mu-Opioid receptor-regulated adenylate cyclase activity in primary cultures of rat striatal neurons upon chronic morphine exposure.

Rat striatal neurons cultured in serum-free, hormone-supplemented medium, were exposed to 10 microM morphine for several hours or days before intracellular cyclic AMP production was measured. Dopamine D1 receptor- and beta-adrenoceptor-stimulated cyclic AMP production were profoundly increased upon morphine exposure (up to 150% of control). In contrast, cyclic AMP production induced by direct activation of the catalytic unit of adenylate cyclase with forskolin remained unaffected. Interestingly, the relative inhibitory effect of the mu-opioid receptor agonist [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO) on dopamine D1 receptor-stimulated cyclic AMP production was unchanged after exposure to morphine. On the other hand, unlike mu-opioid receptors chronically exposed to morphine, beta-adrenoceptors mediating activation of adenylate cyclase were rapidly desensitized upon prolonged exposure of the neurons to isoprenaline. It is suggested that tolerance to morphine may be caused by the fact that morphine is acting against up-regulated signal transduction mechanisms rather than by mu receptor desensitization. Moreover, this enhanced effector system function may be involved in opioid dependence. The adaptive changes following morphine treatment appear to be independent of possible alterations at the level of dopaminergic or noradrenergic nerve terminals which are not present in primary cultures of rat striatum.