Kellstein D E, Mayer D J
Department of Physiology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Brain Res. 1990 May 21;516(2):263-70. doi: 10.1016/0006-8993(90)90927-4.
The effects of acute and chronic (22 days) treatment with the cholecystokinin (CCK) antagonists proglumide and lorglumide on antinociception induced by intrathecal (i.t.) morphine were determined at weekly intervals with the rat tail-flick assay. On day 1, acute pretreatment with either proglumide (20 ng, i.t.) or lorglumide (7 ng, i.t.) enhanced morphine (1 microgram, i.t.) analgesia compared to saline (1 microliter, i.t.) pretreatment, but this facilitation was absent on days 8 and 15 of CCK antagonist treatment and was replaced by attenuation of opioid antinociception on day 22. Following termination of daily proglumide or lorglumide injections, normal (control) morphine response was observed after pretreatment with either CCK antagonist on days 29 and 36. Weekly co-administration of either drug with morphine had similar effects: opioid antinociception was initially enhanced on day 1, but this amplification was lost by day 8 and remained absent for the duration of the study (i.e., up to day 36). Inhibition of morphine analgesia, however, was not observed with this treatment paradigm. Chronic daily administration of either CCK antagonist alone did not lower nociceptive thresholds; further, normal opioid response was retained throughout the study in saline treated controls receiving morphine weekly. This study demonstrates that whereas acute i.t. administration of CCK antagonists enhances i.t. morphine antinociception, chronic treatment causes loss of facilitation or attenuation of opioid antinociception, suggesting that (1) compensatory alterations in CCK-opioid interactions develop during chronic CCK blockade and (2) CCK antagonists may not be useful adjuncts to opioid analgesics in the management of chronic pain in man.
采用大鼠甩尾试验，每周测定一次胆囊收缩素（CCK）拮抗剂丙谷胺和氯谷胺急性（22天）治疗对鞘内注射吗啡诱导的抗伤害感受的影响。第1天，与生理盐水（1微升，鞘内注射）预处理相比，丙谷胺（20纳克，鞘内注射）或氯谷胺（7纳克，鞘内注射）急性预处理增强了吗啡（1微克，鞘内注射）的镇痛作用，但在CCK拮抗剂治疗的第8天和第15天这种促进作用消失，在第22天被阿片类药物抗伤害感受的减弱所取代。在每日丙谷胺或氯谷胺注射终止后，在第29天和第36天用任何一种CCK拮抗剂预处理后观察到正常（对照）吗啡反应。每周将这两种药物与吗啡联合给药有类似的效果：阿片类药物抗伤害感受在第1天最初增强，但这种增强在第8天消失，并且在研究期间（即直至第36天）一直不存在。然而，这种治疗模式未观察到对吗啡镇痛的抑制作用。单独慢性每日给予任何一种CCK拮抗剂均未降低伤害性感受阈值；此外，在每周接受吗啡治疗的生理盐水处理对照组中，整个研究期间均保留了正常的阿片类反应。这项研究表明，虽然鞘内急性给予CCK拮抗剂可增强鞘内吗啡的抗伤害感受，但慢性治疗会导致促进作用丧失或阿片类药物抗伤害感受减弱，提示（1）在慢性CCK阻断期间CCK-阿片类相互作用发生了代偿性改变，以及（2）在人类慢性疼痛管理中，CCK拮抗剂可能不是阿片类镇痛药的有用辅助药物。
