Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
J Pharmacol Exp Ther. 2022 Jul;382(1):44-53. doi: 10.1124/jpet.121.001045. Epub 2022 Apr 30.
Mu opioid receptor (MOR) agonists produce locomotor hyperactivity in mice as one sign of opioid-induced motor disruption. The goal of this study was to evaluate the degree of MOR efficacy required to produce this hyperactivity. Full dose-effect curves were determined for locomotor activation produced in male and female Institute of Cancer Research (ICR) mice by (1) eight different single-molecule opioids with high to low MOR efficacy and (2) a series of fixed-proportion fentanyl/naltrexone mixtures with high to low fentanyl proportions. Data from the mixtures were used to quantify the efficacy requirement for MOR agonist-induced hyperactivity relative to efficacy requirements determined previously for other MOR agonist effects. Specifically, efficacy requirement was quantified as the EP50 value, which is the "Effective Proportion" of fentanyl in a fentanyl/naltrexone mixture that produces a maximal effect equal to 50% of the maximal effect of fentanyl alone. Maximal hyperactivity produced by each drug and mixture in the present study correlated with previously published data for maximal stimulation of GTPɣS binding in MOR-expressing Chinese hamster ovary cells as an in vitro measure of relative efficacy. Additionally, the EP value for hyperactivity induced by fentanyl/naltrexone mixtures indicated that opioid-induced hyperactivity in mice has a relatively high efficacy requirement in comparison with some other MOR agonist effects, and in particular is higher than the efficacy requirement for thermal antinociception in mice or fentanyl discrimination in rats. Taken together, these data show that MOR agonist-induced hyperactivity in mice is efficacy dependent and requires relatively high levels of MOR agonist efficacy for its full expression. SIGNIFICANCE STATEMENT: Mu opioid receptor (MOR) agonist-induced hyperlocomotion in mice is dependent on the MOR efficacy of the agonist and requires a relatively high degree of efficacy for its full expression.
μ 阿片受体（MOR）激动剂会导致小鼠出现运动过度活跃，这是阿片类药物引起运动障碍的一个标志。本研究的目的是评估产生这种过度活跃所需的 MOR 效力程度。通过（1）八种不同的具有高到低 MOR 效力的单分子阿片类药物，以及（2）一系列具有高到低芬太尼比例的固定比例芬太尼/纳曲酮混合物，确定了雄性和雌性 ICR 小鼠运动激活的全剂量效应曲线。混合物的数据用于量化与先前确定的其他 MOR 激动剂效应的效力要求相比，MOR 激动剂诱导的过度活跃所需的效力要求。具体来说，效力要求被量化为 EP50 值，这是芬太尼/纳曲酮混合物中产生与芬太尼单独作用的最大效应相等的 50%的芬太尼的“有效比例”。本研究中每种药物和混合物产生的最大过度活跃与先前发表的数据相关，用于评估在 MOR 表达的中国仓鼠卵巢细胞中最大刺激 GTPγS 结合的最大效应作为相对效力的体外测量。此外，芬太尼/纳曲酮混合物诱导的过度活跃的 EP 值表明，与一些其他 MOR 激动剂效应相比，小鼠中阿片类药物诱导的过度活跃具有相对较高的效力要求，特别是与小鼠中的热镇痛或大鼠中的芬太尼辨别相比更高。综上所述，这些数据表明，MOR 激动剂诱导的小鼠过度活跃是效力依赖性的，并且需要相对较高水平的 MOR 激动剂效力才能完全表达。
