The repeated use of opiate drugs such as morphine to relieve chronic pain results in individuals having to take higher and higher doses of the drug to achieve equivalent pain relief (they are said to exhibit antinociceptive tolerance). The molecular reasons for antinociceptive tolerance are not well defined. However, a new study by Daniela Salvemini and colleagues at Saint Louis University School of Medicine, has identified a crucial role for the chemical peroxynitrite (ONOO-) in this process in mice. These results led the authors and Gavril Pasternak from the Memorial Sloan-Kettering Cancer Center, New York, in an accompanying commentary, to suggest that the development of drugs targeting ONOO- might provide an adjunct therapy for individuals using opiates to relieve chronic pain.
Antinociceptive tolerance in mice repeatedly administered morphine was associated with the accumulation of tyrosine-nitrated proteins in the dorsal horn of the spinal cord, increased production of proinflammatory cytokines, oxidative DNA damage, and activation of the nuclear protein poly(ADP-ribose) polymerase. These changes were inhibited, as was the induction of antinociceptive tolerance, if the morphine was administered together with a pharmacological inhibitor of nitric oxide synthesis, a pharmacological scavenger of superoxide, or a pharmacological catalyst for ONOO- decomposition. Together, these data indicate that ONOO- has a crucial role in the development of morphine-induced antinociceptive tolerance in mice.
TITLE: Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice
AUTHOR CONTACT: Daniela Salvemini
Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 577-8856; Fax: (314) 577-8859; E-mail: salvemd@slu.edu.
MEDIA CONTACT: Donn Walker
Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 977-8015; E-mail: dwalke18@slu.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32420
ACCOMPANYING COMMENTARY
TITLE: When it comes to opiates, just say NO
AUTHOR CONTACT: Gavril W. Pasternak
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: (646) 888-2165; Email: pasterng@mskcc.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34035
Journal
Journal of Clinical Investigation