LACK OF MORPHINE AND ENKEPHALIN TOLERANCE IN 129 SVEV MICE - EVIDENCEFOR A NMDA RECEPTOR DEFECT/

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 p ellets or given daily morphine injections for 5 days. Similarly, the p rogressive and complete loss of analgesia in CD-1 mice seen with repea ted dosing of the delta ligand [D-Pen(2),D-Pen(5)]enkephalin is not ob served in 129/SvEv mice. In contrast, tolerance develops normally to b oth the kappa, drug U50,488H and the kappa, agent naloxone benzoylhdra zone. N-methyl-D-aspartate (NMDA) given alone attenuates morphine anal gesia in CD-1 mice and accelerates the development of tolerance in CD- 1 mice when given daily with morphine. In contrast. NMDA has no signif icant effect in the 129/SvEv mice in either paradigm. Activation of NM DA 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/nitri c 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.