When it comes to opiates, just say NO
Gavril W. Pasternak
Gavril W. Pasternak
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Commentary

When it comes to opiates, just say NO

Abstract

Repeated use of opiate analgesic drugs such as morphine for the relief of chronic pain may result in the development of opiate tolerance and dependence, leading to a narrowing of the drug’s therapeutic index and increased side effects. Previous preclinical work has shown that interruption of a signaling cascade involving the N-methyl-D-aspartate receptor and NO prevents morphine tolerance. In this issue of the JCI, Muscoli and colleagues extend our understanding of the role of NO in tolerance by demonstrating that, in mice, tolerance to chronic morphine administration is associated with NO conversion to peroxynitrite, which accumulates and nitrates tyrosine moieties within various proteins in the spinal cord (see the related article beginning on page 3530). This and other data suggest that peroxynitrite plays a role in opiate tolerance and that regulation of peroxynitrite may be utilized for the management of opiate-induced tolerance.

Authors

Gavril W. Pasternak

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Figure 2

Schematic of the NMDA receptor/NO cascade in opioid tolerance.

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Schematic of the NMDA receptor/NO cascade in opioid tolerance. Activatio...
Activation of the NMDA receptor by glutamate induces the activation of NO synthase, which in turn synthesizes NO. As a gas, NO cannot be stored and immediately diffuses through membranes. NO will complex with heme-containing proteins such as guanylyl cyclase, which is then activated. It will also S-nitrosylate proteins, including subunit 1 and subunit 2 of the NMDA receptor. Finally, when exposed to superoxide, which is generated by superoxide dismutase, NO is converted to peroxynitrite, which will nitrate tyrosine residues within proteins, including the glutamate transporter GLT-1 and the enzyme glutamine synthase, as shown in the report in this issue from Muscoli et al. (20). Thus all three of these putative mechanisms of NO action may be involved in the development of opioid tolerance.