NMDA RECEPTOR ANTAGONISTS AND OPIOID TOLERANCE

对啮齿动物的研究表明， N-甲基-D-谷氨酸（NMDA）受体可减弱 对吗啡的抗伤害作用的耐受性以及 逆转了吗啡的作用 为了支持这种互动 作为阿片类药物耐受的一种普遍现象，并支持其 可能应用于人类，拟议的一系列实验是 旨在将这些发现扩展到a）临床有用的μ-阿片类药物 和B）抗伤害感受的灵长类动物模型。 因此，在本发明中， 实验I和实验II采用大鼠尾部回缩过程来检查 竞争性NMDA受体拮抗剂对发育的影响 吗啡和其他阿片类药物的抗伤害作用 其在μ-阿片受体上的内在功效不同。 实验三考察非竞争性NMDA受体对大鼠脑缺血再灌注损伤的影响。 竞争性NMDA受体拮抗剂，和甘氨酸部分 激动剂对吗啡耐受松鼠的抗伤害作用 猴子在电击滴定仪下的反应。

Research in rodents demonstraties that chemicals that functioning of the Nu-methyl-D-asparte(NMDA) glutamate receptor attenuate the development of tolerance to the antinociceptive effects of morphine as well as reverse pre-existing to morphine. In order to support this interaction as a general phenomenon of opioid tolerance and lend support to its possible application in humans, the proposed series of experiments is designed to extend these findings to a ) clinically-useful mu-opiods other than morphine and b) a primate model of antinoception. Thus, Experiments I and II employ a rat tail-withdrawal proecdure to examine the effects of a competivie NMDA receptor anatagonist on the development of toloerance to be antinoceptive effects of morphine and other opioid that vary on their intrinsic efficacy at the mu-opioid receptor. Experiment III examines the effects of non-competive NMDA receptor antagoist, a competitive NMDA receptor antagnist, and a glycine partial agonist on the antinocieptive effects of morphine-tolerant squirrel monkeys responding under a shock titration proedure.