Lack of morphine and enkephalin tolerance in 129/SvEv mice: Evidence for a NMDA receptor defect Academic Article uri icon


MeSH Major

  • Drug Tolerance
  • Enkephalins
  • Mice, Inbred Strains
  • Morphine
  • Nitric Oxide
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa


  • 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.

publication date

  • February 1998



  • Academic Article



  • eng

PubMed ID

  • 9454784

Additional Document Info

start page

  • 455

end page

  • 9


  • 284


  • 2