Potentiation of morphine analgesia after pretreatment with probenecid or sulfinpyrazone

Pretreatment with uricosuric agents probenecid or sulfinpyrazone potentiate the analgesic effects of morphine sulfate as ascertained using the phenylquinone (PQ)-induced writhing test. Doses of either uricosuric agent at 50 mg/kg had no effect on the number of PQ-induced writhes in test animals while potentiating the analgesic effects of morphine. High doses of probenecid or sulfinpyrazone alone did produce decreases in PQ-induced writing. Probenecid (50 mg/kg) did not alter hot water tail flick latency nor did it influence morphine analgesia. Attempts to uncover the underlying mechanisms in the uricosuric agent plus morphine attenuation of PQ-induced writhing were directed towards a possible displacement of morphine from plasma binding sites. However, administration of N-methyl-H3-morphine and estimation of plasma and brain morphine concentrations indicate no differences in the uricosuric drug pretreated groups compared to controls. The conflicting results in the PQ writhing test vs. hot water tail flick might indicate a false positive response in the former test. On the other hand this might be indicative of differing analgesic mechanisms for different types of pain. If the latter is true, this drug interaction may prove clinically useful.