Dunbar S A, Yaksh T L
Department of Anesthesiology, University of California, San Diego, LaJolla 92103, USA.
J Pharmacol Exp Ther. 1997 Jun;281(3):1219-25.
MK801 (MK), an N-methyl-D-aspartate (NMDA) receptor antagonist, attenuates tolerance to spinal opioids. Whether this applies to other G-protein-coupled receptor systems is unknown. This study examines the effects of continuous spinal MK on tolerance to the antinociceptive effect of continuous spinal infusion of the alpha-2 agonist ST91 (ST). Intrathecal (i.t.) infusion pumps were implanted in rats which delivered for 7 days: saline (1 microl/h); ST (40 nmol/microl/h); MK (10 nmol/microl/h) + ST (40 nmol/microl/h); or MK (10 nmol/microl/h). Antinociception was measured daily on the hot plate. On day 8, groups received i.t. boluses of ST to generate dose-response curves. A separate ST-infused group received MK (10 nmol i.t.) on day 7. Each group received ST (40 nmol i.t.) 7 days after discontinuation of infusion. Co-infusion of MK with ST resulted in attenuation of the right shift in dose response seen in ST-infused rats and a small preservation of effect on daily testing. However, MK-infused rats showed a significant left shift in ST dose response. Acutely administered, MK did not restore ST sensitivity. One week after cessation of infusion, ST and ST + MK groups showed shorter duration of effect after i.t. ST bolus than controls. In conclusion, chronic spinal MK partially attenuates loss of sensitivity to chronic spinal ST. This supports the hypothesis that opioid- and adrenoceptor-induced tolerances are similarly modulated by the NMDA receptor. However, the increased sensitivity induced by MK alone suggests that NMDA receptor antagonism may not prevent the development of tolerance itself but may alter the expression of tolerance by inducing sensitivity via other alterations in cellular function.
MK801（MK）是一种N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，可减轻对脊髓阿片类药物的耐受性。这是否适用于其他G蛋白偶联受体系统尚不清楚。本研究探讨持续脊髓给予MK对持续脊髓输注α2激动剂ST91（ST）的抗伤害感受作用耐受性的影响。将鞘内（i.t.）输注泵植入大鼠体内，持续给药7天：生理盐水（1微升/小时）；ST（40纳摩尔/微升/小时）；MK（10纳摩尔/微升/小时）+ ST（40纳摩尔/微升/小时）；或MK（10纳摩尔/微升/小时）。每天在热板上测量抗伤害感受。在第8天，各组接受i.t.注射ST以生成剂量反应曲线。一个单独的ST输注组在第7天接受MK（10纳摩尔i.t.）。每组在输注停止7天后接受ST（40纳摩尔i.t.）。MK与ST共同输注导致ST输注大鼠中观察到的剂量反应右移减弱，并且在每日测试中对效应有少量保留。然而，MK输注大鼠的ST剂量反应出现显著左移。急性给予MK不能恢复ST敏感性。输注停止1周后，ST组和ST + MK组在i.t.注射ST推注后的效应持续时间比对照组短。总之，慢性脊髓给予MK可部分减轻对慢性脊髓给予ST的敏感性丧失。这支持了阿片受体和肾上腺素能受体诱导的耐受性受NMDA受体类似调节的假说。然而，单独MK诱导的敏感性增加表明，NMDA受体拮抗作用可能不会阻止耐受性本身的发展，但可能通过诱导细胞功能的其他改变来改变耐受性的表达。
