Chronic exposure to morphine and naltrexone induces changes in catecholaminergic neurotransmission in rat brain without altering mu-opioid receptor sensitivity.

In order to investigate the role of mu-opioid receptor regulation in catecholaminergic neurotransmission during morphine tolerance/dependence and supersensitivity, we measured changes in number and functional properties of two distinct types of mu receptors in the brain of rats chronically treated with morphine and naltrexone. In membranes of striatum and cortex of morphine treated rats the binding of mu ligand [3H]DAMGO was unaltered, whereas an increase in mu binding sites was found in these brain regions of naltrexone treated rats. The ability of the mu agonist DAMGO to inhibit the dopamine D-1 receptor stimulated cAMP production in striatal slices and the electrically evoked release of [3H]noradrenaline from cortical slices was unaffected in both experimental groups. The major changes found were an increased D-1 receptor stimulated cAMP production and an enhanced release of noradrenaline in morphine treated rats and a decreased D-1 receptor stimulated cAMP production in naltrexone treated rats. These data support the hypothesis that tolerance and supersensitivity to morphine and other mu-opioids may be caused by up- and down-regulated neuronal second messenger systems linked to mu-opioid receptors, rather than by changes in the sensitivity of the mu-opioid receptor itself.