Davis A M, Inturrisi C E
Department of Pharmacology, Cornell University Medical College, New York, New York, USA.
J Pharmacol Exp Ther. 1999 May;289(2):1048-53.
Previous in vitro and in vivo studies have determined that the d isomer of methadone has N-methyl-D-aspartate (NMDA) receptor antagonist activity. The present studies examined the ability of d-methadone to attenuate the development of morphine tolerance in mice and rats and to modify NMDA-induced hyperalgesia in rats. A decrease in the percentage of mice analgesic (tail-flick response) after 5 days of once-daily morphine (7 mg/kg s.c.) was completely blocked by coadministration of d-methadone given s.c. at 10 mg/kg. Morphine given s.c. to mice on an escalating three times per day dosing schedule resulted in a nearly 3-fold increase in the tail-flick ED50 dose of morphine which was prevented by s.c. coadministered d-methadone at 15 mg/kg. In rats, intrathecal (i.t.) morphine produced a 38-fold increase in the ED50, which was completely prevented by the coadministration of i.t. d-methadone at 160 micrograms/rat. A decrease in thermal paw withdrawal latency induced by the i.t. administration of 1.64 micrograms/rat NMDA was completely blocked by pretreatment with 160 micrograms/rat d-methadone. Thus, systemically coadministered d-methadone prevents systemically induced morphine tolerance in mice, i.t. d-methadone attenuates tolerance produced by i.t. morphine in rats, and i.t. d-methadone, at the same dose which modulates morphine tolerance, blocks NMDA-induced hyperalgesia. These results support the conclusion that d-methadone affects the development of morphine tolerance and NMDA-induced hyperalgesia by virtue of its NMDA receptor antagonist activity.
以往的体外和体内研究已确定美沙酮的d-异构体具有N-甲基-D-天冬氨酸（NMDA）受体拮抗剂活性。本研究检测了d-美沙酮减轻小鼠和大鼠吗啡耐受性发展以及改变大鼠NMDA诱导的痛觉过敏的能力。每日一次皮下注射吗啡（7mg/kg）5天后，小鼠镇痛（甩尾反应）百分比的降低被皮下注射10mg/kg的d-美沙酮共同给药完全阻断。每天三次递增剂量皮下注射吗啡给小鼠，导致吗啡甩尾ED50剂量增加近3倍，而皮下注射15mg/kg的d-美沙酮共同给药可防止这种增加。在大鼠中，鞘内注射吗啡使ED50增加38倍，而鞘内注射160μg/大鼠的d-美沙酮共同给药可完全防止这种增加。鞘内注射1.64μg/大鼠NMDA诱导的热足退缩潜伏期缩短被160μg/大鼠d-美沙酮预处理完全阻断。因此，全身共同给药的d-美沙酮可防止小鼠全身诱导的吗啡耐受性，鞘内注射d-美沙酮可减轻大鼠鞘内注射吗啡产生的耐受性，并且鞘内注射d-美沙酮在调节吗啡耐受性的相同剂量下可阻断NMDA诱导的痛觉过敏。这些结果支持以下结论：d-美沙酮凭借其NMDA受体拮抗剂活性影响吗啡耐受性的发展和NMDA诱导的痛觉过敏。
