INVESTIGATION OF THE ANTINOCICEPTIVE EFFICACY AND RELATIVE POTENCY OFEXTENDED DURATION INJECTABLE 3-ACYLMORPHINE-6-SULFATE PRODRUGS IN RATS

This investigation was designed to examine the antinociceptive activit y in rats of 3-O-acyl prodrugs of M6S relative to the parent drug, aft er intravenous and intramuscular injection, using the tail flick laten cy test of antinociception. M6S, 3-acetylmorphine-6-sulfate (3AcM6S), 3-propionylmorphine-6-sulfate (3PrM6S), 3-butanoylmorphine-6-sulfate ( 3BuM6S) and 3-heptanoylmorphine-6-sulfate (3HpM6S) were administered b y the IV route in a dose of 4.10 mu mol/kg. Relatively high levels of antinociception (>40% Maximum Possible Effect) were achieved following administration of M6S, 3AcM6S and 3PrM6S, whereas insignificant antin ociception (<20%MPE) was achieved following administration of 3BuM6S o r 3HpM6S. Although the mean duration of action for 3AcM6S (6 h) was lo nger than for M6S or 3PrM6S (4 h), the mean area (+/- S.E.M.) under th e degree of antinociception versus time curve (AUG) for 3AcM6S (151.6 +/- 6.9%MPE h) was not significantly different (p <0.05) from that for M6S (120.8 +/- 32.7%MPE h) or for 3PrM6S (106.0 +/- 21.3%MPE h). The mean ED50 (range) doses for M6S, 3AcM6S and 3PrM6S were calculated to be 4.16 (3.61-4.48), 4.32 (3.55-5.09) and 4.54 (4.21-4.79) mu mol/kg, respectively. Preliminary studies were conducted on potential long-act ing formulations containing 8 x ED50 doses of M6S and the 3-acetyl and 3-propionyl esters suspended in soybean oil. These showed that 3PrM6S gave a greater AUC (mean + S.E.M.) (1087.4 +/- 97.4%MPE h) and longer duration of action (20 h) than did M6S (613.1 +/- 155.9%MPE h; 10 h d uration) or 3AcM6S (379.3 + 114.2%MPE h: 8 h duration). Further studie s are needed to more fully investigate these findings. (C) 1998 Elsevi er Science B.V. All rights reserved.