Unequal opiate cross-tolerance to morphine in the locomotor-activation model in the mouse

Dose-response relationships for the opiate-induced stimulation of locomotion in mice were determined for etorphine, fentanyl, levorphanol, lofentanil and morphine, both before and after the subcutaneous implantation of a morphine pellet for 3 days. In non-tolerant mice, the relative potencies of these drugs compared to morphine paralleled those reported for other in vivo models of the actions of opiates. The most potent was lofentanil (ED50 = 3.8 micrograms/kg), which was approx. 6000 times more potent than morphine (ED50 = 24.2 mg/kg). A tolerance-induced 22-fold increase in the ED50 for morphine resulted in a similar cross-tolerance to levorphanol, but there was less cross-tolerance to fentanyl (4-fold), lofentanil (5-fold) and etorphine (7-fold). The smaller cross-tolerances of etorphine and lofentanil to morphine were not accompanied by changes in the levels of [3H]etorphine or [3H]lofentanil in brain, induced by morphine pellets, although the bound fraction of [3H]lofentanil in brain was slightly decreased (11-15%). The implications of the phenomenon of unequal cross-tolerance for the mechanism of tolerance at the opiate mu receptor are discussed.