title: Phosphodiesterase 4 inhibitors, rolipram and diazepam block the adaptive changes observed during morphine withdrawal in the heart.
abstract: In this study, we investigated whether morphine dependence was inhibited by phosphodiesterase (PDE) 4 inhibitors rolipram and diazepam, since a role for the cyclic AMP systems in the development of morphine dependence was reported. Dependence of 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. In order to determine the effect of rolipram or diazepam the animals were injected with these drugs for seven days and 30 min before the administration of naloxone. When opioid withdrawal was precipitated, enhancement of noradrenaline (NA) turnover in the heart was observed 30 min after naloxone administration. Moreover, morphine withdrawal induces Fos expression, increase in cyclic AMP and cyclic GMP levels. Co-administration of rolipram or diazepam with morphine during the pre-treatment period significantly reduces the signs of withdrawal symptoms, the enhancement of NA turnover, the increase in cyclic AMP and the Fos expression. However, these inhibitors did not modify the levels of cyclic GMP. These findings demonstrated that co-administration of rolipram or diazepam with morphine abolish the development of morphine dependence and suggest that these compounds prevent the up-regulation of the cyclic AMP pathway and the associated increase in cyclic AMP level after naloxone administration.
authors.affiliation: Department of Pharmacology, University School of Medicine, 30100 Murcia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: González-Cuello
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Sánchez
authors.forename: Jesús
authors.initials: J
authors.lastname: Hernández
authors.forename: M
authors.initials: M
authors.lastname: Teresa Castells
authors.forename: M
authors.initials: M
authors.lastname: Victoria Milanés
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Laorden
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003975:Diazepam / Q000627:therapeutic use*; D008297:Male; D009021:Morphine Dependence / Q000188:drug therapy / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D009647:Normetanephrine / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000627:therapeutic use*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D009647:Normetanephrine; D000242:Cyclic AMP; D006152:Cyclic GMP; D020889:Rolipram; D003975:Diazepam; D009638:Norepinephrine