Daily mirfentanil induces (cross-) tolerance to the rate-decreasing effects of morphine and not mirfentanil

The fentanyl derivative mirfentanil has a novel set of behavioral effects in non-humans including low-efficacy opioid actions and non-opioid antinociceptive actions. This study evaluated the rate decreasing effects of mirfentanil, morphine, naltrexone and ketamine in pigeons both prior to and during a period of chronic treatment with mirfentanil (3.2-17.8 mg/kg/day). Daily treatment with mirfentanil did not modify the rate-decreasing effects of mirfentanil or ketamine; however, daily treatment decreased sensitivity to the rate decreasing effects of morphine and increased sensitivity to naltrexone. These results demonstrate a lack of tolerance to an apparently non-opioid action (rate-decreasing effect) of mirfentanil, which might predict a lack of tolerance to the non-opioid antinociceptive actions of this compound. These results further indicate that cross-tolerance (to morphine) and dependence (increased sensitivity to naltrexone) can occur in the absence of tolerance (to mirfentanil).