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.
Gavril W. Pasternak
Hypothetical models of drug tolerance.
In drug tolerance, increased amounts of drug are needed to maintain an effect. In the clinical setting, many patients with malignant pain stabilize their dose over prolonged periods of time, with the need for further increases due to the progression of their underlying disease process. Tolerance is often considered as a progressive effect, in which drug doses need to be continually escalated. However, clinical observations suggest that in many situations tolerance can achieve a steady-state in which stable doses of drug are sufficient for extended periods of time.