A rapid, quantitative in vivo assay for narcotic antagonists.

Abstract

Tail skin temperature (TST) response of morphine-dependent rats was evaluated as a potential in vivo assay for the activity of narcotic antagonists. Dependency was produced in rats by repeated subcutaneous implantation of morphine-containing pellets and TST was evaluated by thermistor probes attached to the dorsal surface of the tail. TST was determined prior to and following administration of either naloxone (NAL: 0, 0.01, 0.1, 0.5 or 1.0 mg/kg body weight); naltrexone (NALT: 0.001, 0.005, 0.01, 0.02 or 0.1 mg/kg body weight); or 6-Desoxy-6-methylenenaltrexone (DM-NALT: 0.001, 0.005, 0.01, 0.02 or 0.1 mg/kg body weight). Each of the narcotic antagonists caused a dose-dependent increase in tail skin temperature in morphine dependent rats. The initial TST increase was observed by 5 minutes and the maximal TST response occurred 15 to 25 minutes after drug administration. For each drug evaluated, a linear relationship was observed between the dose and maximal change in TST and between the dose and the area under the TST response curve. Determination of ED50 for the TST response revealed the expected relative potency for the narcotic antagonists evaluated: DM-NALT greater than NALT greater than NAL. Thus, the TST-response test is a rapid and quantitative bioassay for the evaluation of compounds for narcotic antagonistic activity.