Vonvoigtlander P F, Lewis R A
Upjohn Company, Central Nervous System Diseases Research, Kalamazoo, Michigan.
J Pharmacol Exp Ther. 1988 Jul;246(1):259-62.
Spiradoline (a congener of the kappa opioid agonist, U-50488H) was evaluated for analgesic and related activities in rodents. In nine antinociceptive assays utilizing various thermal, pressure and chemical and physical irritants, the potency of spiradoline ranges from 4.7 to 23 (mean = 13) times that of U-50488H. Naloxone blocks the analgesic effect of spiradoline. The in vivo naloxone pA2 for this antagonism is much lower than that for the antagonism of morphine and approximates that of U-50488H. The analgesic potency of spiradoline is greatly reduced in mice made tolerant to U-50488H but not in those made tolerant to morphine. Repeated treatment with spiradoline does not induce physical dependence as evidenced by a lack of naloxone-precipitated jumping and withdrawal-induced hyperalgesia. In sum, these observations suggest that spiradoline is a potent kappa agonist analgesic. However, further evaluation of spiradoline revealed differences between this compound and U-50488H. We have previously shown that the analgesic effect of the latter compound, but not that of morphine, is profoundly antagonized by reserpine or p-chlorophenylalanine. In contrast, spiradoline is only marginally antagonized by these serotonin-depleting treatments. Evaluation of the enantiomers of spiradoline revealed that the (-)-enantiomer is more than 30 times as potent as the (+)-enantiomer in analgesic tests. The (-)-enantiomer is similar to U-50488H with regard to antagonism by p-chlorophenylalanine, lack of physical dependence-inducing properties and cross-tolerance. In contrast the (+)-enantiomer induces physical dependence and displays marked cross-tolerance in morphine-tolerant mice.(ABSTRACT TRUNCATED AT 250 WORDS)
对spira多林（κ阿片受体激动剂U-50488H的同系物）在啮齿动物中的镇痛及相关活性进行了评估。在9种利用各种热、压力、化学和物理刺激物的抗伤害感受试验中，spira多林的效力为U-50488H的4.7至23倍（平均为13倍）。纳洛酮可阻断spira多林的镇痛作用。这种拮抗作用的体内纳洛酮pA2远低于吗啡拮抗作用的pA2，接近U-50488H的pA2。在对U-50488H产生耐受性的小鼠中，spira多林的镇痛效力大幅降低，但在对吗啡产生耐受性的小鼠中则不然。重复给予spira多林不会诱导身体依赖性，这表现为缺乏纳洛酮诱发的跳跃反应和戒断诱发的痛觉过敏。总之，这些观察结果表明spira多林是一种强效的κ受体激动剂镇痛药。然而，对spira多林的进一步评估揭示了该化合物与U-50488H之间的差异。我们之前已表明，利血平或对氯苯丙氨酸可显著拮抗后一种化合物的镇痛作用，但对吗啡的镇痛作用无此影响。相比之下，这些耗竭5-羟色胺的处理对spira多林仅有轻微拮抗作用。对spira多林对映体的评估表明，在镇痛试验中，(-)-对映体的效力是(+)-对映体的30多倍。(-)-对映体在对氯苯丙氨酸拮抗作用、缺乏诱导身体依赖性的特性以及交叉耐受性方面与U-50488H相似。相比之下，(+)-对映体可诱导身体依赖性，并在吗啡耐受的小鼠中表现出明显的交叉耐受性。（摘要截短于250字）
