When it comes to opiates, just say NO
J. Clin. Invest. Gavril W. Pasternak, et al. 117:3185 doi:10.1172/JCI34035 [Go to this article.]

Figure 2
Schematic of the NMDA receptor/NO cascade in opioid tolerance. 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.