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 c atecholaminergic neurotransmission during morphine tolerance/dependenc e and supersensitivity, we measured changes in number and functional p roperties of two distinct types of mu receptors in the brain of rats c hronically treated with morphine and naltrexone. In membranes of stria tum and cortex of morphine treated rats the binding of mu ligand [H-3] DAMGO was unaltered, whereas an increase in mu binding sites was found in these brain regions of naltrexone treated rats. The ablility of th e mu agonist DAMGO to inhibit the dopamine D-1 receptor stimulated cAM P production in striatal slices and the electrically evoked release of [H-3]noradrenaline from cortical slices was unaffected in both experi mental 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 pr oduction 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 syst ems linked to mu-opioid receptors, rather than by changes in the sensi tivity of the mu-opioid receptor itself.