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

Published:February 22, 2018DOI:https://doi.org/10.1016/j.jpain.2018.02.003

      Highlights

      • Opioid antinociceptive and behaviorally disruptive effects are measured concurrently.
      • The ratio of ED50 values for both measures are calculated, and differ among opioids.
      • These ratios indicate the behavioral selectivity of opioid antinociception.
      • ED50 ratios serve as preclinical estimates of therapeutic index.
      • Opioids with differing ED50 ratios may have differing scopes of clinical utility.

      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.

      Key words

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