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 respons e measured by the tail-flick method was determined in male Sprague-Daw ley rats. The analgesic response to morphine was correlated with the l evels of morphine and its metabolites collected by microdialysis from the cortical extracellular fluid (ECF). 2 The analgesic response to mo rphine lasted for 4 h. The concentration of morphine during a 4 h coll ection period was significantly higher than the metabolites concentrat ion. 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 tota l analgesia as determined by the area under the time-response curve (A UG). 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 i ts metabolites were similar, the maximal achievable concentration C-ma x and AUC(0-4h) were lower for metabolites but the time to reach maxim um concentration was higher for morphine metabolites than for morphine . The ratio of the concentration of metabolites to the concentration o f morphine in the cortical ECF increased with time whereas the analges ic response to morphine decreased with time. 5 At several time points following morphine injection even though the levels of morphine were t he same, the concentration of metabolites (mainly M3G) differed and th us 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 th e rat, it is concluded that the levels of this metabolite may regulate the analgesic effect of morphine in the rat.