Dunbar S, Yaksh T L
Department of Anesthesiology, University of California, San Diego, La Jolla 92103, USA.
Anesthesiology. 1996 May;84(5):1177-88. doi: 10.1097/00000542-199605000-00020.
MK801, an N-methyl-D-aspartate receptor antagonist, has recently been reported to attenuate tolerance to, and withdrawal from morphine. This study analyzes tolerance and withdrawal in a chronic intrathecal coinfusion model of morphine and MK801.
Intrathecal catheters, attached to 7-day miniosmotic infusion pumps, were implanted in rats and infused with saline, 20 nM/h morphine, MK801 (10 and 3 nM/h) + morphine; and 10 nM/h MK801. Analgesia was measured on the hot plate daily. On the day 7, groups received 3 mg/kg intraperitoneal naloxone and six signs of withdrawal were assessed: vocalization to air motion or light touch, abnormal posture, spontaneous vocalization, escape attempts, "wet dog shakes," and ejaculation. Similar groups were tested only on days 1 and 7. Intrathecal morphine dose-response curves were obtained on day 8. A separate morphine-tolerant group received 10 nM MK801 on day 7. Rats from each group received 10 nM intrathecal morphine 1 week later.
Coinfusion of MK801 with morphine resulted in a dose-dependent preservation of effect, and attenuated three of six signs of withdrawal. Coinfusion of MK801 (10 and 3 nM/h) prevented the reduction of potency observed with morphine alone. ED50 values (maximum percent effect, nM morphine) were: saline (16), morphine (496), MK801 (10 nM/h) + morphine (4), and 10 nM/h MK801 (0.3). Acute administration of MK801 was ineffective in restoring sensitivity to morphine. One week after cessation of infusion, there was no significant difference between groups.
Chronic spinal MK801 attenuates tolerance to, and withdrawal from spinal morphine in a dose-dependent fashion, supporting the hypothesis that N-methyl-D-aspartate receptor activity plays a role in the reorganization of spinal function produced by chronic opioid receptor activation. Chronic intrathecal MK801 appears to sensitize the spinal cord to intrathecal morphine.
N-甲基-D-天冬氨酸受体拮抗剂MK801最近被报道可减轻对吗啡的耐受性及戒断反应。本研究分析了吗啡与MK801鞘内长期联合输注模型中的耐受性和戒断反应。
将连接到7天微型渗透泵的鞘内导管植入大鼠体内，并分别输注生理盐水、20 nM/h吗啡、MK801（10和3 nM/h）+吗啡以及10 nM/h MK801。每天在热板上测量镇痛效果。在第7天，各组大鼠腹腔注射3 mg/kg纳洛酮，并评估六种戒断症状：对空气流动或轻触发声、异常姿势、自发发声、逃跑企图、“湿狗样抖动”以及射精。相似的组仅在第1天和第7天进行测试。在第8天获得鞘内吗啡剂量-反应曲线。一个单独的吗啡耐受组在第7天接受10 nM MK801。一周后，每组大鼠接受10 nM鞘内吗啡。
MK801与吗啡联合输注导致效应呈剂量依赖性保留，并减轻了六种戒断症状中的三种。MK801（10和3 nM/h）联合输注可防止单独使用吗啡时观察到的效能降低。半数有效剂量（最大效应百分比，吗啡的nM数）分别为：生理盐水组（16）、吗啡组（496）、MK801（10 nM/h）+吗啡组（4）以及10 nM/h MK801组（0.3）。急性给予MK801对恢复对吗啡的敏感性无效。输注停止一周后，各组之间无显著差异。
慢性鞘内注射MK801可剂量依赖性地减轻对鞘内吗啡的耐受性及戒断反应，支持N-甲基-D-天冬氨酸受体活性在慢性阿片受体激活所导致的脊髓功能重组中起作用这一假说。慢性鞘内注射MK801似乎使脊髓对鞘内吗啡敏感。
