Chronic opioid antagonist treatment: assessment of receptor upregulation

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Changes in specific brain opioid binding and opioid pharmacodynamics were determined in mice treated with the opioid antagonist naltrexone (subcutaneously implanted pellets) for 8 days. Chronic opioid antagonist treatment increased the number of binding sites (upregulation) for [ 3H]naloxone (+55%) and [ 3H][D-Ala 2,D-Leu 5]enkephalin (+41%) but did not alter the affinity of the ligands, as determined in saturation studies. Displacement studies of [ 3H]naloxone by morphine also indicated that there was no change in morphine's affinity. In vivo estimation of naloxone affinity (pA 2), agreed with the in vitro results indicating that chronic naltrexone treatment did not alter naloxone affinity. Chronic naltrexone treatment (0.5, 1.0, 15.0 mg pellets) increased the analgesic potency of morphine (supersensitivity) in a dose-dependent manner, up to a maximal increase in relative potency of 1.8. However, in mice tested with the naltrexone pellets still implanted, the 15 mg naltrexone pellet was able to shift the dose-response function for morphine analgesia more than 300-fold. The lowest dose naltrexone pellet (0.5 mg), produced significant antagonism of morphine analgesia, but did not produce significant supersensitivity. Thus, supersensitivity and upregulation are not proportional to the degree of antagonism of opioid effects; and supersensitivity in the mouse is related to increased binding sites and not to changes in receptor affinity as determined by in vivo and in vitro methods.