Makimura M, Sugimoto H, Shinomiya K, Kabasawa Y, Fukuda H
Department of Pharmacology, College of Pharmacy, Nihon University, Chiba, Japan.
J Toxicol Sci. 1996 May;21(2):135-41. doi: 10.2131/jts.21.2_135.
We investigated the effect of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imin ehydrogen maleate (dizocilpine, MK-801), on hippocampal norepinephrine release in morphine-treated rats in order to clarify the relationship between NMDA receptors and the development of morphine dependence. Naloxone hydrochloride injected subcutaneously (s.c.) into morphine-dependent rats, induced an immediate increase in hippocampal norepinephrine release, which was associated with a typical morphine withdrawal syndrome. The increased norepinephrine levels persisted for at least 2 hr, even after the disappearance of the behavioral withdrawal syndrome. This striking effect of naloxone on hippocampal norepinephrine release was dependent on the duration of the intracerebroventricular (i.c.v.) morphine infusion. Pretreatment with dizocilpine (s.c.) before naloxone challenge reduce the rate of the rise in hippocampal norepinephrine release induced by naloxone in morphine-treated rats. Concurrent infusion (i.c.v.) of dizocilpine and morphine decreased the level of hippocampal norepinephrine release after a naloxone challenge. Both pretreatment with dizocilpine (s.c.) before naxolone injection and infusion (i.c.v.) of dizocilpine suppressed rearing and teeth-chattering signs, but not wet-dog shakes in morphine-treated rats. These results suggest that dizocilpine attenuates the development of morphine dependence through NMDA receptors, and thus that interaction between opioid receptors and NMDA receptors may be involved in the development of morphine dependence.
我们研究了一种非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，（+）-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺氢马来酸盐（地佐环平，MK-801）对吗啡处理大鼠海马去甲肾上腺素释放的影响，以阐明NMDA受体与吗啡依赖性发展之间的关系。皮下注射盐酸纳洛酮到吗啡依赖大鼠体内，可立即引起海马去甲肾上腺素释放增加，这与典型的吗啡戒断综合征相关。即使行为戒断综合征消失后，去甲肾上腺素水平升高仍持续至少2小时。纳洛酮对海马去甲肾上腺素释放的这种显著作用取决于脑室内（i.c.v.）注入吗啡的持续时间。在纳洛酮激发前用地佐环平（皮下注射）预处理，可降低吗啡处理大鼠中纳洛酮诱导的海马去甲肾上腺素释放的上升速率。同时脑室内注入地佐环平和吗啡，可降低纳洛酮激发后海马去甲肾上腺素释放水平。在纳洛酮注射前用地佐环平（皮下注射）预处理和脑室内注入地佐环平，均可抑制吗啡处理大鼠的竖毛和牙齿打颤症状，但不能抑制湿狗样抖动。这些结果表明，地佐环平通过NMDA受体减弱吗啡依赖性的发展，因此阿片受体与NMDA受体之间的相互作用可能参与了吗啡依赖性的发展。
