Evaluation of samidorphan, a µ-opioid antagonist, in a drug discrimination assay in rats.

Preclinical Research & Development Background: Samidorphan, a µ-opioid receptor antagonist, is in clinical development for central nervous system related diseases. The discriminative stimulus effects of samidorphan were assessed in rats trained to discriminate the effects of a known morphinan of abuse, morphine, from that of saline. METHODS: Escalating doses of samidorphan were substituted for morphine and rats were allowed to respond on two levers for food reward. Doses of samidorphan were chosen based on other pharmacodynamic assays in which samidorphan blocked the effects of morphine (such as blocking analgesia in a hot plate test; data not shown). In addition, a pharmacokinetic study was conducted to determine if these doses would reflect predicted exposure levels that translate to human equivalent doses. RESULTS: Rats discriminating morphine from vehicle responded predominantly on the vehicle lever after receiving samidorphan. In addition, samidorphan was rapidly absorbed, and plasma concentrations of the doses tested in this study bracket therapeutically relevant concentrations. CONCLUSIONS: In summary, samidorphan produced saline-like behavioral responses over a wide dose range.

Improvements in self-administration studies based on changes in skin button type and surgical technique.

INTRODUCTION: These studies, ranging in duration from 3 to 8months, evaluated the patency and longevity of the intravenous (IV) self-administration surgical model in male Sprague Dawley rats. Surgeries were categorized and assessed based on the number of catheter and/or skin button repairs required per animal across four separate self-administration studies. Design improvements in skin button types and changes in surgical procedures were chronologically tracked and assessed. METHODS: Animals were evaluated under a self-administration paradigm in which they were trained to respond for a food reward under a fixed ratio schedule (FR5 or FR10). Animals were then surgically prepared with a femoral catheter and skin button port. Following recovery, animals were returned to food-maintained responding for at least 5 sessions and subsequently trained to respond for injections of a reinforcing drug. Once drug training criteria was established, the effects of vehicle or varying doses of test articles were evaluated. Animals were tested in operant chambers one hour each day 5days a week and the length of each study was recorded. Differences in the number of repairs per study as well as the total number of repairs were tabulated. RESULTS: Study length was directly correlated to the mean number of repairs occurring per study, with study length increasing as the total number of repairs increased. The majority of repairs were skin button-related issues. Multiple combinations of skin button types and surgical techniques were implemented across time to evaluate model efficiency and decrease overall cycle time per study. Initial combinations produced a greater number of repairs on a per study basis. However, the skin button type and surgical technique combination that resulted in the fewest number of total repairs used a lateral incision with a dorsal biopsy punch. DISCUSSION: The combination of improvements in skin button type and surgical techniques drastically decreased the number of surgical repairs required per study, increasing efficiency and thereby decreasing the overall cycle time for study completion.