An evaluation of morphine dependence in the rat

A semiquantitatiye method for assessing the degree of physical dependence upon morphine in rats has been examined. A time-course measure of dependence due to repetitive and increasing daily doses of morphine was obtained between one and eleven days of treatment utilizing a narcotic antagonist to precipitate withdrawal and scoring six specific withdrawal symptoms. High starting doses of morphine produced a miximal withdrawal score after two days which remained constant until the eleventh day. However, low starting doses of morphine produced a more typical dose-effect relationship from day one through day seven. The scoring system utilized in this study was analyzed and found to be acceptable, but by no means optimal to assess the degree of morphine physical dependence. The effects upon the narcotic antagonist precipitated withdrawal score, and therefore, the degree of physical dependence upon morphine, of concomitantly administered drugs was investigated. Dextroamphetamine, apomorphine and atropine were shown to decrease the total withdrawal score whereas levoamphetamine, haloperidol and atropine methyl nitrate failed to reduce significantly the total withdrawal score. Based upon these data a hypothetical model for the development of morphine physical dependence was, proposed. Although this model appeared to hold for total withdrawal scores certain discrepancies became apparent when drug-induced effects upon individual withdrawal symptoms were analyzed. Irrespective of mechanism, the research shows a clear differential effect between the two isomers of amphetamine, which could be due to differences on central dopaminergic mechanisms.