Paradoxical effect of chronic fentanyl treatment on naltrexone-induced supersensitivity and upregulation

The present study sought to evaluate the influence of chronic opioid antagonist treatment upon the discriminative stimulus and analgesic effects of the opioid receptor agonist fentanyl. Male Wistar rats were trained to discriminate fentanyl (0.04 mg/kg) from saline in a two-lever food reinforced paradigm. After acquisition of the discrimination, they were implanted with osmotic minipumps which delivered either naltrexone (0.07 mg/h) or distilled water, and the sensitivity of discrimination was assessed at various times after pump removal. The influence of chronic naltrexone treatment upon the antinociceptive effects of fentanyl was assessed in drug-naive (control) rats and in rats which had received fentanyl in the same dosage schedule as those in drug discrimination experiments. Chronic infusion of naltrexone for 7 days did not modify the dose-response curve for the fentanyl vs. saline discrimination. Algesiometric tests revealed a significant increase in the antinociceptive effect of fentanyl in control rats after naltrexone treatment. In contrast, such supersensitivity was not observed in rats which had previously received fentanyl injections. Autoradiographic data revealed a naltrexone-induced upregulation of mu opioid receptors in control animals. Paradoxically, this effect was significantly increased in fentanyl-pretreated rats. These data suggest that prior drug experience can affect the development of antagonist-induced supersensitivity to the behavioral actions of opioid agonists. Furthermore, it would appear that after chronic agonist treatment the phenomena of opioid receptor upregulation and functional supersensitivity are dissociated.