Kolesnikov Y, Jain S, Wilson R, Pasternak G W
The Cotzias Laboratory of Neuro-Oncology, Cornell University Medical College, New York, New York, USA.
J Pharmacol Exp Ther. 1998 Feb;284(2):455-9.
In contrast to the rapid development of tolerance to morphine in CD-1 mice, tolerance is not seen in 129/SvEv mice implanted with morphine pellets or given daily morphine injections for 5 days. Similarly, the progressive and complete loss of analgesia in CD-1 mice seen with repeated dosing of the delta ligand [D-Pen2, D-Pen5]enkephalin is not observed in 129/SvEv mice. In contrast, tolerance develops normally to both the kappa1 drug U50,488H and the kappa3 agent naloxone benzoylhdrazone. N-methyl-D-aspartate (NMDA) given alone attenuates morphine analgesia in CD-1 mice and accelerates the development of tolerance in CD-1 mice when given daily with morphine. In contrast, NMDA has no significant effect in the 129/SvEv mice in either paradigm. Activation of NMDA receptors can lead to the production of nitric oxide, which also is involved with morphine tolerance. Sodium nitroprusside and L-arginine increase nitric oxide levels and decrease morphine analgesia in both the control CD-1 and 129/SvEv mice. Thus, the defect in the NMDA/nitric oxide cascade responsible for the loss of morphine tolerance in the 129/SvEv mice rests at the level of the NMDA receptor itself or in the steps up to the activation of nitric oxide synthase.
与CD-1小鼠对吗啡耐受性的快速发展形成对比的是，在植入吗啡丸或每日注射吗啡5天的129/SvEv小鼠中未观察到耐受性。同样，在129/SvEv小鼠中未观察到CD-1小鼠重复给予δ配体[D-青霉胺2，D-青霉胺5]脑啡肽时出现的渐进性和完全性镇痛丧失。相反，对κ1药物U50,488H和κ3药物纳洛酮苯甲酰腙的耐受性正常发展。单独给予N-甲基-D-天冬氨酸（NMDA）可减弱CD-1小鼠的吗啡镇痛作用，并在每日与吗啡一起给药时加速CD-1小鼠耐受性的发展。相比之下，在两种模式下，NMDA对129/SvEv小鼠均无显著影响。NMDA受体的激活可导致一氧化氮的产生，一氧化氮也与吗啡耐受性有关。硝普钠和L-精氨酸可增加对照CD-1和129/SvEv小鼠的一氧化氮水平并降低吗啡镇痛作用。因此，129/SvEv小鼠中导致吗啡耐受性丧失的NMDA/一氧化氮级联缺陷存在于NMDA受体本身水平或直至一氧化氮合酶激活的步骤中。
