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 o xixde (NMDA/NO) cascade. Evidence exploring a daily injection paradigm indicates that agents antagonizing NMDA receptors can prevent toleran ce to morphine and delta drugs, but not kappa agents. Drugs work regar dless of whether they act as competitive or noncompetitive antagonists . Even an agent acting as an antagonist on the glycine site of the NMD A 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 gu anylyl cylase activity, is effective, presumably by blocking cGMP form ation resulting from NO release. These results demonstrate the importa nce of an intact NMDA/NO cascade in the production of opioid tolerance and open new possibilities in the design of agents acting on opioid t olerance.