The PKs PKA and ERK 1/2 are involved in phosphorylation of TH at Serine 40 and 31 during morphine withdrawal in rat hearts
Open Access
- 1 September 2008
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 155 (1), 73-83
- https://doi.org/10.1038/bjp.2008.224
Abstract
Background and purpose: Our previous studies have shown that morphine withdrawal induced hyperactivity of cardiac noradrenergic pathways. The purpose of the present study was to evaluate the effects of morphine withdrawal on site‐specific phosphorylation of TH in the heart. Experimental approach: Dependence on morphine was induced by a 7‐day s.c. implantation of morphine pellets in rats. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (2 mg kg−1). TH phosphorylation was determined by quantitative blot immunolabelling using phosphorylation state‐specific antibodies. Key results: Naloxone‐induced morphine withdrawal induced phosphorylation of TH at serine (Ser)40 and Ser31 in the right ventricle, associated with both an increase in total TH levels and an enhancement of TH activity. When HA‐1004 (PK A inhibitor) was infused, concomitantly with morphine, it diminished the increase in noradrenaline turnover, total TH levels and TH phosphorylation at Ser40 in morphine‐withdrawn rats. In contrast, the infusion of calphostin C (PKC inhibitor), did not modify the morphine withdrawal‐induced increase in noradrenaline turnover and total TH levels. In addition, we show that the ability of morphine withdrawal to stimulate phosphorylation at Ser31 was reduced by SL327, an inhibitor of ERK 1/2 activation. Conclusions and implications: The present findings demonstrate that the enhancement of total TH levels and the increased phosphorylation state of TH during morphine withdrawal were dependent on PKA and ERK activities and suggest that these transduction pathways might contribute to the activation of the cardiac catecholaminergic neurons in response to morphine withdrawal. British Journal of Pharmacology (2008) 155, 73–83; doi:10.1038/bjp.2008.224; published online 9 June 2008This publication has 55 references indexed in Scilit:
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