Concurrent Assessment of the Antinociceptive and Behaviorally Disruptive Effects of Opioids in Squirrel Monkeys

Abstract

Although the clinical application of opioids for pain management is often hindered by undesired behavioral impairment, preclinical assays of antinociception typically do not provide information regarding the behaviorally disruptive effects of opioids that may accompany their antinociceptive effects. To address this, we modified a warm water tail withdrawal procedure to determine concurrently the effects of opioids on tail withdrawal latency (antinociception) and indices of food-maintained operant behavior (rates of responding and reinforcement density) in squirrel monkeys. Six opioid agonists were tested, and all produced dose-dependent antinociception and impairment of operant behavior. The ratio of median effective dose (ED₅₀) values for both measures (behavioral impairment:antinociception) was used as a quantitative measure of therapeutic index. Nalbuphine had the highest ED₅₀ ratio (4.88), reflecting antinociception with minimal behavioral disruption. Oxycodone, heroin, buprenorphine, and methadone all produced similar ED₅₀ ratios (.82-1.14), whereas butorphanol yielded a significantly lower ED₅₀ ratio (.17) reflecting behavioral disruption at doses producing only minimal antinociception. The antinociceptive and behaviorally disruptive effects of oxycodone and buprenorphine were further characterized using Schild analysis to calculate apparent pA₂ values for antagonism of the 2 drugs by naltrexone. These analyses suggest that µ-receptor mechanisms likely mediate the antinociceptive as well as behaviorally disruptive effects of oxycodone (pA₂ values: 8.13 and 8.57) and buprenorphine (pA₂ values: 8.6 and 7.9).

Perspective: This article presents an assay that allows for the concurrent assessment of the antinociceptive and behaviorally disruptive effects of opioids. Our results show that the tail withdrawal assay in squirrel monkeys can provide a useful index of the behavioral selectivity with which opioids produce antinociception.

Keywords: Opioid; antinociception; oxycodone; schedule-controlled behavior; squirrel monkey.