Morphine Tolerance Decreases the Analgesic Effects of Ketamine in Mice

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Abstract
Previous studies have shown that ketamine interacts with opiate receptors, and it has been suggested that ketamine-induced analgesia is mediated through opiate receptors. If so, ketamine should produce less analgesia in morphine tolerant animals, just as morphine does. To test this hypothesis, the analgesic effects of ketamine were tested in mice implanted with placebo pellets and in mice made tolerant to morphine through implantation of morphine pellets, using the abdominal constriction test. The test consisted of ip injection of 1% acetic acid, which caused stretching of hind limbs and constriction of abdominal muscles, also called writhing. The number of writhes was counted for each mouse 10-15 min following acetic acid injection. Morphine pellet implanted mice treated with saline writhed 12.2 .+-. 0.8 times (mean .+-. SEM), not significantly different from 9.8 .+-. 0.9 times seen in placebo pellet implanted mice. Treatment of the animals with ketamine at three doses of 20, 25, and 30 mg/kg, subcutaneously (sc), reduced the number of writhes in the placebo pellet implanted group to 5.8 .+-. 0.8, 4.2 .+-. 0.7, and 1.3 .+-. 0.3, respectively. In the morphine pellet-implanted group, with the same doses of ketamine, the numbers of writhes were 10 .+-. 0.9, 9.3 .+-. 1.1, and 5.2 .+-. 0.9, respectively. Morphine-tolerant animals writhed significantly more at each dose of ketamine, indicating that they were cross tolerant to the analgesic effect of ketamine.