VonVoigtlander P F, Lewis R A
J Pharmacol Methods. 1983 Dec;10(4):277-82. doi: 10.1016/0160-5402(83)90022-0.
The physical dependence-inducing properties of analgesics are commonly assessed by the appearance of typical narcotic withdrawal signs (weight loss, jumping, etc.) upon cessation of administration or treatment with a narcotic antagonist. We sought to develop a simple model of physical dependence based upon withdrawal hyperalgesia. The test compound was injected seven times over a period of three days. At various times after the last injection, 6% aqueous NaCl was injected i.p. and the mice were observed for stereotyped writhing. To assess the magnitude of hyperalgesia, the animals were also challenged with several concentrations of saline administered at the time of peak sensitivity and a saline EC50 was thereby derived. In this manner, it was demonstrated that morphine causes a marked, dose-related physical dependence. Other mixed opioids, pentazocine, ethylketocyclazocine, nalbuphine, and butorphanol (in decreasing order of effectiveness) were also active. In nonpretreated mice, naloxone caused a dose-related appearance of saline-induced writhing, suggestive of a blockade of endogenous analgesic mechanisms. Writhing in response to low concentrations of i.p. saline provides a sensitive test of analgesic physical dependence.
镇痛药诱导身体依赖性的特性通常通过在停止给药或用麻醉拮抗剂治疗后出现典型的麻醉药戒断症状（体重减轻、跳跃等）来评估。我们试图基于戒断性痛觉过敏建立一种简单的身体依赖性模型。在三天的时间内对测试化合物进行七次注射。在最后一次注射后的不同时间，腹腔注射6%的氯化钠水溶液，并观察小鼠是否出现刻板性扭体。为了评估痛觉过敏的程度，在峰值敏感性时还对动物用几种浓度的盐水进行刺激，并由此得出盐水的半数有效浓度（EC50）。通过这种方式，证明了吗啡会引起明显的、剂量相关的身体依赖性。其他混合阿片类药物，喷他佐辛、乙基酮环唑辛、纳布啡和布托啡诺（按有效性递减顺序）也有活性。在未预处理的小鼠中，纳洛酮会引起剂量相关的盐水诱导扭体现象，提示内源性镇痛机制被阻断。对低浓度腹腔注射盐水的扭体反应提供了一种对镇痛药身体依赖性的敏感测试。
