EFFECT OF CHRONIC PRENATAL MORPHINE TREATMENT ON MU-OPIOID RECEPTOR-REGULATED ADENYLATE-CYCLASE ACTIVITY AND NEUROTRANSMITTER RELEASE IN RAT-BRAIN SLICES

Timed-pregnant rats received 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 [H-3]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 mu 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 mechanism, rather than by desensitization of central mu-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 mu-opioid receptors are present. At the same time, these adaptive changes may underlie morphine withdrawl phenomena.