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  • Title: Activation of c-fos expression in the heart after morphine but not U-50,488H withdrawal.
    Author: González-Cuello A, Milanés MV, Castells MT, Laorden ML.
    Journal: Br J Pharmacol; 2003 Feb; 138(4):626-33. PubMed ID: 12598416.
    Abstract:
    1. In the present work we have studied in the heart the expression of Fos, the protein product of the c-fos proto-oncogene and the adaptive changes in noradrenergic neurons after naloxone or nor-binaltorphimine (nor-BNI) administration to morphine or U-50,488H pretreated rats. 2. Male rats were implanted with placebo (naïve) or morphine (tolerant/dependent) pellets for 7 days. On day 8 rats received saline s.c., naloxone (5 mg kg(-1) s.c.) or nor-BNI (5 mg kg(-1) i.p.). Other groups of rats were rendered tolerant/dependent on U-50,488H by injecting the drug twice daily (15 mg kg(-1) i.p.) for 4 days. Control animals received saline. On day 5 the animals were injected with vehicle i.p. or nor-BNI (5 mg kg(-1) i.p.). 3. Using immunohistochemical staining of Fos, present results indicate that morphine withdrawal induced marked Fos immunoreactivity (Fos-IR) within the cardiomyocyte nuclei. Moreover, Western blots analysis revealed a peak expression of c-fos in right and left ventricle after naloxone induced withdrawal in parallel with an increase in noradrenaline (NA) turnover. 4. However, after nor-BNI administration to rats chronically treated with U-50,488H, we found a decrease in the NA turnover. In addition, the administration of nor-BNI to rats chronically treated with U-50,488H or morphine did not induce modifications in the Fos-IR, in the heart. 5. These results demonstrated that morphine withdrawal induces the expression of Fos protein, as well as an enhancement of noradrenergic activity in the heart. In contrast to morphine U-50,488 withdrawal produces no changes in Fos-IR in parallel with a decrease in NA turnover, indicating that the kappa-opioid receptors are not involved in the molecular adaptive mechanisms responsible for the development of opioid dependence in the heart.
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