Increase of tyrosine hydroxylase levels and activity during morphine withdrawal in the heart.

Our previous studies have shown an enhanced activity of the noradrenergic pathways innervating the heart in rats withdrawn from morphine. However, the possible adaptive changes that can occur in these pathways during morphine dependence are not known. We studied the alterations in tyrosine hydroxylase (the rate-limiting enzyme in catecholamines biosynthesis) and tyrosine hydroxylase activity in the heart (right and left ventricle) during morphine withdrawal. In the same paradigm, we measured Fos expression as a marker of neuronal activation and the normetanephrine/noradrenaline ratio (an index of noradrenaline turnover). We evaluated the levels of tyrosine hydroxylase and Fos by quantitative Western blot analysis, and noradrenaline turnover using high-performance liquid chromatography (HPLC). 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 (5 mg/kg s.c.). The results show a significant increase in tyrosine hydroxylase levels and activity in the right and left ventricle 30 or 90 min after naloxone precipitated withdrawal in parallel with an increase in noradrenaline turnover. Morphine withdrawal also induced an increase in the Fos expression, which indicates an activation of cardiac cellular activity. Our results suggest that an increase in tyrosine hydroxylase protein levels and tyrosine hydroxylase enzyme activity might contribute to the enhanced noradrenergic activity in the heart in response to morphine withdrawal.