Attenuation and reversal of morphine tolerance by the competitive N-methyl-D-aspartate receptor antagonist, LY274614.
Attenuation and reversal of morphine tolerance by the competitive N-methyl-D-aspartate receptor antagonist, LY274614.
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发表时间：
1993-03
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通讯作者：
P. Tiseo;C. Inturrisi
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作者：
P. Tiseo;C. Inturrisi
竞争性（LY274614;（+-)-6-磷酸亚甲基-十氢异喹啉-3-羧酸）和非竞争性（MK801;[(+)-5 -甲基-10,11-二氢- 5h -二苯并[a，d]环庚烯-5,10-亚胺马来酸氢）n-甲基-d -天冬氨酸受体拮抗剂）调节吗啡抗伤（镇痛）作用的能力。与LY274614或MK801同时连续s.c输注可显著减弱每日两次注射吗啡（10 mg/kg s.c）产生的吗啡耐受性。LY274614对吗啡耐受的减弱是剂量依赖性的（12或24 mg/kg/24小时静注）。此外，在停止所有药物治疗1周后，观察到动物对吗啡的镇痛敏感性保持不变，而对照组动物则保持相对耐受。这些结果表明，LY274614和MK801并不改变吗啡耐受的表达，而是改变了吗啡耐受的发展。注射LY274614 7天后，吗啡耐受动物对吗啡的镇痛敏感性恢复。此外，LY274614还逆转了耐受动物继续接受吗啡的耐受性发展并恢复了吗啡敏感性。LY274614可以在不降低镇痛反应的情况下阻止和逆转吗啡耐受性的发展，这表明参与耐受性发展和维持的适应性系统需要一个功能性的n -甲基- d -天冬氨酸受体。LY274614缺乏与MK801类似的苯环利定样副作用，这可能有利于这种竞争性n -甲基- d -天冬氨酸受体拮抗剂作为慢性阿片类药物治疗疼痛患者的辅助药物的临床发展。
The ability of a competitive (LY274614; (+-)-6-phosphonomethyl-decahydroisoquinolin-3-carboxylic acid) and a noncompetitive (MK801; [(+)-5 methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate) N-methyl-D-aspartate receptor antagonist to modulate the development of tolerance to morphine's antinociceptive (analgesic) effects was assessed by using hot-plate latency in rats. Concurrent treatment with LY274614 or MK801 by continuous s.c. infusion significantly attenuated the development of morphine tolerance produced by twice daily injections of morphine (10 mg/kg s.c.). This attenuation of morphine tolerance by LY274614 was dose-dependent, 12 or 24 mg/kg/24 hr s.c. infusion). Additionally, animals tested 1 week after the discontinuation of all drug treatments were observed to retain their analgesic sensitivity to morphine, whereas control animals remained relatively tolerant. These results suggest that LY274614 and MK801 do not alter the expression of tolerance but actually modify the development of morphine tolerance. Morphine-tolerant animals infused with LY274614 for 7 days regained their analgesic sensitivity to morphine. Furthermore, LY274614 also reversed the development of tolerance and restored morphine sensitivity in tolerant animals that continued to receive morphine. The demonstration that LY274614 can prevent and reverse the development of morphine tolerance without reducing the analgesic response suggests that the adaptive system involved in the development and maintenance of tolerance requires a functional N-methyl-D-aspartate receptor. LY274614 lacks the phencyclidine-like side effects seen with MK801, and this may favor the clinical development of this competitive N-methyl-D-aspartate receptor antagonist as an adjunct for patients receiving chronic opioids for pain management.