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Implication of the signal transduction pathways in the enhancement of noradrenaline turnover induced by morphine withdrawal in the heart

Elsevier B.V.
Publication Date
DOI: 10.1016/s0014-2999(03)01819-3
  • Morphine Withdrawal
  • Protein Kinase A
  • Protein Kinase C
  • Ca2+Channel
  • Noradrenaline Turnover
  • Heart
  • Biology


Abstract Our previous studies have shown an enhanced activity of the noradrenergic system in the heart in rats withdrawn from morphine. In the current study, we examined the role of protein kinase A, protein kinase C and Ca 2+ entry through L-type Ca 2+ channels in naloxone-precipitated increase turnover of noradrenaline in the right and left ventricle. Chronic pretreatment for 7 days with the selective protein kinase A inhibitor, HA-1004 ( N-(2′ guanidinoethyl)-5-isoquinolinesulfonamide) concomitantly with morphine significantly antagonized the increase in normetanephrine/noradrenaline ratio (an index of noradrenaline turnover) observed in morphine withdrawn rats. However, the infusion of calphostin C (2-(12-(2-(benzoyloxy)propyl)-3,10-dihydro-4,9-dihydroxy-2,6,7,11-tetramethoxy-3,10-dioxo-1-perylenyl)-1 methylethy carbonic acid 4-hydroxyphenyl ester, a selective protein kinase C inhibitor) did not modify the morphine withdrawal-induced increase in noradrenaline turnover. In addition, when the selective L-type Ca 2+ channel antagonist, nimodipine, was infused it diminished the increased in noradrenaline turnover observed after naloxone administration to morphine dependent rats. Taken together, these data might indicate that protein kinase A activity is necessary for the enhancement of noradrenaline turnover during morphine withdrawal and that an up-regulated Ca 2+ system might contribute to the increase of noradrenaline turnover. The present finding suggests that protein kinase A and Ca 2+ influx through L-type Ca 2+ channels might contribute to the activation of noradrenergic system in the heart observed during morphine withdrawal.

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