The effect of fluoxetine on morphine analgesia, respiratory depression, and lethality

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Abstract
The analgesic effect of morphine in a mouse writhing assay was enhanced by the simultaneous administration of fluoxetine, an inhibitor of serotonin uptake. Fluoxetine reduced the ED50 for morphine and extended the duration of morphine analgesia. The potentiation of morphine analgesia was particularly striking in mice made tolerant by repeated morphine injections. Potentiation of morphine by fluoxetine was also observed in a rat tail jerk test for analgesia. The acute lethality of morphine in rats and mice was altered by fluoxetine, yet the therapeutic index of morphine (ratio of LD50 to ED50) was unchanged. The decrease in blood pO2 produced by morphine at doses of 1 and 4 mg/kg in rats was attenuated by fluoxetine, which by itself increased blood pO2. These findings strengthen earlier evidence for an involvement of serotoninergic neurons in the analgesic effects of morphine and support the idea that enhanced serotoninergic function might be a useful means of enhancing morphine's actions in clinical therapy.