Preclinical Pharmacology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts.
Preclinical Pharmacology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts.
J Pain. 2018 Jul;19(7):728-740. doi: 10.1016/j.jpain.2018.02.003. Epub 2018 Mar 2.
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 (ED) values for both measures (behavioral impairment:antinociception) was used as a quantitative measure of therapeutic index. Nalbuphine had the highest ED ratio (4.88), reflecting antinociception with minimal behavioral disruption. Oxycodone, heroin, buprenorphine, and methadone all produced similar ED ratios (.82-1.14), whereas butorphanol yielded a significantly lower ED 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 pA 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 (pA values: 8.13 and 8.57) and buprenorphine (pA values: 8.6 and 7.9).
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.
尽管阿片类药物在疼痛管理中的临床应用常因不良行为损害而受阻，但阿片类药物的抗伤害作用的临床前检测通常无法提供有关其伴随的抗伤害作用的行为干扰作用的信息。为了解决这个问题，我们修改了温水尾巴撤回程序，以确定阿片类药物对尾巴撤回潜伏期（镇痛）和食物维持操作性行为指标（反应率和强化密度）的同时影响。测试了六种阿片类激动剂，所有这些都产生了剂量依赖性的镇痛和操作性行为损害。这两种措施（行为损害：镇痛）的中值有效剂量（ED）值的比值用作治疗指数的定量测量。纳布啡的 ED 比值最高（4.88），反映了最小行为干扰的镇痛作用。羟考酮、海洛因、丁丙诺啡和美沙酮的 ED 比值相似（0.82-1.14），而布托啡诺则产生了明显较低的 ED 比值（0.17），反映了在仅产生最小镇痛作用的剂量下行为破坏。羟考酮和丁丙诺啡的镇痛和行为破坏作用通过 Schild 分析进一步表征，以计算纳曲酮对这两种药物的拮抗作用的表观 pA 值。这些分析表明，μ-受体机制可能介导羟考酮（pA 值：8.13 和 8.57）和丁丙诺啡（pA 值：8.6 和 7.9）的镇痛和行为破坏作用。
本文介绍了一种可同时评估阿片类药物的镇痛和行为破坏作用的检测方法。我们的结果表明，在松鼠猴中，尾巴撤回检测可提供阿片类药物产生镇痛作用的行为选择性的有用指标。
