Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Perspectives on the N-Methyl-D-Aspartate/Nitric Oxide Cascade and Opioid Tolerance


Opioid tolerance can be modulated by the N-methyl-D-aspartate/nitric oxixde (NMDA/NO) cascade. Evidence exploring a daily injection paradigm indicates that agents antagonizing NMDA receptors can prevent tolerance to morphine and delta drugs, but not kappa agents. Drugs work regardless of whether they act as competitive or noncompetitive antagonists. Even an agent acting as an antagonist on the glycine site of the NMDA receptor is effective. Blockade of nitric oxide synthase has similar effects on opioid tolerance, preventing morphine and delta tolerance but not that of kappa drugs. Even methylene blue, which can inhibit guanylyl cyclase activity, is effective, presumably by blocking cGMP formation resulting from NO release. These results demonstrate the importance of an intact NMDA/NO cascade in the production of opioid tolerance and open new possibilities in the design of agents acting on opioid tolerance.

Author information



Corresponding author

Correspondence to Gavril W Pasternak MD, Ph.D.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pasternak, G., Kolesnikov, Y. & Babey, AM. Perspectives on the N-Methyl-D-Aspartate/Nitric Oxide Cascade and Opioid Tolerance. Neuropsychopharmacol 13, 309–313 (1995).

Download citation


  • Opioids
  • Tolerance
  • Dependence
  • Opioid receptor
  • NMDA
  • Nitric oxide
  • Analgesia
  • Methylene blue
  • Withdrawal

Further reading


Quick links