Ontogeny of mu-, delta- and kappa-opioid receptors mediating inhibition of neurotransmitter release and adenylate cyclase activity in rat brain.

The ontogeny was examined of functional opioid receptors mediating presynaptic inhibition of neurotransmitter release and inhibition of dopamine (DA)-sensitive adenylate cyclase in the rat brain, using highly selective agonists for mu-, delta- and kappa-receptors. On gestational day 17 (E17) strong inhibitory effects of the selective mu-agonist DAGO on the electrically evoked release of [3H]noradrenaline from cortical slices and of the selective kappa-agonist U-50,488 on the electrically evoked release of [3H]DA from striatal slices were found. Electrically evoked release of [3H]acetylcholine from striatal slices was not detectable before postnatal day 7 (P7), but on that day it was already strongly inhibited by the selective delta-agonist DPDPE. Although mu- and delta-opioid receptors coupled to DA-sensitive adenylate cyclase in the striatum are likely to be physically associated in an opioid receptor complex in the adult, they were found to develop asynchronously. Whereas selective activation of mu-receptors with DAGO resulted in an inhibition of D1 dopamine receptor-stimulated adenylate cyclase activity on E17, activation of delta-receptors with DPDPE was not effective until P14. This study confirms the early appearance of mu- and kappa-opioid receptors and the relatively late development of delta-opioid receptors in the rat brain. Most importantly, it shows that in an early stage of development opioids are already able to mediate modulation of noradrenergic (via activation of mu-receptors) and dopaminergic (via activation of mu- and kappa-receptors) neurotransmission processes. Therefore, these opioid receptor types could play a role in brain development and/or developmental disturbances.