Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study.

1. The effect of morphine (10 mg kg-1, s.c.) on the analgesic response measured by the tail-flick method was determined in male Sprague-Dawley rats. The analgesic response to morphine was correlated with the levels of morphine and its metabolites collected by microdialysis from the cortical extracellular fluid (ECF). 2. The analgesic response to morphine lasted for 4 h. The concentration of morphine during a 4 h collection period was significantly higher than the metabolites concentration. The relative concentration of morphine and its metabolites during the 4 h period was 70 and 30% respectively. 3. The analgesic response during the first 2.25 h period accounted for more than 82% of the total analgesia as determined by the area under the time-response curve (AUC). The concentration of morphine and its metabolites during the same period were 78 and 22%, respectively, but they did not differ during the 2.25-4.0 h period (52 and 48%). 4. The half-life for morphine and its metabolites were similar, the maximal achievable concentration Cmax and AUC0-4 h were lower for metabolites but the time to reach maximum concentration was higher for morphine metabolites than for morphine. The ratio of the concentration of metabolites to the concentration of morphine in the cortical ECF increased with time whereas the analgesic response to morphine decreased with time. 5. At several time points following morphine injection even though the levels of morphine were the same, the concentration of metabolites (mainly M3G) differed and thus the ratio [metabolite/morphine]. A plot of [metabolite]/[morphine] vs. analgesia gave a high correlation coefficient. Since M3G has been shown to be antianalgesic and is the only metabolite of morphine in the rat, it is concluded that the levels of this metabolite may regulate the analgesic effect of morphine in the rat.