Kellstein David E, Mayer David J
Department of Physiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298 U.S.A.
Pain. 1991 Nov;47(2):221-229. doi: 10.1016/0304-3959(91)90208-F.
The effects of intrathecal (i.t.) co-administration of the cholecystokinin (CCK) antagonists lorglumide or proglumide with a "low" (1 microgram) and "high" (10 micrograms) dose of i.t. morphine on the development of opioid tolerance were determined using the rat tail-flick assay. Although co-injection of 7 ng lorglumide or 20 ng proglumide (doses which have been demonstrated to acutely enhance 1 microgram morphine, i.t.) were without effect, co-administration of 70 ng lorglumide or 64 ng proglumide with 1 microgram morphine for 6 days inhibited development of tolerance to this dose of opioid. Higher doses of CCK antagonists (1400 ng lorglumide and 1280 ng proglumide) were required to prevent the tolerance induced by 10 micrograms morphine. These findings provide further evidence that CCK mediates, at least partially, tolerance which develops to the analgesic effect of opioids and indicate the involvement of CCK pathways in the spinal cord. The results are also consistent with a mechanism in which the level of activation of compensatory, anti-opioid CCK circuitry is increased in proportion to the functional level of opioid pathways.
采用大鼠甩尾试验，确定鞘内注射（i.t.）胆囊收缩素（CCK）拮抗剂洛谷胺或丙谷胺与“低”（1微克）和“高”（10微克）剂量的鞘内吗啡共同给药对阿片类药物耐受性发展的影响。虽然共同注射7纳克洛谷胺或20纳克丙谷胺（已证明这些剂量能急性增强1微克鞘内吗啡的作用）没有效果，但70纳克洛谷胺或64纳克丙谷胺与1微克吗啡共同给药6天可抑制对该剂量阿片类药物耐受性的发展。需要更高剂量的CCK拮抗剂（1400纳克洛谷胺和1280纳克丙谷胺）来预防10微克吗啡诱导的耐受性。这些发现进一步证明CCK至少部分介导了对阿片类药物镇痛作用产生的耐受性，并表明CCK通路参与脊髓作用。结果也与一种机制相符，即代偿性抗阿片类CCK回路的激活水平与阿片类通路的功能水平成比例增加。
