Withdrawal Tolerance and Unidirectional Non-cross-tolerance in Narcotic Pellet-implanted Mice

Analgesic ED50 values were determined for s.c. morphine, etorphine, heroin and methadone in mice implanted for 3 days with etorphine pellets. Tolerance to morphine (9-fold) was greater than to the other agents (2- to 4-fold). These results agreed with the previously reported unidirectional non-cross-tolerance effect seen after morphine pellet implantation where tolerance to the hydrophilic agent (morphine) was greater than for the more lipophilic agents (etorphine and heroin). As greater tolerance was found to s.c. morphine than for i.c.v. morphine, this manifestation of tolerance was described as a dispositional tolerance. Experimentally, we were able to observe two additional manifestations of tolerance. After pellet removal, the ED50 values for s.c. morphine, heroin and methadone initially increased before returning to control values. Similarly, both morphine and etorphine ED50 values, after i.c.v. administration, initially increased after pellet removal. Because this second manifestation of tolerance occurred during the rapid disappearance of the tolerance-induction drug, it was called withdrawal tolerance. The third manifestation of tolerance, seen after 3 days of pellet implantation, was characterized by the animal's return to a normal nociceptive sensitivity (control tail-flick latency) in the continued presence of the narcotic pellet. Because this adjustment involved an adaptation by the mice to high brain concentrations of narcotic, this third manifestation of tolerance was designated as a physiologic or homeostatic tolerance. The lability of this new homeostatic state (physiologic tolerance) may be associated with an altered sensitivity to naloxone as evidenced by naloxone-induced jumping (precipitated withdrawal).