Abstract
Opioid tolerance can be modulated by the N-methyl-D-aspartate/nitric oxide (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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
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Review
MeSH terms
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Animals
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Arginine / analogs & derivatives*
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Arginine / pharmacology
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Enzyme Inhibitors / pharmacology*
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Excitatory Amino Acid Antagonists / pharmacology*
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Morphine / adverse effects
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Morphine / pharmacology
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Narcotics / adverse effects*
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Nitric Oxide Synthase / antagonists & inhibitors*
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Nitroarginine
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Opioid-Related Disorders / drug therapy*
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Opioid-Related Disorders / metabolism
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
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Receptors, N-Methyl-D-Aspartate / drug effects*
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Receptors, N-Methyl-D-Aspartate / physiology
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Receptors, Opioid, delta / drug effects
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Receptors, Opioid, kappa / drug effects
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Substance Withdrawal Syndrome / drug therapy*
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Substance Withdrawal Syndrome / metabolism
Substances
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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Narcotics
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Receptors, N-Methyl-D-Aspartate
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Receptors, Opioid, delta
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Receptors, Opioid, kappa
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Nitroarginine
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Morphine
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Arginine
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Nitric Oxide Synthase