Zhao G M, Bhargava H N
Department of Pharmaceutics and Pharmacodynamics, University of Illinois at Chicago 60612, USA.
Peptides. 1996;17(2):233-36. doi: 10.1016/0196-9781(95)02095-0.
The effects of MK-801, a noncompetitive antagonist of the N-methy1-D-aspartate (NMDA) receptor, and of LY 235959, a competitive antagonist of the NMDA receptor, on the development of tolerance to the analgesic action of [D-Pen2,D-Pen5]enkephalin (DPDPE), a delta 1-opioid receptor agonist were determined in mice. Tolerance to DPDPE was induced in male Swiss Webster mice by twice daily ICV injections of the drug (20 micrograms/mouse) for 4 days. To determine the effects of NMDA receptor antagonists, the drugs were injected IP in appropriate doses 10 min before each injection of DPDPE. The doses of MK-801 were 0.01, 0.03, and 0.10 mg/kg whereas those of LY 235959 were 1, 2, and 4 mg/kg. Chronic administration of NMDA receptor antagonists by themselves did not alter the tail flick response or the analgesic effect of DPDPE (10 micrograms/mouse, ICV). MK-801 given concurrently with DPDPE dose-dependently inhibited the development of tolerance to DPDPE, the significant effect being observed at 0.10 mg/kg dose. Similar inhibitory effects on the development of tolerance to DPDPE were observed with LY 235959 at 1, 2, and 4 mg/kg doses. It is concluded that antagonism of NMDA receptors blocks tolerance to the analgesic action of delta 1-opioid receptor agonist in the mouse.
在小鼠中测定了N-甲基-D-天冬氨酸（NMDA）受体的非竞争性拮抗剂MK-801以及NMDA受体的竞争性拮抗剂LY 235959对[D-青霉胺2，D-青霉胺5]脑啡肽（DPDPE，一种δ1阿片受体激动剂）镇痛作用耐受性发展的影响。通过每天两次脑室内注射该药物（20微克/小鼠），持续4天，在雄性瑞士韦伯斯特小鼠中诱导对DPDPE的耐受性。为了确定NMDA受体拮抗剂的作用，在每次注射DPDPE前10分钟以适当剂量腹腔注射这些药物。MK-801的剂量为0.01、0.03和0.10毫克/千克，而LY 235959的剂量为1、2和4毫克/千克。单独长期给予NMDA受体拮抗剂不会改变甩尾反应或DPDPE（10微克/小鼠，脑室内注射）的镇痛效果。与DPDPE同时给予时，MK-801剂量依赖性地抑制对DPDPE耐受性的发展，在0.10毫克/千克剂量时观察到显著效果。在1、2和4毫克/千克剂量的LY 235959中也观察到对DPDPE耐受性发展的类似抑制作用。得出的结论是，NMDA受体的拮抗作用可阻断小鼠对δ1阿片受体激动剂镇痛作用的耐受性。
