Effect of chronic prenatal morphine treatment on μ-opioid receptor-regulated adenylate cyclase activity and neurotransmitter release in rat brain slices

Taco J. De Vries, Bernard J. Van Vliet, François Hogenboom, George Wardeh, Jan Willem Van der Laan, Arie H. Mulder, Anton N.M. Schoffelmeer

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Timed-pregnant ratsreceived a semisynthetic diet with or without morphine (0.5-1 mg/g) for 2 weeks. After 21 days of gestation the morphine-dependent dams were decapitated and the foetal brains were dissected. Chronic morphine administration caused a profound increase of adenylate cyclase activity stimulated by postsynaptic D1 dopamine receptors in striatal slices. The relative inhibitory effect of [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO) on D1-stimulated cyclic AMP (cAMP) production was unaffected. In contrast, cAMP production induced via direct activation of the catalytic unit of adenylate cyclase with forskolin was not changed upon long-term morphine treatment, although DAGO strongly inhibited the effect of forskolin. The electrically evoked release of [3H]noradrenaline (NA) from superfused neocortical slices was strongly enhanced upon morphine treatment, whereas release induced by the calcium ionophore A23187, bypassing voltage-sensitive calcium channels, was unchanged. Again, the inhibitory effect of the μ receptor agonist DAGO was unaffected in neocortical slices from morphine-treated rats. It is suggested that tolerance to morphine may be caused by the fact that the opiate is acting against up-regulated signal transduction mechanisms, rather than by desensitization of central μ-opioid receptors. The pre- and postsynaptic changes may include an enhanced expression and/or biochemical modification of D1 receptors, Gs proteins and calcium channels in central neurons on which μ-opioid receptors are present. At the same time, these adaptive changes may underlie morphine withdrawal phenomena.

Original languageEnglish
Pages (from-to)97-104
Number of pages8
JournalEuropean Journal of Pharmacology: Molecular Pharmacology
Issue number2
Publication statusPublished - 14 Oct 1991


  • Adenylate cyclase activity
  • Brain (neocortex) slices
  • Morphine treatment (chronic)
  • [H]Noradrenaline release
  • μ Opioid receptors

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