Cross tolerance between ketamine and morphine to some pharmacological and biochemical effects

Whether morphine and ketamine induced cross-tolerance to some of their common pharmacological and biochemical effects, namely analgesia and enhancement of metabolites of dopamine (DA) in the striatum and limbic area of the rat was analysed. Ketamine was given at the dose of 100 mg/kg, twice a day for 8 days. After this treatment, a challenge dose of morphine (15 mg/kg, i.p.) still induced analgesia comparable to that induced by morphine alone, showing no cross-tolerance to this effect. In contrast, the challenge dose of morphine given to ketamine-tolerant rats no longer enhanced metabolism of DA, indicating the appearance of cross-tolerance to this effect. A high degree of tolerance to morphine was obtained after the subcutaneous implantation of rats with pellets of morphine; a challenge dose of ketamine to morphine-tolerant rats induced marked analgesia, with no cross-tolerance to this pharmacological effect, while cross-tolerance was present to the biochemical effect. The existence of a high degree of reciprocal cross-tolerance in both areas and on both metabolites of DA is consistent with the hypothesis of action at a common receptor; the lack of cross-tolerance to the analgesic effect indicates that analgesia is achieved by a different mechanism for the two drugs.