When it comes to opiates, just say NO.
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.
Pasternak
Gavril W
GW
Department of Neurology and The Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. pasterng@mskcc.org
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D004361:Drug Tolerance / Q000502:physiology*; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D000701:Analgesics, Opioid; D016194:Receptors, N-Methyl-D-Aspartate; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D014443:Tyrosine; D009020:Morphine