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

In order to investigate the role of μ-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 μ 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 μ ligand [³H]DAMGO was unaltered, whereas an increase in μ binding sites was found in these brain regions of naltrexone treated rats. The ability of the μ 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 nonadrenaline 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 μ-opioids may be caused by up- and down-regulated neuronal second messenger systems linked to μ-opioid receptors, rather than by changes in the sensitivity of the μ-opioid receptor itself.