Differential Cross-tolerance Between Intrathecal Morphine and Sufentanil in the Rat

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Abstract
By means of a subcutaneously implanted osmotic pump, groups of rats received a constant-rate (1 μ1/h), 7-day Intrathecal Infusion of saline or one of two mu opioid agonists: sufentanil (0.6 nmol/h) or morphine (20 nmol/h). These concentrations of morphine and sufentanil yielded a comparable near maximal hot-plate response latency on day 1 of the infusion. On day 7, the magnitude of tolerance was assessed to each group by establishing intrathecal dose-response curves and ED50 values for sufentanil and morphine given as a bolus injection. Each infused animal was used for a single bolus injection. In all cases, infusion with the opioid resulted in a rightward shift (increase in ED50) for both morphine and sufentanil as compared to saline-infused animals. The magnitude of the shift, however, was different for the two drugs. Thus in morphine-infused rats, the morphine ED50 increased as compared to saline-infused animals by a factor of 44, whereas the sufentanil ED50 shifted by a factor of 10. In sufentanil-infused animals, the respective shifts in the morphine and sufentanil ED50 values were increased by a factor of 9 and 3, respectively. Thus, a significantly greater shift as compared to saline-infused animals was observed in morphine-infused than in sufentanil-infused animals. Conversely, regardless of the opioid to which the animal was exposed, morphine-tested animals showed a greater rightward shift than did sufentanil-tested animals. These data showing a nonsymmetric tolerance between agents acting at the same mu receptor are consistent with the argument that these two agents differ in efficacy, i.e., the fraction of the receptor population each must occupy to produce a given effect. Agents with high efficacy and a significant receptor reserve (e.g., sufentanil) will down-regulate fewer receptors than will agents with low efficacy and a smaller receptor reserve (e.g., morphine). As a result, agents with higher efficacy at a receptor show theoretically less tolerance over time as compared with less efficacious agents acting at the same receptor.