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

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, G_s 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.